Clinical Endocrinology News

Nearly 37 million Americans, or 15%, have chronic kidney disease (CKD), but 9 in 10 adults with the condition are not aware of their diagnosis. A recent study from Stanford University found that screening asymptomatic adults over the age of 35 years would be a cost-effective strategy for identifying patients with CKD before they develop severe illness. 

What should primary care providers be doing differently? 

The current standard of care is to screen people with underlying conditions that put them at higher risk of developing CKD, most commonly diabetes and hypertension. That’s why the American Diabetes Association recommends annual screening for CKD in patients with type 1 diabetes as well as those with type 2 diabetes. 

And the American Heart Association (AHA) released an advisory last year that defined cardiovascular-kidney-metabolic (CKM) syndrome, a constellation of conditions that often occur together: obesity, diabetes, CKD, and cardiovascular disease. They propose a staged approach to identifying and monitoring CKM throughout the lifespan, which includes regular monitoring of the urine albumin-creatinine ratio in patients who have developed diabetes, hypertension, metabolic syndrome, or any signs of kidney disease.

But despite recognition from the subspecialty professional societies of the importance of screening persons with risk factors — additional conditions are obesity and family history of CKD — real-world implementation lags. 

Sylvia Rosas, MD, is a nephrologist and associate professor of medicine at Harvard University in Cambridge, Massachusetts, who also serves as president of the National Kidney Foundation. In an interview with this news organization, she cited several alarming facts about the state of CKD screening in the United States. 

“Of people with diabetes who have insurance, only 40% get both the glomerular filtration rate (GFR) and the albumin performed, and for those who have hypertension, only 10%,” Dr. Rosas said. She is referring to a urine spot test that measures the amount of albumin in the urine, which is then paired with a serum measurement of creatinine to estimate the glomerular filtration rate. Both tests are needed to detect the asymptomatic stages of CKD, because the presence of albumin in the urine usually precedes drops in the GFR, which indicates more serious disease. 

Dr. Rosas said she is frustrated by the low rate of testing compared with other commonly recommended preventive screenings, given the low cost and simplicity of assessment. Serum creatinine often is obtained as part of a routine chemistry panel, and the albumin test requires a single spot urine test. Yet, in 2018, 61% of US adults aged 50-75 years had received a colonoscopy in the past 10 years. Compared with the high price and inconvenience of undergoing colonoscopy, Dr. Rosas has trouble believing that “we cannot get more than 40% of people [with diabetes] to pee in a cup.” 

But the biggest issue is that if people with risk factors don’t get screened before they develop symptoms of CKD, it is often too late to avoid dialysis or the need for transplantation. 

The early warning symptoms are few, according to Nisha Bansal, MD, a professor in the department of nephrology at the University of Washington in Seattle. “New hypertension is a really important early sign,” Dr. Bansal said. “We know kidney disease almost certainly causes hypertension, so I would definitely think about screening for kidney disease.” Other findings on exam are the appearance of new edema or signs of fluid retention in the hands or around the eyes, along with findings in the urine of albumin, protein, or blood. 

But most patients don’t have any symptoms in the early stages, and they can be nonspecific. “It is fatigue and some nausea,” Dr. Rosas said. “It’s only way at the end that you start vomiting, get itchy, or have hiccups.” Data from the Centers for Disease Control and Prevention have shown that over one third of patients at high risk for kidney failure are unaware of their disease. According to Dr. Rosas, these are patients who often receive the diagnosis of CKD and start dialysis the same day. 
 

Why Not Screen Everyone?

For many conditions, like HIV or different types of cancer, the US Preventive Services Task Force (USPSTF) recommends broad screening of asymptomatic individuals so that early treatment can improve outcomes. 

But when the USPSTF considered the question in 2012 of whether adults should be screened for CKD regardless of symptoms, it found little evidence that early detection could change the course of their illness. At that time, the standard of care for treating early stages of CKD generally focused on treating the comorbid conditions, such as diabetes, hypertension, and cardiovascular disease. 

But the equation has changed with the availability of new drugs to treat CKD, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs).

“I consider these blockbuster drugs,” Dr. Bansal said. “For the first time in decades, we’re showing that this class of medications, the SGLT2 inhibitors, substantially reduce risk of loss of kidney function.”

Expressed in the lumen of the proximal renal tubules, SGLT2 reabsorbs filtered glucose from the tubular lumen. Inhibition of SGLT2 promotes urinary glucose excretion and reduces sodium reabsorption, increasing delivery of sodium to the distal tubule. The first SGLT2 inhibitor, canagliflozin, was approved in 2013 for use as an antihyperglycemic agent but subsequently was shown to have serendipitous benefits for the heart and kidneys. 

Clinical trials have documented reductions in the risk for cardiovascular events in patients with type 2 diabetes, as well as decreases in the risk for progression to end-stage renal disease, cardiovascular mortality, and hospitalization for heart failure. Updated international guidelines from 2022 recommend treating all patients with type 2 diabetes and CKD with an estimated GFR ≥ 20 mL/min/1.73 m2 with an SGLT2 inhibitor. 

But several trials of SGLT2 inhibitors also demonstrated benefits in reducing the risk for cardiovascular-related death or hospitalization for heart failure, even in patients without diabetes. Although initial approval from the US Food and Drug Administration was limited to patients with diabetes and heart failure, the agency has recently expanded its indications to include adults with CKD who do not have diabetes. 

Dr. Bansal said she was happy to see this widening of the indications, which makes more patients eligible to receive SGLT2 inhibitors. “I really think this early CKD group is a great group to consider for those medications,” she said. 

Dr. Bansal also pointed out that MRAs are another class of drugs with an interesting history. Earlier steroidal MRAs were found to have anti-inflammatory and antifibrotic properties, and in 1960 spironolactone was approved for use as a diuretic for the management of edema, primary aldosteronism, and hypertension. But even as their use in cardiology rose, MRAs had less utility for CKD, given adverse events such as hyperkalemia and hormonal effects like gynecomastia. 

But the latest generation of nonsteroidal MRAs (nsMRAs) has higher selectivity for the mineralocorticoid receptor than sex-steroid hormone receptors, reducing androgenic side effects and preventing elevated potassium. Finerenone, the only nsMRA approved in the United States, has been shown in clinical trials to reduce the incidence of cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and CKD outcomes, including kidney failure, decrease in estimated GFR, or death from renal causes. 
 

EPIC Changes Coming?

In light of treatment advances that offer hope of preventing progression of CKD in patients identified early, both the National Kidney Foundation and the American Kidney Fund lobbied the USPSTF in 2022 to conduct a fresh review of recent data to evaluate the need for updated screening recommendations. 

The task force completed development of a research plan and collection of public comments in early 2023 and is now reviewing evidence before developing a draft recommendation. 

A team of health policy researchers from Stanford is hoping that some of their recently published work will attract the panel’s attention. The first study, published in 2022, evaluated the cost-effectiveness of dapagliflozin, an SGLT2 inhibitor that has been shown to reduce mortality by 48% in CKD patients without diabetes. 

The Stanford team found that adding dapagliflozin to standard care for these patients improved life expectancy by 2 years and reduced the percentage of those who needed dialysis or kidney transplant from 17% to 11%. 

More recently, Marika Cusick, a doctoral candidate in health policy at the Stanford School of Medicine in Stanford, California, served as first author of an evaluation of the cost-effectiveness of screening asymptomatic adults. “We assessed screening for albuminuria in conjunction with conventional CKD therapy in addition to this new SGLT2 inhibitor class of drugs,” she said. They projected how this might change CKD progression in US adults who are aged 35 or older compared with standard therapy alone. 

The findings were favorable. “A one-time screening would result in a reduction of 398,000 cases of kidney replacement therapy [defined as needing either dialysis or renal transplant] among 158 million US adults who are currently aged 35-75 years,” Ms. Cusick told this news organization.

In terms of quality-adjusted life years (QALYs), a one-time screening at age 55 years yielded an incremental cost-effectiveness ratio of $86,300 per QALY. Screening every 10 years between the ages of 35 and 75 years cost less than $100,000 per QALY gained. 

According to Doug Owens, MD, professor and chair of the department of health policy at Stanford School of Medicine, “There’s a societal decision about how much are we willing to pay for additional length and quality of life. And this fits within what is generally considered reasonable for the US.” 

For example, in the United States, screening for breast cancer among women aged 40-64 years costs $51,000 per QALY, whereas screening for lung cancer using USPSTF guidelines ranges from $72,639 to $156,774 per QALY. 

A former member of the USPSTF, Owens predicted that the current review process would take at least another year. Meanwhile, he and Ms. Cusick are hoping that their work influences the USPSTF to recommend screening asymptomatic adults. “Increasing the awareness of these drugs and their effectiveness is a crucial first step,” he said. 

Although adherence to current recommendations for screening of people at risk is poor, Dr. Rosas suggested that the USPSTF guidelines would be more influential in changing practice among primary care physicians than subspecialty guidelines would. 

“When you have a recommendation like that, they’re putting it in the electronic health record,” she said. By adding best practice alerts to their electronic health record systems, health systems can make it easier for primary care doctors to check all the boxes. 

In line with the AHA’s holistic approach towards managing cardiovascular illnesses, CKD, and metabolic disease, Dr. Bansal suggested an additional strategy: “I think we’re moving toward more interdisciplinary care models, where primary care doctors, nephrologist, cardiologists, and endocrinologists — all of us — should be working together in a collaborative care model, to help break down some of these barriers in terms of screening as well as implementation of these therapies.”

Dr. Bansal, Ms. Cusick, and Dr. Owens reported no financial conflicts of interest. Dr. Rosas receives funding from AstraZeneca and Bayer for serving on advisory boards and clinical research funding, as well as funding from the National Institute of Diabetes and Digestive and Kidney Diseases for clinical trials. 
 

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Oregon.

A version of this article appeared on Medscape.com.

Nearly 37 million Americans, or 15%, have chronic kidney disease (CKD), but 9 in 10 adults with the condition are not aware of their diagnosis. A recent study from Stanford University found that screening asymptomatic adults over the age of 35 years would be a cost-effective strategy for identifying patients with CKD before they develop severe illness. 

What should primary care providers be doing differently? 

The current standard of care is to screen people with underlying conditions that put them at higher risk of developing CKD, most commonly diabetes and hypertension. That’s why the American Diabetes Association recommends annual screening for CKD in patients with type 1 diabetes as well as those with type 2 diabetes. 

And the American Heart Association (AHA) released an advisory last year that defined cardiovascular-kidney-metabolic (CKM) syndrome, a constellation of conditions that often occur together: obesity, diabetes, CKD, and cardiovascular disease. They propose a staged approach to identifying and monitoring CKM throughout the lifespan, which includes regular monitoring of the urine albumin-creatinine ratio in patients who have developed diabetes, hypertension, metabolic syndrome, or any signs of kidney disease.

But despite recognition from the subspecialty professional societies of the importance of screening persons with risk factors — additional conditions are obesity and family history of CKD — real-world implementation lags. 

Sylvia Rosas, MD, is a nephrologist and associate professor of medicine at Harvard University in Cambridge, Massachusetts, who also serves as president of the National Kidney Foundation. In an interview with this news organization, she cited several alarming facts about the state of CKD screening in the United States. 

“Of people with diabetes who have insurance, only 40% get both the glomerular filtration rate (GFR) and the albumin performed, and for those who have hypertension, only 10%,” Dr. Rosas said. She is referring to a urine spot test that measures the amount of albumin in the urine, which is then paired with a serum measurement of creatinine to estimate the glomerular filtration rate. Both tests are needed to detect the asymptomatic stages of CKD, because the presence of albumin in the urine usually precedes drops in the GFR, which indicates more serious disease. 

Dr. Rosas said she is frustrated by the low rate of testing compared with other commonly recommended preventive screenings, given the low cost and simplicity of assessment. Serum creatinine often is obtained as part of a routine chemistry panel, and the albumin test requires a single spot urine test. Yet, in 2018, 61% of US adults aged 50-75 years had received a colonoscopy in the past 10 years. Compared with the high price and inconvenience of undergoing colonoscopy, Dr. Rosas has trouble believing that “we cannot get more than 40% of people [with diabetes] to pee in a cup.” 

But the biggest issue is that if people with risk factors don’t get screened before they develop symptoms of CKD, it is often too late to avoid dialysis or the need for transplantation. 

The early warning symptoms are few, according to Nisha Bansal, MD, a professor in the department of nephrology at the University of Washington in Seattle. “New hypertension is a really important early sign,” Dr. Bansal said. “We know kidney disease almost certainly causes hypertension, so I would definitely think about screening for kidney disease.” Other findings on exam are the appearance of new edema or signs of fluid retention in the hands or around the eyes, along with findings in the urine of albumin, protein, or blood. 

But most patients don’t have any symptoms in the early stages, and they can be nonspecific. “It is fatigue and some nausea,” Dr. Rosas said. “It’s only way at the end that you start vomiting, get itchy, or have hiccups.” Data from the Centers for Disease Control and Prevention have shown that over one third of patients at high risk for kidney failure are unaware of their disease. According to Dr. Rosas, these are patients who often receive the diagnosis of CKD and start dialysis the same day. 
 

Why Not Screen Everyone?

For many conditions, like HIV or different types of cancer, the US Preventive Services Task Force (USPSTF) recommends broad screening of asymptomatic individuals so that early treatment can improve outcomes. 

But when the USPSTF considered the question in 2012 of whether adults should be screened for CKD regardless of symptoms, it found little evidence that early detection could change the course of their illness. At that time, the standard of care for treating early stages of CKD generally focused on treating the comorbid conditions, such as diabetes, hypertension, and cardiovascular disease. 

But the equation has changed with the availability of new drugs to treat CKD, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs).

“I consider these blockbuster drugs,” Dr. Bansal said. “For the first time in decades, we’re showing that this class of medications, the SGLT2 inhibitors, substantially reduce risk of loss of kidney function.”

Expressed in the lumen of the proximal renal tubules, SGLT2 reabsorbs filtered glucose from the tubular lumen. Inhibition of SGLT2 promotes urinary glucose excretion and reduces sodium reabsorption, increasing delivery of sodium to the distal tubule. The first SGLT2 inhibitor, canagliflozin, was approved in 2013 for use as an antihyperglycemic agent but subsequently was shown to have serendipitous benefits for the heart and kidneys. 

Clinical trials have documented reductions in the risk for cardiovascular events in patients with type 2 diabetes, as well as decreases in the risk for progression to end-stage renal disease, cardiovascular mortality, and hospitalization for heart failure. Updated international guidelines from 2022 recommend treating all patients with type 2 diabetes and CKD with an estimated GFR ≥ 20 mL/min/1.73 m2 with an SGLT2 inhibitor. 

But several trials of SGLT2 inhibitors also demonstrated benefits in reducing the risk for cardiovascular-related death or hospitalization for heart failure, even in patients without diabetes. Although initial approval from the US Food and Drug Administration was limited to patients with diabetes and heart failure, the agency has recently expanded its indications to include adults with CKD who do not have diabetes. 

Dr. Bansal said she was happy to see this widening of the indications, which makes more patients eligible to receive SGLT2 inhibitors. “I really think this early CKD group is a great group to consider for those medications,” she said. 

Dr. Bansal also pointed out that MRAs are another class of drugs with an interesting history. Earlier steroidal MRAs were found to have anti-inflammatory and antifibrotic properties, and in 1960 spironolactone was approved for use as a diuretic for the management of edema, primary aldosteronism, and hypertension. But even as their use in cardiology rose, MRAs had less utility for CKD, given adverse events such as hyperkalemia and hormonal effects like gynecomastia. 

But the latest generation of nonsteroidal MRAs (nsMRAs) has higher selectivity for the mineralocorticoid receptor than sex-steroid hormone receptors, reducing androgenic side effects and preventing elevated potassium. Finerenone, the only nsMRA approved in the United States, has been shown in clinical trials to reduce the incidence of cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and CKD outcomes, including kidney failure, decrease in estimated GFR, or death from renal causes. 
 

EPIC Changes Coming?

In light of treatment advances that offer hope of preventing progression of CKD in patients identified early, both the National Kidney Foundation and the American Kidney Fund lobbied the USPSTF in 2022 to conduct a fresh review of recent data to evaluate the need for updated screening recommendations. 

The task force completed development of a research plan and collection of public comments in early 2023 and is now reviewing evidence before developing a draft recommendation. 

A team of health policy researchers from Stanford is hoping that some of their recently published work will attract the panel’s attention. The first study, published in 2022, evaluated the cost-effectiveness of dapagliflozin, an SGLT2 inhibitor that has been shown to reduce mortality by 48% in CKD patients without diabetes. 

The Stanford team found that adding dapagliflozin to standard care for these patients improved life expectancy by 2 years and reduced the percentage of those who needed dialysis or kidney transplant from 17% to 11%. 

More recently, Marika Cusick, a doctoral candidate in health policy at the Stanford School of Medicine in Stanford, California, served as first author of an evaluation of the cost-effectiveness of screening asymptomatic adults. “We assessed screening for albuminuria in conjunction with conventional CKD therapy in addition to this new SGLT2 inhibitor class of drugs,” she said. They projected how this might change CKD progression in US adults who are aged 35 or older compared with standard therapy alone. 

The findings were favorable. “A one-time screening would result in a reduction of 398,000 cases of kidney replacement therapy [defined as needing either dialysis or renal transplant] among 158 million US adults who are currently aged 35-75 years,” Ms. Cusick told this news organization.

In terms of quality-adjusted life years (QALYs), a one-time screening at age 55 years yielded an incremental cost-effectiveness ratio of $86,300 per QALY. Screening every 10 years between the ages of 35 and 75 years cost less than $100,000 per QALY gained. 

According to Doug Owens, MD, professor and chair of the department of health policy at Stanford School of Medicine, “There’s a societal decision about how much are we willing to pay for additional length and quality of life. And this fits within what is generally considered reasonable for the US.” 

For example, in the United States, screening for breast cancer among women aged 40-64 years costs $51,000 per QALY, whereas screening for lung cancer using USPSTF guidelines ranges from $72,639 to $156,774 per QALY. 

A former member of the USPSTF, Owens predicted that the current review process would take at least another year. Meanwhile, he and Ms. Cusick are hoping that their work influences the USPSTF to recommend screening asymptomatic adults. “Increasing the awareness of these drugs and their effectiveness is a crucial first step,” he said. 

Although adherence to current recommendations for screening of people at risk is poor, Dr. Rosas suggested that the USPSTF guidelines would be more influential in changing practice among primary care physicians than subspecialty guidelines would. 

“When you have a recommendation like that, they’re putting it in the electronic health record,” she said. By adding best practice alerts to their electronic health record systems, health systems can make it easier for primary care doctors to check all the boxes. 

In line with the AHA’s holistic approach towards managing cardiovascular illnesses, CKD, and metabolic disease, Dr. Bansal suggested an additional strategy: “I think we’re moving toward more interdisciplinary care models, where primary care doctors, nephrologist, cardiologists, and endocrinologists — all of us — should be working together in a collaborative care model, to help break down some of these barriers in terms of screening as well as implementation of these therapies.”

Dr. Bansal, Ms. Cusick, and Dr. Owens reported no financial conflicts of interest. Dr. Rosas receives funding from AstraZeneca and Bayer for serving on advisory boards and clinical research funding, as well as funding from the National Institute of Diabetes and Digestive and Kidney Diseases for clinical trials. 
 

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Oregon.

A version of this article appeared on Medscape.com.

Nearly 37 million Americans, or 15%, have chronic kidney disease (CKD), but 9 in 10 adults with the condition are not aware of their diagnosis. A recent study from Stanford University found that screening asymptomatic adults over the age of 35 years would be a cost-effective strategy for identifying patients with CKD before they develop severe illness. 

What should primary care providers be doing differently? 

The current standard of care is to screen people with underlying conditions that put them at higher risk of developing CKD, most commonly diabetes and hypertension. That’s why the American Diabetes Association recommends annual screening for CKD in patients with type 1 diabetes as well as those with type 2 diabetes. 

And the American Heart Association (AHA) released an advisory last year that defined cardiovascular-kidney-metabolic (CKM) syndrome, a constellation of conditions that often occur together: obesity, diabetes, CKD, and cardiovascular disease. They propose a staged approach to identifying and monitoring CKM throughout the lifespan, which includes regular monitoring of the urine albumin-creatinine ratio in patients who have developed diabetes, hypertension, metabolic syndrome, or any signs of kidney disease.

But despite recognition from the subspecialty professional societies of the importance of screening persons with risk factors — additional conditions are obesity and family history of CKD — real-world implementation lags. 

Sylvia Rosas, MD, is a nephrologist and associate professor of medicine at Harvard University in Cambridge, Massachusetts, who also serves as president of the National Kidney Foundation. In an interview with this news organization, she cited several alarming facts about the state of CKD screening in the United States. 

“Of people with diabetes who have insurance, only 40% get both the glomerular filtration rate (GFR) and the albumin performed, and for those who have hypertension, only 10%,” Dr. Rosas said. She is referring to a urine spot test that measures the amount of albumin in the urine, which is then paired with a serum measurement of creatinine to estimate the glomerular filtration rate. Both tests are needed to detect the asymptomatic stages of CKD, because the presence of albumin in the urine usually precedes drops in the GFR, which indicates more serious disease. 

Dr. Rosas said she is frustrated by the low rate of testing compared with other commonly recommended preventive screenings, given the low cost and simplicity of assessment. Serum creatinine often is obtained as part of a routine chemistry panel, and the albumin test requires a single spot urine test. Yet, in 2018, 61% of US adults aged 50-75 years had received a colonoscopy in the past 10 years. Compared with the high price and inconvenience of undergoing colonoscopy, Dr. Rosas has trouble believing that “we cannot get more than 40% of people [with diabetes] to pee in a cup.” 

But the biggest issue is that if people with risk factors don’t get screened before they develop symptoms of CKD, it is often too late to avoid dialysis or the need for transplantation. 

The early warning symptoms are few, according to Nisha Bansal, MD, a professor in the department of nephrology at the University of Washington in Seattle. “New hypertension is a really important early sign,” Dr. Bansal said. “We know kidney disease almost certainly causes hypertension, so I would definitely think about screening for kidney disease.” Other findings on exam are the appearance of new edema or signs of fluid retention in the hands or around the eyes, along with findings in the urine of albumin, protein, or blood. 

But most patients don’t have any symptoms in the early stages, and they can be nonspecific. “It is fatigue and some nausea,” Dr. Rosas said. “It’s only way at the end that you start vomiting, get itchy, or have hiccups.” Data from the Centers for Disease Control and Prevention have shown that over one third of patients at high risk for kidney failure are unaware of their disease. According to Dr. Rosas, these are patients who often receive the diagnosis of CKD and start dialysis the same day. 
 

Why Not Screen Everyone?

For many conditions, like HIV or different types of cancer, the US Preventive Services Task Force (USPSTF) recommends broad screening of asymptomatic individuals so that early treatment can improve outcomes. 

But when the USPSTF considered the question in 2012 of whether adults should be screened for CKD regardless of symptoms, it found little evidence that early detection could change the course of their illness. At that time, the standard of care for treating early stages of CKD generally focused on treating the comorbid conditions, such as diabetes, hypertension, and cardiovascular disease. 

But the equation has changed with the availability of new drugs to treat CKD, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs).

“I consider these blockbuster drugs,” Dr. Bansal said. “For the first time in decades, we’re showing that this class of medications, the SGLT2 inhibitors, substantially reduce risk of loss of kidney function.”

Expressed in the lumen of the proximal renal tubules, SGLT2 reabsorbs filtered glucose from the tubular lumen. Inhibition of SGLT2 promotes urinary glucose excretion and reduces sodium reabsorption, increasing delivery of sodium to the distal tubule. The first SGLT2 inhibitor, canagliflozin, was approved in 2013 for use as an antihyperglycemic agent but subsequently was shown to have serendipitous benefits for the heart and kidneys. 

Clinical trials have documented reductions in the risk for cardiovascular events in patients with type 2 diabetes, as well as decreases in the risk for progression to end-stage renal disease, cardiovascular mortality, and hospitalization for heart failure. Updated international guidelines from 2022 recommend treating all patients with type 2 diabetes and CKD with an estimated GFR ≥ 20 mL/min/1.73 m2 with an SGLT2 inhibitor. 

But several trials of SGLT2 inhibitors also demonstrated benefits in reducing the risk for cardiovascular-related death or hospitalization for heart failure, even in patients without diabetes. Although initial approval from the US Food and Drug Administration was limited to patients with diabetes and heart failure, the agency has recently expanded its indications to include adults with CKD who do not have diabetes. 

Dr. Bansal said she was happy to see this widening of the indications, which makes more patients eligible to receive SGLT2 inhibitors. “I really think this early CKD group is a great group to consider for those medications,” she said. 

Dr. Bansal also pointed out that MRAs are another class of drugs with an interesting history. Earlier steroidal MRAs were found to have anti-inflammatory and antifibrotic properties, and in 1960 spironolactone was approved for use as a diuretic for the management of edema, primary aldosteronism, and hypertension. But even as their use in cardiology rose, MRAs had less utility for CKD, given adverse events such as hyperkalemia and hormonal effects like gynecomastia. 

But the latest generation of nonsteroidal MRAs (nsMRAs) has higher selectivity for the mineralocorticoid receptor than sex-steroid hormone receptors, reducing androgenic side effects and preventing elevated potassium. Finerenone, the only nsMRA approved in the United States, has been shown in clinical trials to reduce the incidence of cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and CKD outcomes, including kidney failure, decrease in estimated GFR, or death from renal causes. 
 

EPIC Changes Coming?

In light of treatment advances that offer hope of preventing progression of CKD in patients identified early, both the National Kidney Foundation and the American Kidney Fund lobbied the USPSTF in 2022 to conduct a fresh review of recent data to evaluate the need for updated screening recommendations. 

The task force completed development of a research plan and collection of public comments in early 2023 and is now reviewing evidence before developing a draft recommendation. 

A team of health policy researchers from Stanford is hoping that some of their recently published work will attract the panel’s attention. The first study, published in 2022, evaluated the cost-effectiveness of dapagliflozin, an SGLT2 inhibitor that has been shown to reduce mortality by 48% in CKD patients without diabetes. 

The Stanford team found that adding dapagliflozin to standard care for these patients improved life expectancy by 2 years and reduced the percentage of those who needed dialysis or kidney transplant from 17% to 11%. 

More recently, Marika Cusick, a doctoral candidate in health policy at the Stanford School of Medicine in Stanford, California, served as first author of an evaluation of the cost-effectiveness of screening asymptomatic adults. “We assessed screening for albuminuria in conjunction with conventional CKD therapy in addition to this new SGLT2 inhibitor class of drugs,” she said. They projected how this might change CKD progression in US adults who are aged 35 or older compared with standard therapy alone. 

The findings were favorable. “A one-time screening would result in a reduction of 398,000 cases of kidney replacement therapy [defined as needing either dialysis or renal transplant] among 158 million US adults who are currently aged 35-75 years,” Ms. Cusick told this news organization.

In terms of quality-adjusted life years (QALYs), a one-time screening at age 55 years yielded an incremental cost-effectiveness ratio of $86,300 per QALY. Screening every 10 years between the ages of 35 and 75 years cost less than $100,000 per QALY gained. 

According to Doug Owens, MD, professor and chair of the department of health policy at Stanford School of Medicine, “There’s a societal decision about how much are we willing to pay for additional length and quality of life. And this fits within what is generally considered reasonable for the US.” 

For example, in the United States, screening for breast cancer among women aged 40-64 years costs $51,000 per QALY, whereas screening for lung cancer using USPSTF guidelines ranges from $72,639 to $156,774 per QALY. 

A former member of the USPSTF, Owens predicted that the current review process would take at least another year. Meanwhile, he and Ms. Cusick are hoping that their work influences the USPSTF to recommend screening asymptomatic adults. “Increasing the awareness of these drugs and their effectiveness is a crucial first step,” he said. 

Although adherence to current recommendations for screening of people at risk is poor, Dr. Rosas suggested that the USPSTF guidelines would be more influential in changing practice among primary care physicians than subspecialty guidelines would. 

“When you have a recommendation like that, they’re putting it in the electronic health record,” she said. By adding best practice alerts to their electronic health record systems, health systems can make it easier for primary care doctors to check all the boxes. 

In line with the AHA’s holistic approach towards managing cardiovascular illnesses, CKD, and metabolic disease, Dr. Bansal suggested an additional strategy: “I think we’re moving toward more interdisciplinary care models, where primary care doctors, nephrologist, cardiologists, and endocrinologists — all of us — should be working together in a collaborative care model, to help break down some of these barriers in terms of screening as well as implementation of these therapies.”

Dr. Bansal, Ms. Cusick, and Dr. Owens reported no financial conflicts of interest. Dr. Rosas receives funding from AstraZeneca and Bayer for serving on advisory boards and clinical research funding, as well as funding from the National Institute of Diabetes and Digestive and Kidney Diseases for clinical trials. 
 

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Oregon.

A version of this article appeared on Medscape.com.

To assess thyroid function, clinicians typically determine blood levels of thyroid-stimulating hormone (TSH) and thyroxine (T4) and do not directly measure triiodothyronine (T3).

However, findings from a large observational study of a US sample of adults with normal thyroid function suggested that subclinical variation in the hypothalamic-pituitary-thyroid (HPT)–axis effector hormone T3 “is an important and overlooked factor linking socioeconomic forces, human biology, and aging,” researchers reported.

The study, with lead author Ralph I. Lawton, an MD-PhD student at Harvard Medical School, Boston, was published online on January 4, 2024, in Proceedings of the National Academy of Sciences. In this national sample of healthy adults older than 20, free T3 was negatively related to household income. At age 40 and older, free T3 was significantly linked to being employed. Among adults from age 51 to 80, free T3 levels were inversely related to mortality.

“It is important to note that the more typically measured biomarkers for thyroid function (T4 and TSH) are poorly linked to free T3 levels,” Dr. Lawton and colleagues wrote.

The ratio of TSH:T4 explained only 1.7% of variation in T3 levels, they noted, which suggested that TSH and T4 may not be accurate surrogates of free T3. Thus, “direct measurement of free T3 is likely vital to properly stratify the effects of HPT-axis variation,” they maintained. “Improved methods for measurement [of T3] and further investigation of the role of free T3 in clinical conditions may be high yield,” according to the researchers.

Further studies of the relationship between the action of deiodinase in converting T4 to T3 and social forces and aging could elucidate critical biology. “New therapeutics targeting T3/T4 ratios,” they suggested, “may be more beneficial for a significant cohort of older individuals [with hypothyroidism] currently treated with levothyroxine [(LT4)].”
 

‘Cherry on Top’

“I think this is a really important paper,” thyroidology expert Antonio Bianco, MD, PhD, professor of medicine, The University of Chicago, who was not involved with this research, told this news organization.

His research group and others “have slowly been providing evidence of the relevance of measuring T3 levels,” he said. “This paper is sort of a cherry on top. It is really the most recent strong evidence that looking at T3 levels in plasma is really important. We need to do a better job at developing a much more precise assay for T3,” he said, “because now we know T3 is a very important parameter that endocrinologists should be looking for. We know that about 20 million Americans have hypothyroidism, and are being treated with T4 (levothyroxine),” Dr. Bianco continued.

“As endocrinologists, we believe that if you treat someone with levothyroxine, you normalize T3 levels. However, many times, with standard of care with levothyroxine, T3 levels are not normalized.”
 

Larger Variations in T3

Thyroid hormones (TSH, free T4, and free T3) influence many aspects of human physiology and behavior, but it is not known how variations in these levels in a population free of thyroid disease are associated with mortality and socioeconomic factors.

The researchers analyzed data from 7626 adults over age 20 up to age 80 who participated in the National Health and Nutrition Examination Survey during 2007-2012 and had blood tests to determine TSH, free T4, and free T3 and were not being actively treated for thyroid conditions. Among the 3603 older adults (over age 50), there were 981 deaths up until the end of 2019. TSH levels were not linked to mortality, but increasing levels of free T3 and decreasing levels of free T4 were protective for mortality (hazard ratios, 0.88 and 1.26, respectively; P < .01).

There was a robust negative relationship between household income and employment and free T3 but no relationship between these factors and T4. There was a much larger variation across age in levels of free T3 than in levels of TSH or free T4. Free T4 and free T3 diverged at older ages, when free T4 increased and free T3 continually decreased.

Older adults with symptoms of hypothyroidism may have high free T4 levels despite low free T3, the researchers noted.

“In a nonclinical sample representative of the US population,” they summarized, “we find that free T3 is much more strongly related to all domains studied — age, sex, seasonality, household income, employment, and longevity — than the other molecules of the HPT axis.”

This work was supported by the Burroughs Wellcome Fund Career at Scientific Interface award, a Brain and Behavior Research Foundation young investigator award, the Howard Hughes Medical Institute, the National Institute of Aging, and the National Institute of General Medical Sciences. Dr. Bianco served as a consultant for AbbVie, Avion Pharmaceuticals, Synthonics, Synthion, and Thyron and recently published the book Rethinking Hypothyroidism: Why Treatment Must Change and What Patients Can Do.
 

A version of this article appeared on Medscape.com.

To assess thyroid function, clinicians typically determine blood levels of thyroid-stimulating hormone (TSH) and thyroxine (T4) and do not directly measure triiodothyronine (T3).

However, findings from a large observational study of a US sample of adults with normal thyroid function suggested that subclinical variation in the hypothalamic-pituitary-thyroid (HPT)–axis effector hormone T3 “is an important and overlooked factor linking socioeconomic forces, human biology, and aging,” researchers reported.

The study, with lead author Ralph I. Lawton, an MD-PhD student at Harvard Medical School, Boston, was published online on January 4, 2024, in Proceedings of the National Academy of Sciences. In this national sample of healthy adults older than 20, free T3 was negatively related to household income. At age 40 and older, free T3 was significantly linked to being employed. Among adults from age 51 to 80, free T3 levels were inversely related to mortality.

“It is important to note that the more typically measured biomarkers for thyroid function (T4 and TSH) are poorly linked to free T3 levels,” Dr. Lawton and colleagues wrote.

The ratio of TSH:T4 explained only 1.7% of variation in T3 levels, they noted, which suggested that TSH and T4 may not be accurate surrogates of free T3. Thus, “direct measurement of free T3 is likely vital to properly stratify the effects of HPT-axis variation,” they maintained. “Improved methods for measurement [of T3] and further investigation of the role of free T3 in clinical conditions may be high yield,” according to the researchers.

Further studies of the relationship between the action of deiodinase in converting T4 to T3 and social forces and aging could elucidate critical biology. “New therapeutics targeting T3/T4 ratios,” they suggested, “may be more beneficial for a significant cohort of older individuals [with hypothyroidism] currently treated with levothyroxine [(LT4)].”
 

‘Cherry on Top’

“I think this is a really important paper,” thyroidology expert Antonio Bianco, MD, PhD, professor of medicine, The University of Chicago, who was not involved with this research, told this news organization.

His research group and others “have slowly been providing evidence of the relevance of measuring T3 levels,” he said. “This paper is sort of a cherry on top. It is really the most recent strong evidence that looking at T3 levels in plasma is really important. We need to do a better job at developing a much more precise assay for T3,” he said, “because now we know T3 is a very important parameter that endocrinologists should be looking for. We know that about 20 million Americans have hypothyroidism, and are being treated with T4 (levothyroxine),” Dr. Bianco continued.

“As endocrinologists, we believe that if you treat someone with levothyroxine, you normalize T3 levels. However, many times, with standard of care with levothyroxine, T3 levels are not normalized.”
 

Larger Variations in T3

Thyroid hormones (TSH, free T4, and free T3) influence many aspects of human physiology and behavior, but it is not known how variations in these levels in a population free of thyroid disease are associated with mortality and socioeconomic factors.

The researchers analyzed data from 7626 adults over age 20 up to age 80 who participated in the National Health and Nutrition Examination Survey during 2007-2012 and had blood tests to determine TSH, free T4, and free T3 and were not being actively treated for thyroid conditions. Among the 3603 older adults (over age 50), there were 981 deaths up until the end of 2019. TSH levels were not linked to mortality, but increasing levels of free T3 and decreasing levels of free T4 were protective for mortality (hazard ratios, 0.88 and 1.26, respectively; P < .01).

There was a robust negative relationship between household income and employment and free T3 but no relationship between these factors and T4. There was a much larger variation across age in levels of free T3 than in levels of TSH or free T4. Free T4 and free T3 diverged at older ages, when free T4 increased and free T3 continually decreased.

Older adults with symptoms of hypothyroidism may have high free T4 levels despite low free T3, the researchers noted.

“In a nonclinical sample representative of the US population,” they summarized, “we find that free T3 is much more strongly related to all domains studied — age, sex, seasonality, household income, employment, and longevity — than the other molecules of the HPT axis.”

This work was supported by the Burroughs Wellcome Fund Career at Scientific Interface award, a Brain and Behavior Research Foundation young investigator award, the Howard Hughes Medical Institute, the National Institute of Aging, and the National Institute of General Medical Sciences. Dr. Bianco served as a consultant for AbbVie, Avion Pharmaceuticals, Synthonics, Synthion, and Thyron and recently published the book Rethinking Hypothyroidism: Why Treatment Must Change and What Patients Can Do.
 

A version of this article appeared on Medscape.com.

To assess thyroid function, clinicians typically determine blood levels of thyroid-stimulating hormone (TSH) and thyroxine (T4) and do not directly measure triiodothyronine (T3).

However, findings from a large observational study of a US sample of adults with normal thyroid function suggested that subclinical variation in the hypothalamic-pituitary-thyroid (HPT)–axis effector hormone T3 “is an important and overlooked factor linking socioeconomic forces, human biology, and aging,” researchers reported.

The study, with lead author Ralph I. Lawton, an MD-PhD student at Harvard Medical School, Boston, was published online on January 4, 2024, in Proceedings of the National Academy of Sciences. In this national sample of healthy adults older than 20, free T3 was negatively related to household income. At age 40 and older, free T3 was significantly linked to being employed. Among adults from age 51 to 80, free T3 levels were inversely related to mortality.

“It is important to note that the more typically measured biomarkers for thyroid function (T4 and TSH) are poorly linked to free T3 levels,” Dr. Lawton and colleagues wrote.

The ratio of TSH:T4 explained only 1.7% of variation in T3 levels, they noted, which suggested that TSH and T4 may not be accurate surrogates of free T3. Thus, “direct measurement of free T3 is likely vital to properly stratify the effects of HPT-axis variation,” they maintained. “Improved methods for measurement [of T3] and further investigation of the role of free T3 in clinical conditions may be high yield,” according to the researchers.

Further studies of the relationship between the action of deiodinase in converting T4 to T3 and social forces and aging could elucidate critical biology. “New therapeutics targeting T3/T4 ratios,” they suggested, “may be more beneficial for a significant cohort of older individuals [with hypothyroidism] currently treated with levothyroxine [(LT4)].”
 

‘Cherry on Top’

“I think this is a really important paper,” thyroidology expert Antonio Bianco, MD, PhD, professor of medicine, The University of Chicago, who was not involved with this research, told this news organization.

His research group and others “have slowly been providing evidence of the relevance of measuring T3 levels,” he said. “This paper is sort of a cherry on top. It is really the most recent strong evidence that looking at T3 levels in plasma is really important. We need to do a better job at developing a much more precise assay for T3,” he said, “because now we know T3 is a very important parameter that endocrinologists should be looking for. We know that about 20 million Americans have hypothyroidism, and are being treated with T4 (levothyroxine),” Dr. Bianco continued.

“As endocrinologists, we believe that if you treat someone with levothyroxine, you normalize T3 levels. However, many times, with standard of care with levothyroxine, T3 levels are not normalized.”
 

Larger Variations in T3

Thyroid hormones (TSH, free T4, and free T3) influence many aspects of human physiology and behavior, but it is not known how variations in these levels in a population free of thyroid disease are associated with mortality and socioeconomic factors.

The researchers analyzed data from 7626 adults over age 20 up to age 80 who participated in the National Health and Nutrition Examination Survey during 2007-2012 and had blood tests to determine TSH, free T4, and free T3 and were not being actively treated for thyroid conditions. Among the 3603 older adults (over age 50), there were 981 deaths up until the end of 2019. TSH levels were not linked to mortality, but increasing levels of free T3 and decreasing levels of free T4 were protective for mortality (hazard ratios, 0.88 and 1.26, respectively; P < .01).

There was a robust negative relationship between household income and employment and free T3 but no relationship between these factors and T4. There was a much larger variation across age in levels of free T3 than in levels of TSH or free T4. Free T4 and free T3 diverged at older ages, when free T4 increased and free T3 continually decreased.

Older adults with symptoms of hypothyroidism may have high free T4 levels despite low free T3, the researchers noted.

“In a nonclinical sample representative of the US population,” they summarized, “we find that free T3 is much more strongly related to all domains studied — age, sex, seasonality, household income, employment, and longevity — than the other molecules of the HPT axis.”

This work was supported by the Burroughs Wellcome Fund Career at Scientific Interface award, a Brain and Behavior Research Foundation young investigator award, the Howard Hughes Medical Institute, the National Institute of Aging, and the National Institute of General Medical Sciences. Dr. Bianco served as a consultant for AbbVie, Avion Pharmaceuticals, Synthonics, Synthion, and Thyron and recently published the book Rethinking Hypothyroidism: Why Treatment Must Change and What Patients Can Do.
 

A version of this article appeared on Medscape.com.

TOPLINE:

The efficacy of clascoterone cream 1% for treating acne vulgaris appears to increase over time after 12 weeks of use and up to 1 year.

METHODOLOGY:

• A 1% cream formulation of clascoterone, a topical androgen receptor inhibitor, is approved for the treatment of acne vulgaris in patients aged 12 years and older based on results from two identical phase 3 12-week trials, NCT02608450 and NCT02608476, and a long-term extension (LTE) study.
• The purpose of the current study was to evaluate the integrated efficacy of clascoterone cream 1% (Winlevi) in the intention-to-treat population of patients from all three trials.
• In the pivotal trials, investigators randomized patients with acne 1:1 to receive clascoterone cream 1% or vehicle twice daily for 12 weeks. Participants were eligible to enter the LTE study, in which patients applied clascoterone to the face, and if they wanted to, the trunk for up to 9 more months.
• To assess combined efficacy, researchers evaluated the proportion of patients who achieved an Investigator’s Global Assessment (IGA) of 0 or 1.

TAKEAWAY:

• Of the 1143 patients from the pivotal trials who completed 12 weeks of treatment, 576 were in the clascoterone group and 567 were in the vehicle group. Of the 600 patients who entered the LTE study, 311 were in the clascoterone group and 289 were in the vehicle group. Of these, 343 completed the LTE study.
• At week 12, the proportion of patients who achieved treatment success was higher in the clascoterone group than in the vehicle group (19.9% vs 7.7%, respectively; P < .0001).
• In the LTE study, the proportion of patients previously treated with clascoterone who achieved a facial IGA of 0/1 increased from 13.5% at extension day 0 to 29.9% at extension day 274, while the proportion of patients previously treated with vehicle and switched to clascoterone who achieved a facial IGA of 0/1 increased from 6.2% at extension day 0 to 30.4% at extension day 274.
• Similarly, the proportion of patients in the LTE study with a truncal IGA of 0/1 increased from 4.9% at extension day 0 to 31.7% on extension day 274.

IN PRACTICE:

“Clinicians may consider counseling patients that treatment persistence is required to maximize the efficacy of clascoterone treatment,” the authors concluded.

SOURCE:

Lawrence F. Eichenfield, MD, of the departments of dermatology and pediatrics at the University of California and Rady Children’s Hospital, San Diego, California, led the research. The study was published in the January 2024 issue of the Journal of Drugs in Dermatology.

LIMITATIONS:

There was a high patient discontinuation rate before and during the LET study. Also, no assessment was made as to how clascoterone affected patients’ quality of life.

DISCLOSURES:

Clascoterone manufacturer Cassiopea funded the studies. Dr. Eichenfield and fellow investigators Adelaide A. Hebert, MD, and Linda Stein Gold, MD, received compensation from Cassiopea as advisers and disclosed ties to many other pharmaceutical companies.
 

A version of this article appeared on Medscape.com.

TOPLINE:

The efficacy of clascoterone cream 1% for treating acne vulgaris appears to increase over time after 12 weeks of use and up to 1 year.

METHODOLOGY:

• A 1% cream formulation of clascoterone, a topical androgen receptor inhibitor, is approved for the treatment of acne vulgaris in patients aged 12 years and older based on results from two identical phase 3 12-week trials, NCT02608450 and NCT02608476, and a long-term extension (LTE) study.
• The purpose of the current study was to evaluate the integrated efficacy of clascoterone cream 1% (Winlevi) in the intention-to-treat population of patients from all three trials.
• In the pivotal trials, investigators randomized patients with acne 1:1 to receive clascoterone cream 1% or vehicle twice daily for 12 weeks. Participants were eligible to enter the LTE study, in which patients applied clascoterone to the face, and if they wanted to, the trunk for up to 9 more months.
• To assess combined efficacy, researchers evaluated the proportion of patients who achieved an Investigator’s Global Assessment (IGA) of 0 or 1.

TAKEAWAY:

• Of the 1143 patients from the pivotal trials who completed 12 weeks of treatment, 576 were in the clascoterone group and 567 were in the vehicle group. Of the 600 patients who entered the LTE study, 311 were in the clascoterone group and 289 were in the vehicle group. Of these, 343 completed the LTE study.
• At week 12, the proportion of patients who achieved treatment success was higher in the clascoterone group than in the vehicle group (19.9% vs 7.7%, respectively; P < .0001).
• In the LTE study, the proportion of patients previously treated with clascoterone who achieved a facial IGA of 0/1 increased from 13.5% at extension day 0 to 29.9% at extension day 274, while the proportion of patients previously treated with vehicle and switched to clascoterone who achieved a facial IGA of 0/1 increased from 6.2% at extension day 0 to 30.4% at extension day 274.
• Similarly, the proportion of patients in the LTE study with a truncal IGA of 0/1 increased from 4.9% at extension day 0 to 31.7% on extension day 274.

IN PRACTICE:

“Clinicians may consider counseling patients that treatment persistence is required to maximize the efficacy of clascoterone treatment,” the authors concluded.

SOURCE:

Lawrence F. Eichenfield, MD, of the departments of dermatology and pediatrics at the University of California and Rady Children’s Hospital, San Diego, California, led the research. The study was published in the January 2024 issue of the Journal of Drugs in Dermatology.

LIMITATIONS:

There was a high patient discontinuation rate before and during the LET study. Also, no assessment was made as to how clascoterone affected patients’ quality of life.

DISCLOSURES:

Clascoterone manufacturer Cassiopea funded the studies. Dr. Eichenfield and fellow investigators Adelaide A. Hebert, MD, and Linda Stein Gold, MD, received compensation from Cassiopea as advisers and disclosed ties to many other pharmaceutical companies.
 

A version of this article appeared on Medscape.com.

TOPLINE:

The efficacy of clascoterone cream 1% for treating acne vulgaris appears to increase over time after 12 weeks of use and up to 1 year.

METHODOLOGY:

• A 1% cream formulation of clascoterone, a topical androgen receptor inhibitor, is approved for the treatment of acne vulgaris in patients aged 12 years and older based on results from two identical phase 3 12-week trials, NCT02608450 and NCT02608476, and a long-term extension (LTE) study.
• The purpose of the current study was to evaluate the integrated efficacy of clascoterone cream 1% (Winlevi) in the intention-to-treat population of patients from all three trials.
• In the pivotal trials, investigators randomized patients with acne 1:1 to receive clascoterone cream 1% or vehicle twice daily for 12 weeks. Participants were eligible to enter the LTE study, in which patients applied clascoterone to the face, and if they wanted to, the trunk for up to 9 more months.
• To assess combined efficacy, researchers evaluated the proportion of patients who achieved an Investigator’s Global Assessment (IGA) of 0 or 1.

TAKEAWAY:

• Of the 1143 patients from the pivotal trials who completed 12 weeks of treatment, 576 were in the clascoterone group and 567 were in the vehicle group. Of the 600 patients who entered the LTE study, 311 were in the clascoterone group and 289 were in the vehicle group. Of these, 343 completed the LTE study.
• At week 12, the proportion of patients who achieved treatment success was higher in the clascoterone group than in the vehicle group (19.9% vs 7.7%, respectively; P < .0001).
• In the LTE study, the proportion of patients previously treated with clascoterone who achieved a facial IGA of 0/1 increased from 13.5% at extension day 0 to 29.9% at extension day 274, while the proportion of patients previously treated with vehicle and switched to clascoterone who achieved a facial IGA of 0/1 increased from 6.2% at extension day 0 to 30.4% at extension day 274.
• Similarly, the proportion of patients in the LTE study with a truncal IGA of 0/1 increased from 4.9% at extension day 0 to 31.7% on extension day 274.

IN PRACTICE:

“Clinicians may consider counseling patients that treatment persistence is required to maximize the efficacy of clascoterone treatment,” the authors concluded.

SOURCE:

Lawrence F. Eichenfield, MD, of the departments of dermatology and pediatrics at the University of California and Rady Children’s Hospital, San Diego, California, led the research. The study was published in the January 2024 issue of the Journal of Drugs in Dermatology.

LIMITATIONS:

There was a high patient discontinuation rate before and during the LET study. Also, no assessment was made as to how clascoterone affected patients’ quality of life.

DISCLOSURES:

Clascoterone manufacturer Cassiopea funded the studies. Dr. Eichenfield and fellow investigators Adelaide A. Hebert, MD, and Linda Stein Gold, MD, received compensation from Cassiopea as advisers and disclosed ties to many other pharmaceutical companies.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Previous gestational diabetes mellitus (GDM) nearly doubles future chronic kidney disease (CKD) risk, irrespective of subsequent diabetes and hypertension, a study showed.

METHODOLOGY:

• A nationwide, cohort study was based on data from the Danish Medical Birth Register and included 697,622 women who gave birth between 1997 and 2018.
• Of all study participants, 3.4% reported GDM in at least one pregnancy, and 12.8% of women with GDM received insulin, a proxy for a more severe metabolic dysfunction.
• The women were followed up for a median of 11.9 years.
• Researchers studied CKD and acute kidney disease as the outcomes of interest, the mediating effects of subsequent diabetes and hypertension on future CKD, and how GDM severity affected later risk for kidney disease.

TAKEAWAY:

• Women with GDM showed significantly higher CKD risk than those without GDM (adjusted hazard ratio [aHR], 1.92; 95% CI, 1.67-2.21).
• Women who received insulin during pregnancy due to severe metabolic dysfunction but did not develop subsequent diabetes had a proportionally higher risk for CKD (aHR, 2.35; 95% CI, 1.39-3.97).
• Women with GDM who went on to develop diabetes or hypertension faced even higher risks for CKD, suggesting that preventing diabetes and hypertension after GDM may reduce the development of CKD.
• GDM did not affect the risk for acute kidney disease (aHR, 1.08; 95% CI, 0.90-1.29).

IN PRACTICE:

“Women with severe metabolic dysfunction during pregnancy constitute a high-risk group regarding future CKD,” the authors wrote. “The significantly elevated CKD risk was observed from 2 years after pregnancy and beyond.”

SOURCE:

The study, with first author Maria Hornstrup Christensen, of Odense University Hospital, Odense, Denmark, was published online on December 15 in Diabetes Care.

LIMITATIONS:

GDM may be underdiagnosed, and undiagnosed diabetes may be misclassified as GDM. The proxies of GDM and insulin treatment may not have captured the increasing severity of metabolic dysfunction. The prevalence of insulin treatment was lower than expected, perhaps due to the practice of providing a patient’s first insulin pen without a prescription and perhaps not recording it in a patient’s health record.

DISCLOSURES:

This work received financial support from the University of Southern Denmark, the Region of Southern Denmark, and the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Previous gestational diabetes mellitus (GDM) nearly doubles future chronic kidney disease (CKD) risk, irrespective of subsequent diabetes and hypertension, a study showed.

METHODOLOGY:

• A nationwide, cohort study was based on data from the Danish Medical Birth Register and included 697,622 women who gave birth between 1997 and 2018.
• Of all study participants, 3.4% reported GDM in at least one pregnancy, and 12.8% of women with GDM received insulin, a proxy for a more severe metabolic dysfunction.
• The women were followed up for a median of 11.9 years.
• Researchers studied CKD and acute kidney disease as the outcomes of interest, the mediating effects of subsequent diabetes and hypertension on future CKD, and how GDM severity affected later risk for kidney disease.

TAKEAWAY:

• Women with GDM showed significantly higher CKD risk than those without GDM (adjusted hazard ratio [aHR], 1.92; 95% CI, 1.67-2.21).
• Women who received insulin during pregnancy due to severe metabolic dysfunction but did not develop subsequent diabetes had a proportionally higher risk for CKD (aHR, 2.35; 95% CI, 1.39-3.97).
• Women with GDM who went on to develop diabetes or hypertension faced even higher risks for CKD, suggesting that preventing diabetes and hypertension after GDM may reduce the development of CKD.
• GDM did not affect the risk for acute kidney disease (aHR, 1.08; 95% CI, 0.90-1.29).

IN PRACTICE:

“Women with severe metabolic dysfunction during pregnancy constitute a high-risk group regarding future CKD,” the authors wrote. “The significantly elevated CKD risk was observed from 2 years after pregnancy and beyond.”

SOURCE:

The study, with first author Maria Hornstrup Christensen, of Odense University Hospital, Odense, Denmark, was published online on December 15 in Diabetes Care.

LIMITATIONS:

GDM may be underdiagnosed, and undiagnosed diabetes may be misclassified as GDM. The proxies of GDM and insulin treatment may not have captured the increasing severity of metabolic dysfunction. The prevalence of insulin treatment was lower than expected, perhaps due to the practice of providing a patient’s first insulin pen without a prescription and perhaps not recording it in a patient’s health record.

DISCLOSURES:

This work received financial support from the University of Southern Denmark, the Region of Southern Denmark, and the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Previous gestational diabetes mellitus (GDM) nearly doubles future chronic kidney disease (CKD) risk, irrespective of subsequent diabetes and hypertension, a study showed.

METHODOLOGY:

• A nationwide, cohort study was based on data from the Danish Medical Birth Register and included 697,622 women who gave birth between 1997 and 2018.
• Of all study participants, 3.4% reported GDM in at least one pregnancy, and 12.8% of women with GDM received insulin, a proxy for a more severe metabolic dysfunction.
• The women were followed up for a median of 11.9 years.
• Researchers studied CKD and acute kidney disease as the outcomes of interest, the mediating effects of subsequent diabetes and hypertension on future CKD, and how GDM severity affected later risk for kidney disease.

TAKEAWAY:

• Women with GDM showed significantly higher CKD risk than those without GDM (adjusted hazard ratio [aHR], 1.92; 95% CI, 1.67-2.21).
• Women who received insulin during pregnancy due to severe metabolic dysfunction but did not develop subsequent diabetes had a proportionally higher risk for CKD (aHR, 2.35; 95% CI, 1.39-3.97).
• Women with GDM who went on to develop diabetes or hypertension faced even higher risks for CKD, suggesting that preventing diabetes and hypertension after GDM may reduce the development of CKD.
• GDM did not affect the risk for acute kidney disease (aHR, 1.08; 95% CI, 0.90-1.29).

IN PRACTICE:

“Women with severe metabolic dysfunction during pregnancy constitute a high-risk group regarding future CKD,” the authors wrote. “The significantly elevated CKD risk was observed from 2 years after pregnancy and beyond.”

SOURCE:

The study, with first author Maria Hornstrup Christensen, of Odense University Hospital, Odense, Denmark, was published online on December 15 in Diabetes Care.

LIMITATIONS:

GDM may be underdiagnosed, and undiagnosed diabetes may be misclassified as GDM. The proxies of GDM and insulin treatment may not have captured the increasing severity of metabolic dysfunction. The prevalence of insulin treatment was lower than expected, perhaps due to the practice of providing a patient’s first insulin pen without a prescription and perhaps not recording it in a patient’s health record.

DISCLOSURES:

This work received financial support from the University of Southern Denmark, the Region of Southern Denmark, and the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

Women with autoimmune disease are more likely to have perinatal depression (PND), according to findings from a new study that also suggested the reverse relationship is true: Women with a history of PND have a higher risk of developing autoimmune disease.

The research, published online on January 9, 2024, in Molecular Psychiatry, was led by Emma Bränn, PhD, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.

The researchers used data from the Swedish Medical Birth Register and identified all women who had given birth in Sweden between 2001 and 2013. Out of the group of approximately 815,000 women and 1.3 million pregnancies, just more than 55,000 women had been diagnosed with depression during their pregnancy or within a year after delivery.

The researchers then compared the incidence of 41 autoimmune diseases in women who had and did not have PND. They controlled for factors including genetic makeup and childhood environment.

Results indicated that women with autoimmune disease were 30% more likely to have PND (odds ratio, 1.30; 95% CI, 1.25-1.35). Conversely, women with PND were 30% more likely than women with no PND to develop an autoimmune disease (hazard ratio, 1.30; 95% CI, 1.25-1.36).

A sibling comparison helped confirm the results by controlling for some shared genetic and early life environmental factors related to the household in which sisters grew up.
 

Potential Shared Biological Mechanisms

The association was independent of psychiatric comorbidities, suggesting there may be shared biological mechanisms.

Dr. Bränn told this news organization that the research team wanted to do the study because previous research has shown involvement of the immune system in depression, with similarities in both the symptoms of immune system–activated diseases and depression and the molecular pathways activated by the immune system.

“Adding on top of the tremendous changes in the immune system that we see in the body of the woman during the perinatal period, we hypothesized that autoimmune diseases could be associated to perinatal depression,” she said. “This had also been shown in some previous literature but not to the extent as what we have investigated in this paper.”

She said their results help make a case for counseling women at several points in healthcare interactions — before and after conception and childbirth — and in rheumatology visits to inform women with autoimmune diseases who are contemplating motherhood of the association with developing PND. The results may also demonstrate a need for monitoring women in these groups for depression or autoimmune disease.

Fred Miller, MD, PhD, retired Scientist Emeritus of the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences, who was not part of the study, said the results seem plausible as they build on early work that demonstrated selected associations between autoimmune conditions and mental illness.

“These associations may be the result of shared genetic and environmental risk factors, including stress, hormonal changes, medications, and the proinflammatory states that can lead to both,” he said.

The novelty, he said, is in the relatively strong associations of PND with autoimmune disease overall and with specific autoimmune diseases.
 

Strong Link Found With Multiple Sclerosis (MS)

According to the paper, a significant positive bidirectional link was found for autoimmune thyroid disease, psoriasis, MS, ulcerative colitis, and celiac disease.

Researchers found a particularly strong association — double the risk in both directions — between PND and MS.

Dr. Miller said though it is unclear from this study why the association of PND with MS was stronger than with other autoimmune diseases, people with MS are known to be at a high risk for depression in general. That may come from greater shared genetic and environmental risk factors, he added.

Additionally, MS is one of the more common autoimmune diseases, he noted, so the population is larger for study.

He said he was surprised the researchers didn’t investigate medication use because medications used in depression have immunologic effects and medications used in autoimmune diseases could have effects on mental conditions.

The study has implications for clinicians in a wide variety of specialties, Dr. Miller noted.

“It suggests that caregivers be more alert to the signs of developing autoimmune disease in women with perinatal depression and to the signs of developing perinatal depression in those with autoimmune disease,” Dr. Miller said, “so that appropriate screening, diagnostics, and interventions may be undertaken.”

The researchers say they will continue to examine the long-term effects of depression during pregnancy and in the year after childbirth.

“Depression during this sensitive period can have serious consequences for both the mother and the baby,” Dr. Bränn said. “We hope that our results will help decision-makers to steer funding toward maternal healthcare so that more women can get help and support in time.”

The study was financed by Karolinska Institute, Forte (the Swedish Research Council for Health, Working Life and Welfare), the Swedish Research Council, and the Icelandic Research Fund.

The researchers and Dr. Miller reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Women with autoimmune disease are more likely to have perinatal depression (PND), according to findings from a new study that also suggested the reverse relationship is true: Women with a history of PND have a higher risk of developing autoimmune disease.

The research, published online on January 9, 2024, in Molecular Psychiatry, was led by Emma Bränn, PhD, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.

The researchers used data from the Swedish Medical Birth Register and identified all women who had given birth in Sweden between 2001 and 2013. Out of the group of approximately 815,000 women and 1.3 million pregnancies, just more than 55,000 women had been diagnosed with depression during their pregnancy or within a year after delivery.

The researchers then compared the incidence of 41 autoimmune diseases in women who had and did not have PND. They controlled for factors including genetic makeup and childhood environment.

Results indicated that women with autoimmune disease were 30% more likely to have PND (odds ratio, 1.30; 95% CI, 1.25-1.35). Conversely, women with PND were 30% more likely than women with no PND to develop an autoimmune disease (hazard ratio, 1.30; 95% CI, 1.25-1.36).

A sibling comparison helped confirm the results by controlling for some shared genetic and early life environmental factors related to the household in which sisters grew up.
 

Potential Shared Biological Mechanisms

The association was independent of psychiatric comorbidities, suggesting there may be shared biological mechanisms.

Dr. Bränn told this news organization that the research team wanted to do the study because previous research has shown involvement of the immune system in depression, with similarities in both the symptoms of immune system–activated diseases and depression and the molecular pathways activated by the immune system.

“Adding on top of the tremendous changes in the immune system that we see in the body of the woman during the perinatal period, we hypothesized that autoimmune diseases could be associated to perinatal depression,” she said. “This had also been shown in some previous literature but not to the extent as what we have investigated in this paper.”

She said their results help make a case for counseling women at several points in healthcare interactions — before and after conception and childbirth — and in rheumatology visits to inform women with autoimmune diseases who are contemplating motherhood of the association with developing PND. The results may also demonstrate a need for monitoring women in these groups for depression or autoimmune disease.

Fred Miller, MD, PhD, retired Scientist Emeritus of the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences, who was not part of the study, said the results seem plausible as they build on early work that demonstrated selected associations between autoimmune conditions and mental illness.

“These associations may be the result of shared genetic and environmental risk factors, including stress, hormonal changes, medications, and the proinflammatory states that can lead to both,” he said.

The novelty, he said, is in the relatively strong associations of PND with autoimmune disease overall and with specific autoimmune diseases.
 

Strong Link Found With Multiple Sclerosis (MS)

According to the paper, a significant positive bidirectional link was found for autoimmune thyroid disease, psoriasis, MS, ulcerative colitis, and celiac disease.

Researchers found a particularly strong association — double the risk in both directions — between PND and MS.

Dr. Miller said though it is unclear from this study why the association of PND with MS was stronger than with other autoimmune diseases, people with MS are known to be at a high risk for depression in general. That may come from greater shared genetic and environmental risk factors, he added.

Additionally, MS is one of the more common autoimmune diseases, he noted, so the population is larger for study.

He said he was surprised the researchers didn’t investigate medication use because medications used in depression have immunologic effects and medications used in autoimmune diseases could have effects on mental conditions.

The study has implications for clinicians in a wide variety of specialties, Dr. Miller noted.

“It suggests that caregivers be more alert to the signs of developing autoimmune disease in women with perinatal depression and to the signs of developing perinatal depression in those with autoimmune disease,” Dr. Miller said, “so that appropriate screening, diagnostics, and interventions may be undertaken.”

The researchers say they will continue to examine the long-term effects of depression during pregnancy and in the year after childbirth.

“Depression during this sensitive period can have serious consequences for both the mother and the baby,” Dr. Bränn said. “We hope that our results will help decision-makers to steer funding toward maternal healthcare so that more women can get help and support in time.”

The study was financed by Karolinska Institute, Forte (the Swedish Research Council for Health, Working Life and Welfare), the Swedish Research Council, and the Icelandic Research Fund.

The researchers and Dr. Miller reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Women with autoimmune disease are more likely to have perinatal depression (PND), according to findings from a new study that also suggested the reverse relationship is true: Women with a history of PND have a higher risk of developing autoimmune disease.

The research, published online on January 9, 2024, in Molecular Psychiatry, was led by Emma Bränn, PhD, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.

The researchers used data from the Swedish Medical Birth Register and identified all women who had given birth in Sweden between 2001 and 2013. Out of the group of approximately 815,000 women and 1.3 million pregnancies, just more than 55,000 women had been diagnosed with depression during their pregnancy or within a year after delivery.

The researchers then compared the incidence of 41 autoimmune diseases in women who had and did not have PND. They controlled for factors including genetic makeup and childhood environment.

Results indicated that women with autoimmune disease were 30% more likely to have PND (odds ratio, 1.30; 95% CI, 1.25-1.35). Conversely, women with PND were 30% more likely than women with no PND to develop an autoimmune disease (hazard ratio, 1.30; 95% CI, 1.25-1.36).

A sibling comparison helped confirm the results by controlling for some shared genetic and early life environmental factors related to the household in which sisters grew up.
 

Potential Shared Biological Mechanisms

The association was independent of psychiatric comorbidities, suggesting there may be shared biological mechanisms.

Dr. Bränn told this news organization that the research team wanted to do the study because previous research has shown involvement of the immune system in depression, with similarities in both the symptoms of immune system–activated diseases and depression and the molecular pathways activated by the immune system.

“Adding on top of the tremendous changes in the immune system that we see in the body of the woman during the perinatal period, we hypothesized that autoimmune diseases could be associated to perinatal depression,” she said. “This had also been shown in some previous literature but not to the extent as what we have investigated in this paper.”

She said their results help make a case for counseling women at several points in healthcare interactions — before and after conception and childbirth — and in rheumatology visits to inform women with autoimmune diseases who are contemplating motherhood of the association with developing PND. The results may also demonstrate a need for monitoring women in these groups for depression or autoimmune disease.

Fred Miller, MD, PhD, retired Scientist Emeritus of the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences, who was not part of the study, said the results seem plausible as they build on early work that demonstrated selected associations between autoimmune conditions and mental illness.

“These associations may be the result of shared genetic and environmental risk factors, including stress, hormonal changes, medications, and the proinflammatory states that can lead to both,” he said.

The novelty, he said, is in the relatively strong associations of PND with autoimmune disease overall and with specific autoimmune diseases.
 

Strong Link Found With Multiple Sclerosis (MS)

According to the paper, a significant positive bidirectional link was found for autoimmune thyroid disease, psoriasis, MS, ulcerative colitis, and celiac disease.

Researchers found a particularly strong association — double the risk in both directions — between PND and MS.

Dr. Miller said though it is unclear from this study why the association of PND with MS was stronger than with other autoimmune diseases, people with MS are known to be at a high risk for depression in general. That may come from greater shared genetic and environmental risk factors, he added.

Additionally, MS is one of the more common autoimmune diseases, he noted, so the population is larger for study.

He said he was surprised the researchers didn’t investigate medication use because medications used in depression have immunologic effects and medications used in autoimmune diseases could have effects on mental conditions.

The study has implications for clinicians in a wide variety of specialties, Dr. Miller noted.

“It suggests that caregivers be more alert to the signs of developing autoimmune disease in women with perinatal depression and to the signs of developing perinatal depression in those with autoimmune disease,” Dr. Miller said, “so that appropriate screening, diagnostics, and interventions may be undertaken.”

The researchers say they will continue to examine the long-term effects of depression during pregnancy and in the year after childbirth.

“Depression during this sensitive period can have serious consequences for both the mother and the baby,” Dr. Bränn said. “We hope that our results will help decision-makers to steer funding toward maternal healthcare so that more women can get help and support in time.”

The study was financed by Karolinska Institute, Forte (the Swedish Research Council for Health, Working Life and Welfare), the Swedish Research Council, and the Icelandic Research Fund.

The researchers and Dr. Miller reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Medicare will now cover the use of an AI-based test for prostate cancer that can predict which men will benefit from potentially disabling androgen deprivation therapy.

The Centers for Medicare & Medicare Services (CMS) on January 1 approved the payment rate for ArteraAI as a clinical diagnostic laboratory test. The test is the first that can both predict therapeutic benefit and prognosticate long-term outcomes in localized prostate cancer. 

Daniel Spratt, MD, chair of radiation oncology at UH Seidman Cancer Center in Cleveland, who has been involved in researching ArteraAI, told this news organization that the test improves risk stratification or prognostication over standard clinical and pathologic tools, such as prostate-specific antigen, Gleason score, and T-stage, or risk groupings such as those from the National Comprehensive Cancer Network (NCCN).

“Medicare approval allows this test to reach more patients without the financial burden of covering the test out of pocket. The test is found among other tests in NCCN guidelines as a tool to improve risk stratification and personalization of treatment,” said Dr. Spratt, who serves on the network’s prostate cancer panel.

ArteraAI combines a patient’s standard clinical and pathologic information into an algorithm, alongside a digitized image analysis of the patients’ prostate biopsy. The result is a score that estimates a patient’s risk of developing metastasis or dying from prostate cancer.

Dr. Spratt was the lead author of article last June in NEJM Evidence that validated ArteraAI. He said ArteraAI is 80% accurate as a prognostic test compared with 65% accuracy using NCCN stratification systems. 

The AI test spares about two thirds of men with intermediate-risk prostate cancer who are starting radiation therapy from androgen deprivation and its side effects, such as weight gain, breast enlargement, hot flashes, heart disease, and brain problems, Dr. Spratt added. 

Andre Esteva, CEO and co-founder of San Francisco-based ArteraAI, said, “After someone is diagnosed with localized prostate cancer, deciding on a treatment can feel very overwhelming as there are so many factors to consider. During this time, knowledge is power, and having detailed, personalized information can increase confidence when making these challenging decisions. The ArteraAI Prostate Test was developed with this in mind and can predict whether a patient will benefit from hormone therapy and estimate long-term outcomes.”

Bruno Barrey is one of Dr. Spratt’s patients. Barrey, a robotics engineer from suburban Detroit who was transitioning from active surveillance with Gleason 3+4 intermediate-risk prostate cancer to radiation therapy, said, “I was concerned about the side effects from androgen-deprivation therapy. I was relieved that the AI test allowed me to avoid hormone therapy.”

Dr. Spratt reported working with NRG Oncology, a clinical trials group funded by the National Cancer Institute, and as an academic collaborator with ArteraAI. 

A version of this article appeared on Medscape.com.

Medicare will now cover the use of an AI-based test for prostate cancer that can predict which men will benefit from potentially disabling androgen deprivation therapy.

The Centers for Medicare & Medicare Services (CMS) on January 1 approved the payment rate for ArteraAI as a clinical diagnostic laboratory test. The test is the first that can both predict therapeutic benefit and prognosticate long-term outcomes in localized prostate cancer. 

Daniel Spratt, MD, chair of radiation oncology at UH Seidman Cancer Center in Cleveland, who has been involved in researching ArteraAI, told this news organization that the test improves risk stratification or prognostication over standard clinical and pathologic tools, such as prostate-specific antigen, Gleason score, and T-stage, or risk groupings such as those from the National Comprehensive Cancer Network (NCCN).

“Medicare approval allows this test to reach more patients without the financial burden of covering the test out of pocket. The test is found among other tests in NCCN guidelines as a tool to improve risk stratification and personalization of treatment,” said Dr. Spratt, who serves on the network’s prostate cancer panel.

ArteraAI combines a patient’s standard clinical and pathologic information into an algorithm, alongside a digitized image analysis of the patients’ prostate biopsy. The result is a score that estimates a patient’s risk of developing metastasis or dying from prostate cancer.

Dr. Spratt was the lead author of article last June in NEJM Evidence that validated ArteraAI. He said ArteraAI is 80% accurate as a prognostic test compared with 65% accuracy using NCCN stratification systems. 

The AI test spares about two thirds of men with intermediate-risk prostate cancer who are starting radiation therapy from androgen deprivation and its side effects, such as weight gain, breast enlargement, hot flashes, heart disease, and brain problems, Dr. Spratt added. 

Andre Esteva, CEO and co-founder of San Francisco-based ArteraAI, said, “After someone is diagnosed with localized prostate cancer, deciding on a treatment can feel very overwhelming as there are so many factors to consider. During this time, knowledge is power, and having detailed, personalized information can increase confidence when making these challenging decisions. The ArteraAI Prostate Test was developed with this in mind and can predict whether a patient will benefit from hormone therapy and estimate long-term outcomes.”

Bruno Barrey is one of Dr. Spratt’s patients. Barrey, a robotics engineer from suburban Detroit who was transitioning from active surveillance with Gleason 3+4 intermediate-risk prostate cancer to radiation therapy, said, “I was concerned about the side effects from androgen-deprivation therapy. I was relieved that the AI test allowed me to avoid hormone therapy.”

Dr. Spratt reported working with NRG Oncology, a clinical trials group funded by the National Cancer Institute, and as an academic collaborator with ArteraAI. 

A version of this article appeared on Medscape.com.

Medicare will now cover the use of an AI-based test for prostate cancer that can predict which men will benefit from potentially disabling androgen deprivation therapy.

The Centers for Medicare & Medicare Services (CMS) on January 1 approved the payment rate for ArteraAI as a clinical diagnostic laboratory test. The test is the first that can both predict therapeutic benefit and prognosticate long-term outcomes in localized prostate cancer. 

Daniel Spratt, MD, chair of radiation oncology at UH Seidman Cancer Center in Cleveland, who has been involved in researching ArteraAI, told this news organization that the test improves risk stratification or prognostication over standard clinical and pathologic tools, such as prostate-specific antigen, Gleason score, and T-stage, or risk groupings such as those from the National Comprehensive Cancer Network (NCCN).

“Medicare approval allows this test to reach more patients without the financial burden of covering the test out of pocket. The test is found among other tests in NCCN guidelines as a tool to improve risk stratification and personalization of treatment,” said Dr. Spratt, who serves on the network’s prostate cancer panel.

ArteraAI combines a patient’s standard clinical and pathologic information into an algorithm, alongside a digitized image analysis of the patients’ prostate biopsy. The result is a score that estimates a patient’s risk of developing metastasis or dying from prostate cancer.

Dr. Spratt was the lead author of article last June in NEJM Evidence that validated ArteraAI. He said ArteraAI is 80% accurate as a prognostic test compared with 65% accuracy using NCCN stratification systems. 

The AI test spares about two thirds of men with intermediate-risk prostate cancer who are starting radiation therapy from androgen deprivation and its side effects, such as weight gain, breast enlargement, hot flashes, heart disease, and brain problems, Dr. Spratt added. 

Andre Esteva, CEO and co-founder of San Francisco-based ArteraAI, said, “After someone is diagnosed with localized prostate cancer, deciding on a treatment can feel very overwhelming as there are so many factors to consider. During this time, knowledge is power, and having detailed, personalized information can increase confidence when making these challenging decisions. The ArteraAI Prostate Test was developed with this in mind and can predict whether a patient will benefit from hormone therapy and estimate long-term outcomes.”

Bruno Barrey is one of Dr. Spratt’s patients. Barrey, a robotics engineer from suburban Detroit who was transitioning from active surveillance with Gleason 3+4 intermediate-risk prostate cancer to radiation therapy, said, “I was concerned about the side effects from androgen-deprivation therapy. I was relieved that the AI test allowed me to avoid hormone therapy.”

Dr. Spratt reported working with NRG Oncology, a clinical trials group funded by the National Cancer Institute, and as an academic collaborator with ArteraAI. 

A version of this article appeared on Medscape.com.

TOPLINE:

Testosterone replacement therapy in middle-aged and older men with hypogonadism does not increase the risk for high-grade or any prostate cancer, new data confirmed.

METHODOLOGY:

• The relationship between testosterone replacement therapy and prostate cancer risk remains unclear.
• Epidemiologic studies have shown inconsistent findings, and clinical trials have not examined prostate safety. As a result, guidelines generally advise against testosterone replacement therapy in men with a history of or increased risk for prostate cancer.
• The current placebo-controlled, double-blind, parallel-group randomized study included 5204 men, ages 45-80, who had two fasting testosterone concentrations < 300 ng/dL, one or more hypogonadal symptoms, and a history of cardiovascular disease or increased . Patients were randomly assigned 1:1 to receive either testosterone replacement therapy or placebo.
• The primary prostate safety endpoint was incident high-grade prostate cancer (Gleason score 4 + 3 or higher).
• Secondary endpoints included incidence of any prostate cancer, acute urinary retention, invasive procedure for , , and new pharmacologic treatment for lower urinary tract symptoms.

TAKEAWAY:

• The incidence of high-grade prostate cancer did not differ significantly between groups. Over a mean follow-up of 33 months, only 0.19% (5 of 2596 participants) in the testosterone replacement therapy group and 0.12% (3 of 2602) in the placebo group were diagnosed with high-grade disease (hazard ratio [HR], 1.62; P = .51).
• The rate of any prostate cancer also did not differ significantly between the testosterone vs placebo groups (0.46% vs 0.42%; HR, 1.07; P = .87).
• The rates of acute urinary retention (0.77% vs 0.61%; HR, 1.25; P = .50), invasive procedures for benign prostatic hyperplasia (0.89% vs 0.46%; HR, 1.91; P = .07), prostate biopsy (0.62% vs 0.54%; HR, 1.13; P = .74), or new treatment for lower urinary tract symptoms (3.89% vs 3.34%; HR, 1.16; P = .32) did not differ significantly between the testosterone vs placebo groups.
• Compared with placebo, testosterone therapy did increase prostate-specific antigen (PSA) levels, but the differences were small and did not increase after 12 months.

IN PRACTICE:

In a population of middle-aged and older men with hypogonadism, “the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men,” the authors concluded. “The study’s findings will facilitate a more informed appraisal of the potential prostate risks of testosterone replacement therapy.”

SOURCE:

This study, led by Shalender Bhasin, MB, BS, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, was published online in JAMA Network Open.

LIMITATIONS:

These study findings do not apply to men with known prostate cancer, higher PSA values, or those without confirmed hypogonadism. The study design did not include prostate imaging or other biomarker tests after PSA testing, which may have affected the decision to perform a biopsy. Also, the rates of treatment discontinuation and loss to follow-up were high.

DISCLOSURES:

This study was funded by a consortium of testosterone manufacturers led by AbbVie Inc., with additional financial support from Endo Pharmaceuticals, Acerus Pharmaceuticals Corporation, and Upsher-Smith Laboratories. Bhasin, Lincoff, and Khera reported receiving grants and consulting and personal fees from various sources. The remaining authors disclosed no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Testosterone replacement therapy in middle-aged and older men with hypogonadism does not increase the risk for high-grade or any prostate cancer, new data confirmed.

METHODOLOGY:

• The relationship between testosterone replacement therapy and prostate cancer risk remains unclear.
• Epidemiologic studies have shown inconsistent findings, and clinical trials have not examined prostate safety. As a result, guidelines generally advise against testosterone replacement therapy in men with a history of or increased risk for prostate cancer.
• The current placebo-controlled, double-blind, parallel-group randomized study included 5204 men, ages 45-80, who had two fasting testosterone concentrations < 300 ng/dL, one or more hypogonadal symptoms, and a history of cardiovascular disease or increased . Patients were randomly assigned 1:1 to receive either testosterone replacement therapy or placebo.
• The primary prostate safety endpoint was incident high-grade prostate cancer (Gleason score 4 + 3 or higher).
• Secondary endpoints included incidence of any prostate cancer, acute urinary retention, invasive procedure for , , and new pharmacologic treatment for lower urinary tract symptoms.

TAKEAWAY:

• The incidence of high-grade prostate cancer did not differ significantly between groups. Over a mean follow-up of 33 months, only 0.19% (5 of 2596 participants) in the testosterone replacement therapy group and 0.12% (3 of 2602) in the placebo group were diagnosed with high-grade disease (hazard ratio [HR], 1.62; P = .51).
• The rate of any prostate cancer also did not differ significantly between the testosterone vs placebo groups (0.46% vs 0.42%; HR, 1.07; P = .87).
• The rates of acute urinary retention (0.77% vs 0.61%; HR, 1.25; P = .50), invasive procedures for benign prostatic hyperplasia (0.89% vs 0.46%; HR, 1.91; P = .07), prostate biopsy (0.62% vs 0.54%; HR, 1.13; P = .74), or new treatment for lower urinary tract symptoms (3.89% vs 3.34%; HR, 1.16; P = .32) did not differ significantly between the testosterone vs placebo groups.
• Compared with placebo, testosterone therapy did increase prostate-specific antigen (PSA) levels, but the differences were small and did not increase after 12 months.

IN PRACTICE:

In a population of middle-aged and older men with hypogonadism, “the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men,” the authors concluded. “The study’s findings will facilitate a more informed appraisal of the potential prostate risks of testosterone replacement therapy.”

SOURCE:

This study, led by Shalender Bhasin, MB, BS, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, was published online in JAMA Network Open.

LIMITATIONS:

These study findings do not apply to men with known prostate cancer, higher PSA values, or those without confirmed hypogonadism. The study design did not include prostate imaging or other biomarker tests after PSA testing, which may have affected the decision to perform a biopsy. Also, the rates of treatment discontinuation and loss to follow-up were high.

DISCLOSURES:

This study was funded by a consortium of testosterone manufacturers led by AbbVie Inc., with additional financial support from Endo Pharmaceuticals, Acerus Pharmaceuticals Corporation, and Upsher-Smith Laboratories. Bhasin, Lincoff, and Khera reported receiving grants and consulting and personal fees from various sources. The remaining authors disclosed no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Testosterone replacement therapy in middle-aged and older men with hypogonadism does not increase the risk for high-grade or any prostate cancer, new data confirmed.

METHODOLOGY:

• The relationship between testosterone replacement therapy and prostate cancer risk remains unclear.
• Epidemiologic studies have shown inconsistent findings, and clinical trials have not examined prostate safety. As a result, guidelines generally advise against testosterone replacement therapy in men with a history of or increased risk for prostate cancer.
• The current placebo-controlled, double-blind, parallel-group randomized study included 5204 men, ages 45-80, who had two fasting testosterone concentrations < 300 ng/dL, one or more hypogonadal symptoms, and a history of cardiovascular disease or increased . Patients were randomly assigned 1:1 to receive either testosterone replacement therapy or placebo.
• The primary prostate safety endpoint was incident high-grade prostate cancer (Gleason score 4 + 3 or higher).
• Secondary endpoints included incidence of any prostate cancer, acute urinary retention, invasive procedure for , , and new pharmacologic treatment for lower urinary tract symptoms.

TAKEAWAY:

• The incidence of high-grade prostate cancer did not differ significantly between groups. Over a mean follow-up of 33 months, only 0.19% (5 of 2596 participants) in the testosterone replacement therapy group and 0.12% (3 of 2602) in the placebo group were diagnosed with high-grade disease (hazard ratio [HR], 1.62; P = .51).
• The rate of any prostate cancer also did not differ significantly between the testosterone vs placebo groups (0.46% vs 0.42%; HR, 1.07; P = .87).
• The rates of acute urinary retention (0.77% vs 0.61%; HR, 1.25; P = .50), invasive procedures for benign prostatic hyperplasia (0.89% vs 0.46%; HR, 1.91; P = .07), prostate biopsy (0.62% vs 0.54%; HR, 1.13; P = .74), or new treatment for lower urinary tract symptoms (3.89% vs 3.34%; HR, 1.16; P = .32) did not differ significantly between the testosterone vs placebo groups.
• Compared with placebo, testosterone therapy did increase prostate-specific antigen (PSA) levels, but the differences were small and did not increase after 12 months.

IN PRACTICE:

In a population of middle-aged and older men with hypogonadism, “the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men,” the authors concluded. “The study’s findings will facilitate a more informed appraisal of the potential prostate risks of testosterone replacement therapy.”

SOURCE:

This study, led by Shalender Bhasin, MB, BS, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, was published online in JAMA Network Open.

LIMITATIONS:

These study findings do not apply to men with known prostate cancer, higher PSA values, or those without confirmed hypogonadism. The study design did not include prostate imaging or other biomarker tests after PSA testing, which may have affected the decision to perform a biopsy. Also, the rates of treatment discontinuation and loss to follow-up were high.

DISCLOSURES:

This study was funded by a consortium of testosterone manufacturers led by AbbVie Inc., with additional financial support from Endo Pharmaceuticals, Acerus Pharmaceuticals Corporation, and Upsher-Smith Laboratories. Bhasin, Lincoff, and Khera reported receiving grants and consulting and personal fees from various sources. The remaining authors disclosed no conflicts of interest.

A version of this article appeared on Medscape.com.

Prophylactic treatment with zoledronic acid (ZA) in individuals at high genetic risk for Paget disease of the bone (PDB) can prevent the development or progression of the condition, according to a new study. The authors argued that the positive results from the trial suggest that individuals with a familial history of PDB should undergo genetic screening.

“If it’s positive, you should be able to have a bone scan and take it from there,” senior author Stuart Ralston, MBChB, MD, professor of rheumatology at the University of Edinburgh (Scotland), said in an interview.

Dr. Ralston

PDB is a chronic skeletal growth disorder that affects an estimated 1-3 million people in the United States and is most prevalent in individuals over 65 years old. Symptoms of the disease may not present until later stages when there is already skeletal damage that cannot be resolved by medications. Earlier intervention in individuals who have not yet shown signs of the condition could potentially halt disease progression, Dr. Ralston said.

Genetics plays a substantial role in PDB, especially pathogenic variants of the gene SQSTM1. An estimated 40%-50% of people with a familial history of PDB have these variants, according to the study, which are associated with earlier PDB onset and more severe disease.

However, it was unclear if early interventions in these higher-risk individuals may result in better health outcomes.

In this new study, published on December 20, 2023, in Annals of the Rheumatic Diseases, researchers recruited participants through family members already diagnosed with PDB who received treatment at outpatient clinics. Over 1400 individuals with PDB underwent genetic testing for pathogenic SQSTM1 variants. If they tested positive, their first-degree relatives — primarily children — were offered the same genetic test. In total, 350 relatives tested positive for these pathogenic SQSTM1 variants, and of these individuals, 222 agreed to participate in the trial.

At the beginning of the study, all participants received a radionuclide bone scan to screen for bone lesions. They also underwent testing for the bone resorption marker type I collagen C-terminal telopeptides (CTX) and the bone formation marker procollagen type I amino-terminal propeptide (P1NP).

Participants were then randomized to receive either a single intravenous infusion of 5 mg of ZA or placebo treatment. Researchers followed up with participants annually for a median of 84 months (7 years), and then baseline assessments were repeated.

A total of 90 individuals in the ZA treatment group and 90 individuals in the placebo group completed the trial.

Participants were, on average, 50 years old at the beginning of the study. In the ZA group, nine individuals had lesions detected in bone scans at baseline, compared with just one at the study’s end. In the placebo group, 12 individuals had detectable lesions at baseline, compared with 11 individuals at the study’s end.

While the proportion of individuals with lesions was similar between the two groups, there were about twice as many lesions overall in the placebo group, compared with the ZA group (29 vs 15), which researchers said was by chance. All but two lesions disappeared in the ZA group, compared with 26 lesions remaining in the placebo group (P < .0001).

“The bone scan reversal of abnormalities was amazing,” said Ralston, where eight of nine patients with lesions in the ZA group “had their bone scan evidence completely wiped out,” he said. “That’s a very powerful result.”

Both CTX and P1NP concentrations fell in the ZA group at 12 months and remained significantly lower than the placebo group throughout the study (P < .0001 for each).

Overall, the researchers reported that eight individuals in the placebo group and no individuals in the ZA group had a poor outcome, defined as new bone lesions or lesions that were unchanged or progressed (odds ratio, 0.08; P = .003). Two individuals in the placebo group developed lesions during the study, compared with none in the ZA group, but this difference was not statistically significant.

Importantly, there were no differences in adverse events between the two groups.

While only a small number of people in the study had legions — around 9% of participants — the effect of ZA is “dramatic,” Linda A. Russell, MD, director of the Osteoporosis and Metabolic Bone Health Center at the Hospital for Special Surgery in New York City, told this news organization.

While clinicians primarily diagnose PDB with X-rays or an alkaline phosphatase blood test, testing for SQSTM1 is a new way to understand if someone is at higher risk for the disease, she said.

“Now, it seems like [the test] is fairly easily available, so probably it’s something we can begin to incorporate into our armamentarium,” Dr. Russell said.

Individuals who test positive for pathogenic variants of SQSTM1 could then get a bone scan, while those who tested negative may not need any additional testing, she added.

Dr. Ralston and coauthors noted that the effect size shown in this study is similar to that of studies examining adjuvant bisphosphonate therapy for postmenopausal women with early breast cancer. That practice, they write, is now a part of the standard of care.

“We believe that a similar approach is now justified in people with a family history of PDB who test positive for SQSTM1 mutations,” they wrote.

However, it is not clear if all individuals with pathogenic SQSTM1 should receive ZA treatment or if treatment should be given to only those with bone lesions.

“Future research to gather the views of people with a family history of PDB will help to inform the most appropriate way forward,” the authors wrote.

The UK Medical Research Council and Arthritis Research UK funded the trial. Zoledronic acid and a placebo were supplied by Novartis. Dr. Ralston reported funding to his institution from Kyowa Kirin, UCB, the Paget’s Association, and the Royal Osteoporosis Society. Some coauthors reported financial relationships with pharmaceutical companies outside the trial. Dr. Russell had no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Prophylactic treatment with zoledronic acid (ZA) in individuals at high genetic risk for Paget disease of the bone (PDB) can prevent the development or progression of the condition, according to a new study. The authors argued that the positive results from the trial suggest that individuals with a familial history of PDB should undergo genetic screening.

“If it’s positive, you should be able to have a bone scan and take it from there,” senior author Stuart Ralston, MBChB, MD, professor of rheumatology at the University of Edinburgh (Scotland), said in an interview.

Dr. Ralston

PDB is a chronic skeletal growth disorder that affects an estimated 1-3 million people in the United States and is most prevalent in individuals over 65 years old. Symptoms of the disease may not present until later stages when there is already skeletal damage that cannot be resolved by medications. Earlier intervention in individuals who have not yet shown signs of the condition could potentially halt disease progression, Dr. Ralston said.

Genetics plays a substantial role in PDB, especially pathogenic variants of the gene SQSTM1. An estimated 40%-50% of people with a familial history of PDB have these variants, according to the study, which are associated with earlier PDB onset and more severe disease.

However, it was unclear if early interventions in these higher-risk individuals may result in better health outcomes.

In this new study, published on December 20, 2023, in Annals of the Rheumatic Diseases, researchers recruited participants through family members already diagnosed with PDB who received treatment at outpatient clinics. Over 1400 individuals with PDB underwent genetic testing for pathogenic SQSTM1 variants. If they tested positive, their first-degree relatives — primarily children — were offered the same genetic test. In total, 350 relatives tested positive for these pathogenic SQSTM1 variants, and of these individuals, 222 agreed to participate in the trial.

At the beginning of the study, all participants received a radionuclide bone scan to screen for bone lesions. They also underwent testing for the bone resorption marker type I collagen C-terminal telopeptides (CTX) and the bone formation marker procollagen type I amino-terminal propeptide (P1NP).

Participants were then randomized to receive either a single intravenous infusion of 5 mg of ZA or placebo treatment. Researchers followed up with participants annually for a median of 84 months (7 years), and then baseline assessments were repeated.

A total of 90 individuals in the ZA treatment group and 90 individuals in the placebo group completed the trial.

Participants were, on average, 50 years old at the beginning of the study. In the ZA group, nine individuals had lesions detected in bone scans at baseline, compared with just one at the study’s end. In the placebo group, 12 individuals had detectable lesions at baseline, compared with 11 individuals at the study’s end.

While the proportion of individuals with lesions was similar between the two groups, there were about twice as many lesions overall in the placebo group, compared with the ZA group (29 vs 15), which researchers said was by chance. All but two lesions disappeared in the ZA group, compared with 26 lesions remaining in the placebo group (P < .0001).

“The bone scan reversal of abnormalities was amazing,” said Ralston, where eight of nine patients with lesions in the ZA group “had their bone scan evidence completely wiped out,” he said. “That’s a very powerful result.”

Both CTX and P1NP concentrations fell in the ZA group at 12 months and remained significantly lower than the placebo group throughout the study (P < .0001 for each).

Overall, the researchers reported that eight individuals in the placebo group and no individuals in the ZA group had a poor outcome, defined as new bone lesions or lesions that were unchanged or progressed (odds ratio, 0.08; P = .003). Two individuals in the placebo group developed lesions during the study, compared with none in the ZA group, but this difference was not statistically significant.

Importantly, there were no differences in adverse events between the two groups.

While only a small number of people in the study had legions — around 9% of participants — the effect of ZA is “dramatic,” Linda A. Russell, MD, director of the Osteoporosis and Metabolic Bone Health Center at the Hospital for Special Surgery in New York City, told this news organization.

While clinicians primarily diagnose PDB with X-rays or an alkaline phosphatase blood test, testing for SQSTM1 is a new way to understand if someone is at higher risk for the disease, she said.

“Now, it seems like [the test] is fairly easily available, so probably it’s something we can begin to incorporate into our armamentarium,” Dr. Russell said.

Individuals who test positive for pathogenic variants of SQSTM1 could then get a bone scan, while those who tested negative may not need any additional testing, she added.

Dr. Ralston and coauthors noted that the effect size shown in this study is similar to that of studies examining adjuvant bisphosphonate therapy for postmenopausal women with early breast cancer. That practice, they write, is now a part of the standard of care.

“We believe that a similar approach is now justified in people with a family history of PDB who test positive for SQSTM1 mutations,” they wrote.

However, it is not clear if all individuals with pathogenic SQSTM1 should receive ZA treatment or if treatment should be given to only those with bone lesions.

“Future research to gather the views of people with a family history of PDB will help to inform the most appropriate way forward,” the authors wrote.

The UK Medical Research Council and Arthritis Research UK funded the trial. Zoledronic acid and a placebo were supplied by Novartis. Dr. Ralston reported funding to his institution from Kyowa Kirin, UCB, the Paget’s Association, and the Royal Osteoporosis Society. Some coauthors reported financial relationships with pharmaceutical companies outside the trial. Dr. Russell had no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Prophylactic treatment with zoledronic acid (ZA) in individuals at high genetic risk for Paget disease of the bone (PDB) can prevent the development or progression of the condition, according to a new study. The authors argued that the positive results from the trial suggest that individuals with a familial history of PDB should undergo genetic screening.

“If it’s positive, you should be able to have a bone scan and take it from there,” senior author Stuart Ralston, MBChB, MD, professor of rheumatology at the University of Edinburgh (Scotland), said in an interview.

Dr. Ralston

PDB is a chronic skeletal growth disorder that affects an estimated 1-3 million people in the United States and is most prevalent in individuals over 65 years old. Symptoms of the disease may not present until later stages when there is already skeletal damage that cannot be resolved by medications. Earlier intervention in individuals who have not yet shown signs of the condition could potentially halt disease progression, Dr. Ralston said.

Genetics plays a substantial role in PDB, especially pathogenic variants of the gene SQSTM1. An estimated 40%-50% of people with a familial history of PDB have these variants, according to the study, which are associated with earlier PDB onset and more severe disease.

However, it was unclear if early interventions in these higher-risk individuals may result in better health outcomes.

In this new study, published on December 20, 2023, in Annals of the Rheumatic Diseases, researchers recruited participants through family members already diagnosed with PDB who received treatment at outpatient clinics. Over 1400 individuals with PDB underwent genetic testing for pathogenic SQSTM1 variants. If they tested positive, their first-degree relatives — primarily children — were offered the same genetic test. In total, 350 relatives tested positive for these pathogenic SQSTM1 variants, and of these individuals, 222 agreed to participate in the trial.

At the beginning of the study, all participants received a radionuclide bone scan to screen for bone lesions. They also underwent testing for the bone resorption marker type I collagen C-terminal telopeptides (CTX) and the bone formation marker procollagen type I amino-terminal propeptide (P1NP).

Participants were then randomized to receive either a single intravenous infusion of 5 mg of ZA or placebo treatment. Researchers followed up with participants annually for a median of 84 months (7 years), and then baseline assessments were repeated.

A total of 90 individuals in the ZA treatment group and 90 individuals in the placebo group completed the trial.

Participants were, on average, 50 years old at the beginning of the study. In the ZA group, nine individuals had lesions detected in bone scans at baseline, compared with just one at the study’s end. In the placebo group, 12 individuals had detectable lesions at baseline, compared with 11 individuals at the study’s end.

While the proportion of individuals with lesions was similar between the two groups, there were about twice as many lesions overall in the placebo group, compared with the ZA group (29 vs 15), which researchers said was by chance. All but two lesions disappeared in the ZA group, compared with 26 lesions remaining in the placebo group (P < .0001).

“The bone scan reversal of abnormalities was amazing,” said Ralston, where eight of nine patients with lesions in the ZA group “had their bone scan evidence completely wiped out,” he said. “That’s a very powerful result.”

Both CTX and P1NP concentrations fell in the ZA group at 12 months and remained significantly lower than the placebo group throughout the study (P < .0001 for each).

Overall, the researchers reported that eight individuals in the placebo group and no individuals in the ZA group had a poor outcome, defined as new bone lesions or lesions that were unchanged or progressed (odds ratio, 0.08; P = .003). Two individuals in the placebo group developed lesions during the study, compared with none in the ZA group, but this difference was not statistically significant.

Importantly, there were no differences in adverse events between the two groups.

While only a small number of people in the study had legions — around 9% of participants — the effect of ZA is “dramatic,” Linda A. Russell, MD, director of the Osteoporosis and Metabolic Bone Health Center at the Hospital for Special Surgery in New York City, told this news organization.

While clinicians primarily diagnose PDB with X-rays or an alkaline phosphatase blood test, testing for SQSTM1 is a new way to understand if someone is at higher risk for the disease, she said.

“Now, it seems like [the test] is fairly easily available, so probably it’s something we can begin to incorporate into our armamentarium,” Dr. Russell said.

Individuals who test positive for pathogenic variants of SQSTM1 could then get a bone scan, while those who tested negative may not need any additional testing, she added.

Dr. Ralston and coauthors noted that the effect size shown in this study is similar to that of studies examining adjuvant bisphosphonate therapy for postmenopausal women with early breast cancer. That practice, they write, is now a part of the standard of care.

“We believe that a similar approach is now justified in people with a family history of PDB who test positive for SQSTM1 mutations,” they wrote.

However, it is not clear if all individuals with pathogenic SQSTM1 should receive ZA treatment or if treatment should be given to only those with bone lesions.

“Future research to gather the views of people with a family history of PDB will help to inform the most appropriate way forward,” the authors wrote.

The UK Medical Research Council and Arthritis Research UK funded the trial. Zoledronic acid and a placebo were supplied by Novartis. Dr. Ralston reported funding to his institution from Kyowa Kirin, UCB, the Paget’s Association, and the Royal Osteoporosis Society. Some coauthors reported financial relationships with pharmaceutical companies outside the trial. Dr. Russell had no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

There’s no question that glucagon-like peptide 1 (GLP-1) agonists represent a major advance in the treatment of obesity for patients with or without diabetes. In clinical trials, participants lost 15%-20% of their body weight, depending on the drug.

But studies also have shown that once people stop taking these drugs — either by choice, because of shortage, or lack of access — they regain most, if not all, the weight they lost.

Arguably more frustrating is the fact that those who continue on the drug eventually reach a plateau, at which point, the body seemingly stubbornly refuses to lose more weight. Essentially, it stabilizes at its set point, said Fatima Cody Stanford, MD, MPH, MPA, MBA, an obesity medicine physician at Massachusetts General Hospital and associate professor at Harvard Medical School in Boston.
 

‘Tug of War’

Every study of weight loss drugs done over the past 40 years or so shows a plateau, Dr. Stanford told this news organization. “If you look at the phentermine/topiramate studies, there’s a plateau. If you look at the bupropion/naltrexone studies, there’s a plateau. Or if we look at bariatric surgery, there’s a plateau. And it’s the same for the newer GLP-1 drugs.”

The reason? “It really depends on where the body gets to,” Dr. Stanford said. “The body knows what it needs to do to maintain itself, and the brain knows where it’s supposed to be. And when you lose weight and reach what you feel is a lower set point, the body resists.”

When the body goes below its set point, the hunger hormone ghrelin, which is housed in the brain, gets reactivated and gradually starts to reemerge, she explained. GLP-1, which is housed in the distal portion of the small intestine and in the colon, also starts to reemerge over time.

“It becomes kind of a tug of war” between the body and whatever weight loss strategy is being implemented, from drugs to surgery to lifestyle changes, Dr. Stanford said. “The patient will start to notice changes in how their body is responding. Usually, they’ll say they don’t feel like the treatment is working the same. But the treatment is working the same as it’s always been working — except their body is now acclimated to it.”

Anne L. Peters, MD, CDE, professor and clinical scholar, Keck School of Medicine of the University of Southern California, and director, agreed that in the simplest terms, a plateau occurs because “the body becomes more and more used to” the weight loss intervention.

However, when you lose weight, you lose both fat mass and lean body mass, and lean body mass is the metabolically active part of your body, explained Dr. Peters. “That’s what burns and basically makes up your basal metabolic rate.”

With weight loss, the metabolism slows down, she said. If patients need 2000 calories a day to survive at a certain weight and then lose 50 pounds, they may then need only a 1000 calories a day. “With any obesity treatment, you reach a point at which your metabolic rate and your daily caloric requirements become equal, and you stop losing weight, even though your daily caloric requirement is less than it was when your weight was higher.”
 

Managing the Plateau

Several strategies can be used to help patients break through a plateau. One is to try multiple weight loss agents with different targets — something often done in the real world, Dr. Stanford said. “You don’t see this in the studies, which are focused on just one drug, but many of our patients are on combination therapy. They’re on a GLP-1 drug plus phentermine/topiramate plus metformin, and more. They’re usually on three, four, five drugs, similar to what we would see with resistant hypertension.”

If a patient plateaus on a GLP-1 drug, Dr. Stanford might add phentermine. When the patient reaches a plateau on phentermine, she would switch again to another agent. “The goal is to use agents that treat different receptors in the brain,” she said. “You would never use two GLP-1 agonists; you would use the GLP-1, and then something that treats norepinephrine, for example.”

At the same time, Dr. Peters noted, “try to get them off the drugs that cause weight gain, like insulin and sulfonylurea agents.”

Tapering the GLP-1 dose can also help, Dr. Peters said. However, she added, “If I’m using a GLP-1 drug for type 2 diabetes, it’s different than if I’m using it just for weight loss. With type 2 diabetes, if you taper too much, the blood sugar and weight will go back up, so you need to reach a balance.”

Dr. Peters has successfully tapered patients from a 2-mg dose down to 1 mg. She has also changed the strategy for some — ie, the patient takes the drug every other week instead of every week. “I even have a patient or two who just take it once a month and that seems to be enough,” she said. “You want to help them be at the dose that maintains their weight and keeps them healthy with the least possible medication.”

Emphasizing lifestyle changes is also important, she said. Although resistance training won’t necessarily help with weight loss, “it’s critical to maintaining lean body mass. If people keep losing and regaining weight, they’re going to lose more and more lean body mass and gain the weight back primarily as fat mass. So, their exercise should include about half aerobic activity and half resistance training.”
 

Long-term Journey

Setting appropriate expectations is a key part of helping patients accept and deal with a plateau. “This is long-term, lifelong journey,” Dr. Stanford said. “We need to think about obesity as a complex, multifactorial chronic disease, like we think about hypertension or type 2 diabetes or hyperlipidemia.”

Furthermore, and in keeping with that perspective, emerging evidence is demonstrating that GLP-1 drugs also have important nonglycemic benefits that can be achieved and maintained, Dr. Peters said. “Obviously weight loss matters, and weight loss is good for you if you’re overweight or obese. But now we know that GLP-1 drugs have wonderful benefits for the heart as well as renal function.” These are reasons to continue the drugs even in the face of a plateau.

One of Dr. Peters’ patients, a physician with type 2 diabetes, had “fought with her weight her whole life. She’s been on one or another GLP-1 drug for more than 15 years, and while none seem to impact her weight, she’s gone from having relatively poorly controlled to now beautifully controlled diabetes,” Dr. Peters said. “Even if she hasn’t lost, she’s maintained her weight, a benefit since people tend to gain weight as they get older, and she hasn’t gained.”

Another patient was disabled, on oxygen, and had recurrent pulmonary embolisms. “She weighed 420 pounds, and I put her on semaglutide because she was too sick to be considered for bariatric surgery.” When that didn’t work, Dr. Peters switched her to tirzepatide, gradually increasing the dose; the patient lost 80 pounds, her emboli are gone, she can walk down the street, and went back to work.

“Part of why she could do that is that she started exercising,” Dr. Peters noted. “She felt so much better from the drug-related weight loss that she began to do things that help enhance weight loss. She became happier because she was no longer homebound.”

This points to another element that can help patients break through a plateau over time, Dr. Peters said — namely, behavioral health. “The more people lose weight, the more they feel better about themselves, and that may mean that they take better care of themselves. The psychological part of this journey is as important as anything else. Not everyone has the same response to these agents, and there are all sorts of issues behind why people are overweight that physicians can’t ignore.

“So, in addition to managing the drugs and lifestyle, it’s important to make sure that people access the behavioral health help they need, and that once they break through a plateau, they don’t develop an eating disorder or go to the opposite extreme and become too thin, which has happened with some of my patients,” she said. “We need to remember that we’re not just giving patients a miraculous weight loss. We’re helping them to be healthier, mentally as well as physically.”

Dr. Stanford disclosed that she had been a consultant for Calibrate, GoodRx, Pfizer, Eli Lilly, Boehringer Ingelheim, Gelesis, Vida Health, Life Force, Ilant Health, Melli Cell, and Novo Nordisk. Dr. Peters disclosed that she had been a consultant for Vertex, Medscape Medical News, and Lilly; received funding from Abbott and Insulet; and had stock options in Omada Health.

A version of this article appeared on Medscape.com.

There’s no question that glucagon-like peptide 1 (GLP-1) agonists represent a major advance in the treatment of obesity for patients with or without diabetes. In clinical trials, participants lost 15%-20% of their body weight, depending on the drug.

But studies also have shown that once people stop taking these drugs — either by choice, because of shortage, or lack of access — they regain most, if not all, the weight they lost.

Arguably more frustrating is the fact that those who continue on the drug eventually reach a plateau, at which point, the body seemingly stubbornly refuses to lose more weight. Essentially, it stabilizes at its set point, said Fatima Cody Stanford, MD, MPH, MPA, MBA, an obesity medicine physician at Massachusetts General Hospital and associate professor at Harvard Medical School in Boston.
 

‘Tug of War’

Every study of weight loss drugs done over the past 40 years or so shows a plateau, Dr. Stanford told this news organization. “If you look at the phentermine/topiramate studies, there’s a plateau. If you look at the bupropion/naltrexone studies, there’s a plateau. Or if we look at bariatric surgery, there’s a plateau. And it’s the same for the newer GLP-1 drugs.”

The reason? “It really depends on where the body gets to,” Dr. Stanford said. “The body knows what it needs to do to maintain itself, and the brain knows where it’s supposed to be. And when you lose weight and reach what you feel is a lower set point, the body resists.”

When the body goes below its set point, the hunger hormone ghrelin, which is housed in the brain, gets reactivated and gradually starts to reemerge, she explained. GLP-1, which is housed in the distal portion of the small intestine and in the colon, also starts to reemerge over time.

“It becomes kind of a tug of war” between the body and whatever weight loss strategy is being implemented, from drugs to surgery to lifestyle changes, Dr. Stanford said. “The patient will start to notice changes in how their body is responding. Usually, they’ll say they don’t feel like the treatment is working the same. But the treatment is working the same as it’s always been working — except their body is now acclimated to it.”

Anne L. Peters, MD, CDE, professor and clinical scholar, Keck School of Medicine of the University of Southern California, and director, agreed that in the simplest terms, a plateau occurs because “the body becomes more and more used to” the weight loss intervention.

However, when you lose weight, you lose both fat mass and lean body mass, and lean body mass is the metabolically active part of your body, explained Dr. Peters. “That’s what burns and basically makes up your basal metabolic rate.”

With weight loss, the metabolism slows down, she said. If patients need 2000 calories a day to survive at a certain weight and then lose 50 pounds, they may then need only a 1000 calories a day. “With any obesity treatment, you reach a point at which your metabolic rate and your daily caloric requirements become equal, and you stop losing weight, even though your daily caloric requirement is less than it was when your weight was higher.”
 

Managing the Plateau

Several strategies can be used to help patients break through a plateau. One is to try multiple weight loss agents with different targets — something often done in the real world, Dr. Stanford said. “You don’t see this in the studies, which are focused on just one drug, but many of our patients are on combination therapy. They’re on a GLP-1 drug plus phentermine/topiramate plus metformin, and more. They’re usually on three, four, five drugs, similar to what we would see with resistant hypertension.”

If a patient plateaus on a GLP-1 drug, Dr. Stanford might add phentermine. When the patient reaches a plateau on phentermine, she would switch again to another agent. “The goal is to use agents that treat different receptors in the brain,” she said. “You would never use two GLP-1 agonists; you would use the GLP-1, and then something that treats norepinephrine, for example.”

At the same time, Dr. Peters noted, “try to get them off the drugs that cause weight gain, like insulin and sulfonylurea agents.”

Tapering the GLP-1 dose can also help, Dr. Peters said. However, she added, “If I’m using a GLP-1 drug for type 2 diabetes, it’s different than if I’m using it just for weight loss. With type 2 diabetes, if you taper too much, the blood sugar and weight will go back up, so you need to reach a balance.”

Dr. Peters has successfully tapered patients from a 2-mg dose down to 1 mg. She has also changed the strategy for some — ie, the patient takes the drug every other week instead of every week. “I even have a patient or two who just take it once a month and that seems to be enough,” she said. “You want to help them be at the dose that maintains their weight and keeps them healthy with the least possible medication.”

Emphasizing lifestyle changes is also important, she said. Although resistance training won’t necessarily help with weight loss, “it’s critical to maintaining lean body mass. If people keep losing and regaining weight, they’re going to lose more and more lean body mass and gain the weight back primarily as fat mass. So, their exercise should include about half aerobic activity and half resistance training.”
 

Long-term Journey

Setting appropriate expectations is a key part of helping patients accept and deal with a plateau. “This is long-term, lifelong journey,” Dr. Stanford said. “We need to think about obesity as a complex, multifactorial chronic disease, like we think about hypertension or type 2 diabetes or hyperlipidemia.”

Furthermore, and in keeping with that perspective, emerging evidence is demonstrating that GLP-1 drugs also have important nonglycemic benefits that can be achieved and maintained, Dr. Peters said. “Obviously weight loss matters, and weight loss is good for you if you’re overweight or obese. But now we know that GLP-1 drugs have wonderful benefits for the heart as well as renal function.” These are reasons to continue the drugs even in the face of a plateau.

One of Dr. Peters’ patients, a physician with type 2 diabetes, had “fought with her weight her whole life. She’s been on one or another GLP-1 drug for more than 15 years, and while none seem to impact her weight, she’s gone from having relatively poorly controlled to now beautifully controlled diabetes,” Dr. Peters said. “Even if she hasn’t lost, she’s maintained her weight, a benefit since people tend to gain weight as they get older, and she hasn’t gained.”

Another patient was disabled, on oxygen, and had recurrent pulmonary embolisms. “She weighed 420 pounds, and I put her on semaglutide because she was too sick to be considered for bariatric surgery.” When that didn’t work, Dr. Peters switched her to tirzepatide, gradually increasing the dose; the patient lost 80 pounds, her emboli are gone, she can walk down the street, and went back to work.

“Part of why she could do that is that she started exercising,” Dr. Peters noted. “She felt so much better from the drug-related weight loss that she began to do things that help enhance weight loss. She became happier because she was no longer homebound.”

This points to another element that can help patients break through a plateau over time, Dr. Peters said — namely, behavioral health. “The more people lose weight, the more they feel better about themselves, and that may mean that they take better care of themselves. The psychological part of this journey is as important as anything else. Not everyone has the same response to these agents, and there are all sorts of issues behind why people are overweight that physicians can’t ignore.

“So, in addition to managing the drugs and lifestyle, it’s important to make sure that people access the behavioral health help they need, and that once they break through a plateau, they don’t develop an eating disorder or go to the opposite extreme and become too thin, which has happened with some of my patients,” she said. “We need to remember that we’re not just giving patients a miraculous weight loss. We’re helping them to be healthier, mentally as well as physically.”

Dr. Stanford disclosed that she had been a consultant for Calibrate, GoodRx, Pfizer, Eli Lilly, Boehringer Ingelheim, Gelesis, Vida Health, Life Force, Ilant Health, Melli Cell, and Novo Nordisk. Dr. Peters disclosed that she had been a consultant for Vertex, Medscape Medical News, and Lilly; received funding from Abbott and Insulet; and had stock options in Omada Health.

A version of this article appeared on Medscape.com.

There’s no question that glucagon-like peptide 1 (GLP-1) agonists represent a major advance in the treatment of obesity for patients with or without diabetes. In clinical trials, participants lost 15%-20% of their body weight, depending on the drug.

But studies also have shown that once people stop taking these drugs — either by choice, because of shortage, or lack of access — they regain most, if not all, the weight they lost.

Arguably more frustrating is the fact that those who continue on the drug eventually reach a plateau, at which point, the body seemingly stubbornly refuses to lose more weight. Essentially, it stabilizes at its set point, said Fatima Cody Stanford, MD, MPH, MPA, MBA, an obesity medicine physician at Massachusetts General Hospital and associate professor at Harvard Medical School in Boston.
 

‘Tug of War’

Every study of weight loss drugs done over the past 40 years or so shows a plateau, Dr. Stanford told this news organization. “If you look at the phentermine/topiramate studies, there’s a plateau. If you look at the bupropion/naltrexone studies, there’s a plateau. Or if we look at bariatric surgery, there’s a plateau. And it’s the same for the newer GLP-1 drugs.”

The reason? “It really depends on where the body gets to,” Dr. Stanford said. “The body knows what it needs to do to maintain itself, and the brain knows where it’s supposed to be. And when you lose weight and reach what you feel is a lower set point, the body resists.”

When the body goes below its set point, the hunger hormone ghrelin, which is housed in the brain, gets reactivated and gradually starts to reemerge, she explained. GLP-1, which is housed in the distal portion of the small intestine and in the colon, also starts to reemerge over time.

“It becomes kind of a tug of war” between the body and whatever weight loss strategy is being implemented, from drugs to surgery to lifestyle changes, Dr. Stanford said. “The patient will start to notice changes in how their body is responding. Usually, they’ll say they don’t feel like the treatment is working the same. But the treatment is working the same as it’s always been working — except their body is now acclimated to it.”

Anne L. Peters, MD, CDE, professor and clinical scholar, Keck School of Medicine of the University of Southern California, and director, agreed that in the simplest terms, a plateau occurs because “the body becomes more and more used to” the weight loss intervention.

However, when you lose weight, you lose both fat mass and lean body mass, and lean body mass is the metabolically active part of your body, explained Dr. Peters. “That’s what burns and basically makes up your basal metabolic rate.”

With weight loss, the metabolism slows down, she said. If patients need 2000 calories a day to survive at a certain weight and then lose 50 pounds, they may then need only a 1000 calories a day. “With any obesity treatment, you reach a point at which your metabolic rate and your daily caloric requirements become equal, and you stop losing weight, even though your daily caloric requirement is less than it was when your weight was higher.”
 

Managing the Plateau

Several strategies can be used to help patients break through a plateau. One is to try multiple weight loss agents with different targets — something often done in the real world, Dr. Stanford said. “You don’t see this in the studies, which are focused on just one drug, but many of our patients are on combination therapy. They’re on a GLP-1 drug plus phentermine/topiramate plus metformin, and more. They’re usually on three, four, five drugs, similar to what we would see with resistant hypertension.”

If a patient plateaus on a GLP-1 drug, Dr. Stanford might add phentermine. When the patient reaches a plateau on phentermine, she would switch again to another agent. “The goal is to use agents that treat different receptors in the brain,” she said. “You would never use two GLP-1 agonists; you would use the GLP-1, and then something that treats norepinephrine, for example.”

At the same time, Dr. Peters noted, “try to get them off the drugs that cause weight gain, like insulin and sulfonylurea agents.”

Tapering the GLP-1 dose can also help, Dr. Peters said. However, she added, “If I’m using a GLP-1 drug for type 2 diabetes, it’s different than if I’m using it just for weight loss. With type 2 diabetes, if you taper too much, the blood sugar and weight will go back up, so you need to reach a balance.”

Dr. Peters has successfully tapered patients from a 2-mg dose down to 1 mg. She has also changed the strategy for some — ie, the patient takes the drug every other week instead of every week. “I even have a patient or two who just take it once a month and that seems to be enough,” she said. “You want to help them be at the dose that maintains their weight and keeps them healthy with the least possible medication.”

Emphasizing lifestyle changes is also important, she said. Although resistance training won’t necessarily help with weight loss, “it’s critical to maintaining lean body mass. If people keep losing and regaining weight, they’re going to lose more and more lean body mass and gain the weight back primarily as fat mass. So, their exercise should include about half aerobic activity and half resistance training.”
 

Long-term Journey

Setting appropriate expectations is a key part of helping patients accept and deal with a plateau. “This is long-term, lifelong journey,” Dr. Stanford said. “We need to think about obesity as a complex, multifactorial chronic disease, like we think about hypertension or type 2 diabetes or hyperlipidemia.”

Furthermore, and in keeping with that perspective, emerging evidence is demonstrating that GLP-1 drugs also have important nonglycemic benefits that can be achieved and maintained, Dr. Peters said. “Obviously weight loss matters, and weight loss is good for you if you’re overweight or obese. But now we know that GLP-1 drugs have wonderful benefits for the heart as well as renal function.” These are reasons to continue the drugs even in the face of a plateau.

One of Dr. Peters’ patients, a physician with type 2 diabetes, had “fought with her weight her whole life. She’s been on one or another GLP-1 drug for more than 15 years, and while none seem to impact her weight, she’s gone from having relatively poorly controlled to now beautifully controlled diabetes,” Dr. Peters said. “Even if she hasn’t lost, she’s maintained her weight, a benefit since people tend to gain weight as they get older, and she hasn’t gained.”

Another patient was disabled, on oxygen, and had recurrent pulmonary embolisms. “She weighed 420 pounds, and I put her on semaglutide because she was too sick to be considered for bariatric surgery.” When that didn’t work, Dr. Peters switched her to tirzepatide, gradually increasing the dose; the patient lost 80 pounds, her emboli are gone, she can walk down the street, and went back to work.

“Part of why she could do that is that she started exercising,” Dr. Peters noted. “She felt so much better from the drug-related weight loss that she began to do things that help enhance weight loss. She became happier because she was no longer homebound.”

This points to another element that can help patients break through a plateau over time, Dr. Peters said — namely, behavioral health. “The more people lose weight, the more they feel better about themselves, and that may mean that they take better care of themselves. The psychological part of this journey is as important as anything else. Not everyone has the same response to these agents, and there are all sorts of issues behind why people are overweight that physicians can’t ignore.

“So, in addition to managing the drugs and lifestyle, it’s important to make sure that people access the behavioral health help they need, and that once they break through a plateau, they don’t develop an eating disorder or go to the opposite extreme and become too thin, which has happened with some of my patients,” she said. “We need to remember that we’re not just giving patients a miraculous weight loss. We’re helping them to be healthier, mentally as well as physically.”

Dr. Stanford disclosed that she had been a consultant for Calibrate, GoodRx, Pfizer, Eli Lilly, Boehringer Ingelheim, Gelesis, Vida Health, Life Force, Ilant Health, Melli Cell, and Novo Nordisk. Dr. Peters disclosed that she had been a consultant for Vertex, Medscape Medical News, and Lilly; received funding from Abbott and Insulet; and had stock options in Omada Health.

A version of this article appeared on Medscape.com.

The relationship between lipid levels and the development of dementia is an evolving but confusing landscape.

“This is an incredibly complex area, and there really isn’t a clear consensus on this subject because different lipid classes reflect different things,” according to Betsy Mills, PhD, assistant director of aging and Alzheimer’s prevention at the Alzheimer’s Drug Discovery Foundation.

Some studies suggest that excessive lipid levels may increase the risk of developing dementia and Alzheimer’s disease (AD). Others imply that elevated low-density lipoprotein (LDL) cholesterol or even triglycerides may offer some protection against subsequent dementia whereas higher levels of high-density lipoprotein (HDL) cholesterol, hitherto thought to be protective, may have a deleterious effect.

“It depends on what lipids you’re measuring, what you’re using to measure those lipids, what age the person is, and multiple other factors,” Dr. Mills told this news organization.

Teasing out the variables and potential mechanisms for the association between lipids and dementia risk necessitates understanding the role that lipids play in the healthy brain, the negative impact of brain lipid dysregulation, and the interplay between cholesterol in the central nervous system (CNS) and the cholesterol in the rest of the body.

 

Beyond Amyloid

The role of lipids in AD risk has historically been “overlooked,” says Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida.

“The common narrative is that amyloid is the culprit in AD and certainly that’s the case in familial AD,” he told this news organization. “It’s been assumed that because amyloid deposits are also found in the brains of people with late-onset AD — which is the vast majority of cases — amyloid is the cause, but that’s not clear at all.”

The “limited clinical success” of aducanumab, its “extremely small efficacy” — despite its obvious success in eradicating the amyloid plaques — suggests there’s “much more to the story than amyloid.”

He and a growing community of scientists recognize the role of inflammation and lipids. “The major finding of my lab is that cholesterol actually drives the synthesis of amyloid via inflammation. In other words, amyloid is downstream of cholesterol. Cholesterol drives the inflammation, and the inflammation drives amyloid,” he said.
 

‘Lipid Invasion Model’

Because the brain is an incredibly lipid-rich organ, Dr. Mills said that “any dysregulation in lipid homeostasis will impact the brain because cholesterol is needed for the myelin sheaths, cell membranes, and other functions.”

A healthy brain relies upon healthy lipid regulation, and “since the first description of AD over 100 years ago, the disease has been associated with altered lipids in the brain,” Dr. Hansen noted.

He cited the “ lipid invasion model” as a way of understanding brain lipid dysregulation. This hypothesis posits that AD is driven by external lipids that enter the brain as a result of damage to the blood-brain barrier (BBB).

“Cholesterol in the brain and cholesterol in the periphery — meaning, in the rest of the body, outside the brain — are separate,” Dr. Hansen explained. “The brain produces its own cholesterol and keeps tight control of it.”

Under normal circumstances, cholesterol from the diet doesn’t enter the brain. “Each pool of cholesterol — in the brain and in the periphery — has its own distinct regulatory mechanisms, target cells, and transport mechanisms.”

When the BBB has been compromised, it becomes permeable, allowing LDL cholesterol to enter the brain, said Dr. Hansen. Then the brain’s own lipoproteins transport the invading cholesterol, allowing it to be taken up by neurons. In turn, this causes neuronal amyloid levels to rise, ultimately leading to the creation of amyloid-b plaques. It also plays a role in tau phosphorylation. Both are key features of AD pathology.

Elevated levels of cholesterol and other lipids have been found in amyloid plaques, Dr. Hansen noted. Moreover, studies of brains of patients with AD have pointed to BBB damage.

And the risk factors for AD overlap with the risk factors for damage to the BBB (such as, aging, brain trauma, hypertension, stress, sleep deprivation, smoking, excess alcohol, obesity, diabetes, and APOE4 genotype), according to the lipid invasion model paper cited by Dr. Hansen.
 

‘Chicken and Egg’

“There is a strong link between the brain and the heart, and we know that cardiovascular risk factors have an overlap with dementia risk factors — especially vascular dementia,” said Dr. Mills. 

She explained that an atherogenic lipid profile results in narrowing of the arteries, with less blood reaching the brain. “This can lead to stress in the brain, which drives inflammation and pathology.”

But cholesterol itself plays an important role in inflammation, Dr. Hansen said. In the periphery, it is “part of an integral response to tissue damage and infection.”

In the brain, once cholesterol is synthesized by the astrocytes, it is transported to neurons via the apolipoprotein E (APOE) protein, which plays a role in brain cholesterol homeostasis, Dr. Mills explained. Those with the ε4 allele of APOE (APOE4) tend to have faultier transport and storage of lipids in the brain, relative to the other APOE variants.

It’s known that individuals with APOE4 are particularly vulnerable to late-onset AD, Dr. Hansen observed. By contrast, APOE2 has a more protective effect. “Most people have APOE3, which is ‘in between,’ ” he said.

When there is neuronal uptake of “invading cholesterol,” not only is amyloid produced but also neuroinflammatory cytokines, further driving inflammation. A vicious cycle ensues: Cholesterol induces cytokine release; and cytokine release, in turn, induces cholesterol synthesis — which “suggests an autocatalytic function of cholesterol in the escalation of inflammation,” Dr. Hansen suggested. He noted that permeability of the BBB also allows inflammatory cytokines from elsewhere in the body to invade the brain, further driving inflammation.

Dr. Mills elaborated: “We know that generally, in dementia, there appear to be some changes in cholesterol metabolism in the brain, but it’s a chicken-and-egg question. We know that as the disease progresses, neurons are dying and getting remodeled. Do these changes have to do with the degenerative process, or are the changes in the cholesterol metabolism actually driving the degenerative disease process? It’s probably a combination, but it’s unclear at this point.”
 

Lipids in Plasma vs CSF

Dr. Mills explained that HDL particles in the brain differ from those in the periphery. “In the CNS, you have ‘HDL-like particles,’ which are similar in size and composition [to HDL in the periphery] but aren’t the same particles.” The brain itself generates HDL-like lipoproteins, which are produced by astrocytes and other glial cells and found in cerebrospinal fluid (CSF).

Dyslipidemia in the periphery can be a marker for cardiovascular pathology. In the brain, “it can be an indication that there is active damage going on, depending on which compartment you’re looking at.”

She noted that plasma lipid levels and brain CSF lipid levels are “very different.” Research suggests that HDL in the CSF exhibits similar heterogeneity to plasma HDL, but these CSF lipoproteins present at 100-fold lower concentrations, compared to plasma HDL and have unique combinations of protein subpopulations. Lipidomics analysis studies show that these compartments “get very different readings, in terms of the predominant lipid disease state, and they are regulated differently from the way lipids in the periphery are regulated.” 

In the brain, the cholesterol “needs to get shuttled from glial cells to neurons,” so defects in the transport process can disrupt overall brain homeostasis, said Dr. Mills. But since the brain system is separate from the peripheral system, measuring plasma lipids is more likely to point to cardiovascular risks, while changes reflected in CSF lipids are “more indicative of alteration in lipid homeostasis in the brain.”
 

HDL and Triglycerides: A Complicated Story

Dr. Mills noted that HDL in the periphery is “very complicated,” and the idea that HDL, as a measure on its own, is “necessarily ‘good’ isn’t particularly informative.” Rather, HDL is “extremely heterogeneous, very diverse, has different lipid compositions, different classes, and different modifications.” For example, like oxidized LDL, oxidized HDL is also “bad,” preventing the HDL from having protective functions.

Similarly, the apolipoproteins associated with HDL can affect the function of the HDL. “Our understanding of the HDL-like particles in the CNS is limited, but we do understand the APOE4 link,” Dr. Mills said. “It seems that the HDL-like particles containing APOE2 or APOE3 are larger and are more effective at transferring the lipids and cholesterol linked to them relative to APOE4-containing particles.” 

Because HDL is more complex than simply being “good,” measuring HDL doesn’t “give you the full story,” said Dr. Mills. She speculates that this may be why there are studies suggesting that high levels of HDL might not have protective benefits and might even be detrimental. This makes it difficult to look at population studies, where the different subclasses of HDL are not necessarily captured in depth. 

Dr. Mills pointed to another confounding factor, which is that much of the risk for the development of AD appears to be related to the interaction of HDL, LDL, and triglycerides. “When you look at each of these individually, you get a lot of heterogeneity, and it’s unclear what’s driving what,” she said.

An advantage of observational studies is that they give information about which of these markers are associated with trends and disease risks in specific groups vs others. 

“For example, higher levels of triglycerides are associated with cardiovascular risk more in women, relative to men,” she said. And the triglyceride-to-HDL ratio seems “particularly robust” as a measure of cardiovascular health and risk. 

The interpretation of associations with triglycerides can be “tricky” and “confusing” because results differ so much between studies, she said. “There are differences between middle age and older age, which have to do with age-related changes in metabolism and lipid metabolism and not necessarily that the markers are indicating something different,” she said.

Some research has suggested that triglycerides may have a protective effect against dementia, noted Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and director of nutritional psychiatry at MGH Academy.

This may be because the brain “runs mostly on energy from burning triglycerides,” suggested Dr. Naidoo, author of the books Calm Your Mind With Food and This Is Your Brain on Food.

In addition, having higher levels of triglycerides may be linked with having overall healthier behaviors, Dr. Naidoo told this news organization.

Dr. Mills said that in middle-aged individuals, high levels of LDL-C and triglycerides are “often indicative of more atherogenic particles and risk to cardiovascular health, which is a generally negative trajectory. But in older individuals, things become more complicated because there are differences in terms of clearance of some of these particles, tissue clearance and distribution, and nutrient status. So for older individuals, it seems that fluctuations in either direction—either too high or too low—tend to be more informative that some overall dysregulation is going on the system.” 

She emphasized that, in this “emerging area, looking at only one or two studies is confusing. But if you look at the spectrum of studies, you can see a pattern, which is that the regulation gets ‘off,’ as people age.”

 

The Potential Role of Statins

Dr. Mills speculated that there may be “neuroprotective benefits for some of the statins which appear to be related to cardiovascular benefits. But at this point, we don’t have any clear data whether statins actually directly impact brain cholesterol, since it’s a separate pool.”

They could help “by increasing blood flow and reducing narrowing of the arteries, but any direct impact on the brain is still under investigation.”

Dr. Hansen pointed to research suggesting statins taken at midlife appear to be cardioprotective and may be protective of brain health as well, whereas statins initiated in older age do not appear to have these benefits.

He speculated that one reason statins seem less helpful when initiated later in life is that the BBB has already been damaged by systemic inflammation in the periphery, and the neuroinflammatory process resulting in neuronal destruction is already underway. “I think statins aren’t going to fix that problem, so although lowering cholesterol can be helpful in some respects, it might be too late to affect cognition because the nerves have already died and won’t grow back.”
 

Can Dietary Approaches Help?

Dr. Naidoo said that when looking at neurologic and psychiatric disease, “it’s important to think about the ‘long game’ — how can we improve our blood and cardiovascular health earlier in life to help potentiate healthy aging?”

From a nutritional psychiatry standpoint, Dr. Naidoo focuses on nourishing the gut microbiome and decreasing inflammation. “A healthy and balanced microbiome supports cognition, while the composition of gut bacteria is actually drastically different in patients with neurological diseases, such as AD.” 

She recommends a nutrient-dense, anti-inflammatory diet including probiotic-rich foods (such as kimchi, sauerkraut, plain yogurt, and miso). Moreover, “the quality and structure of our fatty acids may be relevant as well: Increasing our intake of polyunsaturated fatty acids and avoiding processed fats like trans fats and hydrogenated oils may benefit our overall brain health.”

Dr. Naidoo recommends extra-virgin olive oil as a source of healthy fat. Its consumption is linked to lower incidence of AD by way of encouraging autophagy, which she calls “our own process of “cellular cleanup.’”

Dr. Naidoo believes that clinicians’ guidance to patients should “focus on healthy nutrition and other lifestyle practices, such as exercise, outdoor time, good sleep, and stress reduction.” 

Dr. Mills notes the importance of omega-3 fatty acids, such as docosahexaenoic acid (DHA) , for brain health. “DHA is a major lipid component of neuronal membranes,” she said. “Because of inefficiencies in metabolism with APOE4, people tend to metabolize more of the lipids on the membranes themselves, so they have higher lipid membrane turnover and a greater need to supplement. Supplementing particularly through diet, with foods such as fatty fish rich in omega-3, can help boost the levels to help keep neuronal membranes intact.”
 

What This Means for the Clinician

“At this point, we see all of these associations between lipids and dementia, but we haven’t worked out exactly what it means on the individual level for an individual patient,” said Dr. Mills. Certainly, the picture is complex, and the understanding is growing and shifting. “The clinical applications remain unclear.”

One potential clinical take-home is that clinicians might consider tracking lipid levels over time. “If you follow a patient and see an increase or decrease [in lipid levels], that can be informative.” Looking at ratios of lipids might be more useful than looking only at a change in a single measure. “If you see trends in a variety of measures that track with one another, it might be more of a sign that something is potentially wrong.” 

Whether the patient should first try a lifestyle intervention or might need medication is a “personalized clinical decision, depending on the individual, their risk factors, and how their levels are going,” said Dr. Mills. 

Dr. Mills, Dr. Hansen, and Dr. Naidoo declared no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

The relationship between lipid levels and the development of dementia is an evolving but confusing landscape.

“This is an incredibly complex area, and there really isn’t a clear consensus on this subject because different lipid classes reflect different things,” according to Betsy Mills, PhD, assistant director of aging and Alzheimer’s prevention at the Alzheimer’s Drug Discovery Foundation.

Some studies suggest that excessive lipid levels may increase the risk of developing dementia and Alzheimer’s disease (AD). Others imply that elevated low-density lipoprotein (LDL) cholesterol or even triglycerides may offer some protection against subsequent dementia whereas higher levels of high-density lipoprotein (HDL) cholesterol, hitherto thought to be protective, may have a deleterious effect.

“It depends on what lipids you’re measuring, what you’re using to measure those lipids, what age the person is, and multiple other factors,” Dr. Mills told this news organization.

Teasing out the variables and potential mechanisms for the association between lipids and dementia risk necessitates understanding the role that lipids play in the healthy brain, the negative impact of brain lipid dysregulation, and the interplay between cholesterol in the central nervous system (CNS) and the cholesterol in the rest of the body.

 

Beyond Amyloid

The role of lipids in AD risk has historically been “overlooked,” says Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida.

“The common narrative is that amyloid is the culprit in AD and certainly that’s the case in familial AD,” he told this news organization. “It’s been assumed that because amyloid deposits are also found in the brains of people with late-onset AD — which is the vast majority of cases — amyloid is the cause, but that’s not clear at all.”

The “limited clinical success” of aducanumab, its “extremely small efficacy” — despite its obvious success in eradicating the amyloid plaques — suggests there’s “much more to the story than amyloid.”

He and a growing community of scientists recognize the role of inflammation and lipids. “The major finding of my lab is that cholesterol actually drives the synthesis of amyloid via inflammation. In other words, amyloid is downstream of cholesterol. Cholesterol drives the inflammation, and the inflammation drives amyloid,” he said.
 

‘Lipid Invasion Model’

Because the brain is an incredibly lipid-rich organ, Dr. Mills said that “any dysregulation in lipid homeostasis will impact the brain because cholesterol is needed for the myelin sheaths, cell membranes, and other functions.”

A healthy brain relies upon healthy lipid regulation, and “since the first description of AD over 100 years ago, the disease has been associated with altered lipids in the brain,” Dr. Hansen noted.

He cited the “ lipid invasion model” as a way of understanding brain lipid dysregulation. This hypothesis posits that AD is driven by external lipids that enter the brain as a result of damage to the blood-brain barrier (BBB).

“Cholesterol in the brain and cholesterol in the periphery — meaning, in the rest of the body, outside the brain — are separate,” Dr. Hansen explained. “The brain produces its own cholesterol and keeps tight control of it.”

Under normal circumstances, cholesterol from the diet doesn’t enter the brain. “Each pool of cholesterol — in the brain and in the periphery — has its own distinct regulatory mechanisms, target cells, and transport mechanisms.”

When the BBB has been compromised, it becomes permeable, allowing LDL cholesterol to enter the brain, said Dr. Hansen. Then the brain’s own lipoproteins transport the invading cholesterol, allowing it to be taken up by neurons. In turn, this causes neuronal amyloid levels to rise, ultimately leading to the creation of amyloid-b plaques. It also plays a role in tau phosphorylation. Both are key features of AD pathology.

Elevated levels of cholesterol and other lipids have been found in amyloid plaques, Dr. Hansen noted. Moreover, studies of brains of patients with AD have pointed to BBB damage.

And the risk factors for AD overlap with the risk factors for damage to the BBB (such as, aging, brain trauma, hypertension, stress, sleep deprivation, smoking, excess alcohol, obesity, diabetes, and APOE4 genotype), according to the lipid invasion model paper cited by Dr. Hansen.
 

‘Chicken and Egg’

“There is a strong link between the brain and the heart, and we know that cardiovascular risk factors have an overlap with dementia risk factors — especially vascular dementia,” said Dr. Mills. 

She explained that an atherogenic lipid profile results in narrowing of the arteries, with less blood reaching the brain. “This can lead to stress in the brain, which drives inflammation and pathology.”

But cholesterol itself plays an important role in inflammation, Dr. Hansen said. In the periphery, it is “part of an integral response to tissue damage and infection.”

In the brain, once cholesterol is synthesized by the astrocytes, it is transported to neurons via the apolipoprotein E (APOE) protein, which plays a role in brain cholesterol homeostasis, Dr. Mills explained. Those with the ε4 allele of APOE (APOE4) tend to have faultier transport and storage of lipids in the brain, relative to the other APOE variants.

It’s known that individuals with APOE4 are particularly vulnerable to late-onset AD, Dr. Hansen observed. By contrast, APOE2 has a more protective effect. “Most people have APOE3, which is ‘in between,’ ” he said.

When there is neuronal uptake of “invading cholesterol,” not only is amyloid produced but also neuroinflammatory cytokines, further driving inflammation. A vicious cycle ensues: Cholesterol induces cytokine release; and cytokine release, in turn, induces cholesterol synthesis — which “suggests an autocatalytic function of cholesterol in the escalation of inflammation,” Dr. Hansen suggested. He noted that permeability of the BBB also allows inflammatory cytokines from elsewhere in the body to invade the brain, further driving inflammation.

Dr. Mills elaborated: “We know that generally, in dementia, there appear to be some changes in cholesterol metabolism in the brain, but it’s a chicken-and-egg question. We know that as the disease progresses, neurons are dying and getting remodeled. Do these changes have to do with the degenerative process, or are the changes in the cholesterol metabolism actually driving the degenerative disease process? It’s probably a combination, but it’s unclear at this point.”
 

Lipids in Plasma vs CSF

Dr. Mills explained that HDL particles in the brain differ from those in the periphery. “In the CNS, you have ‘HDL-like particles,’ which are similar in size and composition [to HDL in the periphery] but aren’t the same particles.” The brain itself generates HDL-like lipoproteins, which are produced by astrocytes and other glial cells and found in cerebrospinal fluid (CSF).

Dyslipidemia in the periphery can be a marker for cardiovascular pathology. In the brain, “it can be an indication that there is active damage going on, depending on which compartment you’re looking at.”

She noted that plasma lipid levels and brain CSF lipid levels are “very different.” Research suggests that HDL in the CSF exhibits similar heterogeneity to plasma HDL, but these CSF lipoproteins present at 100-fold lower concentrations, compared to plasma HDL and have unique combinations of protein subpopulations. Lipidomics analysis studies show that these compartments “get very different readings, in terms of the predominant lipid disease state, and they are regulated differently from the way lipids in the periphery are regulated.” 

In the brain, the cholesterol “needs to get shuttled from glial cells to neurons,” so defects in the transport process can disrupt overall brain homeostasis, said Dr. Mills. But since the brain system is separate from the peripheral system, measuring plasma lipids is more likely to point to cardiovascular risks, while changes reflected in CSF lipids are “more indicative of alteration in lipid homeostasis in the brain.”
 

HDL and Triglycerides: A Complicated Story

Dr. Mills noted that HDL in the periphery is “very complicated,” and the idea that HDL, as a measure on its own, is “necessarily ‘good’ isn’t particularly informative.” Rather, HDL is “extremely heterogeneous, very diverse, has different lipid compositions, different classes, and different modifications.” For example, like oxidized LDL, oxidized HDL is also “bad,” preventing the HDL from having protective functions.

Similarly, the apolipoproteins associated with HDL can affect the function of the HDL. “Our understanding of the HDL-like particles in the CNS is limited, but we do understand the APOE4 link,” Dr. Mills said. “It seems that the HDL-like particles containing APOE2 or APOE3 are larger and are more effective at transferring the lipids and cholesterol linked to them relative to APOE4-containing particles.” 

Because HDL is more complex than simply being “good,” measuring HDL doesn’t “give you the full story,” said Dr. Mills. She speculates that this may be why there are studies suggesting that high levels of HDL might not have protective benefits and might even be detrimental. This makes it difficult to look at population studies, where the different subclasses of HDL are not necessarily captured in depth. 

Dr. Mills pointed to another confounding factor, which is that much of the risk for the development of AD appears to be related to the interaction of HDL, LDL, and triglycerides. “When you look at each of these individually, you get a lot of heterogeneity, and it’s unclear what’s driving what,” she said.

An advantage of observational studies is that they give information about which of these markers are associated with trends and disease risks in specific groups vs others. 

“For example, higher levels of triglycerides are associated with cardiovascular risk more in women, relative to men,” she said. And the triglyceride-to-HDL ratio seems “particularly robust” as a measure of cardiovascular health and risk. 

The interpretation of associations with triglycerides can be “tricky” and “confusing” because results differ so much between studies, she said. “There are differences between middle age and older age, which have to do with age-related changes in metabolism and lipid metabolism and not necessarily that the markers are indicating something different,” she said.

Some research has suggested that triglycerides may have a protective effect against dementia, noted Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and director of nutritional psychiatry at MGH Academy.

This may be because the brain “runs mostly on energy from burning triglycerides,” suggested Dr. Naidoo, author of the books Calm Your Mind With Food and This Is Your Brain on Food.

In addition, having higher levels of triglycerides may be linked with having overall healthier behaviors, Dr. Naidoo told this news organization.

Dr. Mills said that in middle-aged individuals, high levels of LDL-C and triglycerides are “often indicative of more atherogenic particles and risk to cardiovascular health, which is a generally negative trajectory. But in older individuals, things become more complicated because there are differences in terms of clearance of some of these particles, tissue clearance and distribution, and nutrient status. So for older individuals, it seems that fluctuations in either direction—either too high or too low—tend to be more informative that some overall dysregulation is going on the system.” 

She emphasized that, in this “emerging area, looking at only one or two studies is confusing. But if you look at the spectrum of studies, you can see a pattern, which is that the regulation gets ‘off,’ as people age.”

 

The Potential Role of Statins

Dr. Mills speculated that there may be “neuroprotective benefits for some of the statins which appear to be related to cardiovascular benefits. But at this point, we don’t have any clear data whether statins actually directly impact brain cholesterol, since it’s a separate pool.”

They could help “by increasing blood flow and reducing narrowing of the arteries, but any direct impact on the brain is still under investigation.”

Dr. Hansen pointed to research suggesting statins taken at midlife appear to be cardioprotective and may be protective of brain health as well, whereas statins initiated in older age do not appear to have these benefits.

He speculated that one reason statins seem less helpful when initiated later in life is that the BBB has already been damaged by systemic inflammation in the periphery, and the neuroinflammatory process resulting in neuronal destruction is already underway. “I think statins aren’t going to fix that problem, so although lowering cholesterol can be helpful in some respects, it might be too late to affect cognition because the nerves have already died and won’t grow back.”
 

Can Dietary Approaches Help?

Dr. Naidoo said that when looking at neurologic and psychiatric disease, “it’s important to think about the ‘long game’ — how can we improve our blood and cardiovascular health earlier in life to help potentiate healthy aging?”

From a nutritional psychiatry standpoint, Dr. Naidoo focuses on nourishing the gut microbiome and decreasing inflammation. “A healthy and balanced microbiome supports cognition, while the composition of gut bacteria is actually drastically different in patients with neurological diseases, such as AD.” 

She recommends a nutrient-dense, anti-inflammatory diet including probiotic-rich foods (such as kimchi, sauerkraut, plain yogurt, and miso). Moreover, “the quality and structure of our fatty acids may be relevant as well: Increasing our intake of polyunsaturated fatty acids and avoiding processed fats like trans fats and hydrogenated oils may benefit our overall brain health.”

Dr. Naidoo recommends extra-virgin olive oil as a source of healthy fat. Its consumption is linked to lower incidence of AD by way of encouraging autophagy, which she calls “our own process of “cellular cleanup.’”

Dr. Naidoo believes that clinicians’ guidance to patients should “focus on healthy nutrition and other lifestyle practices, such as exercise, outdoor time, good sleep, and stress reduction.” 

Dr. Mills notes the importance of omega-3 fatty acids, such as docosahexaenoic acid (DHA) , for brain health. “DHA is a major lipid component of neuronal membranes,” she said. “Because of inefficiencies in metabolism with APOE4, people tend to metabolize more of the lipids on the membranes themselves, so they have higher lipid membrane turnover and a greater need to supplement. Supplementing particularly through diet, with foods such as fatty fish rich in omega-3, can help boost the levels to help keep neuronal membranes intact.”
 

What This Means for the Clinician

“At this point, we see all of these associations between lipids and dementia, but we haven’t worked out exactly what it means on the individual level for an individual patient,” said Dr. Mills. Certainly, the picture is complex, and the understanding is growing and shifting. “The clinical applications remain unclear.”

One potential clinical take-home is that clinicians might consider tracking lipid levels over time. “If you follow a patient and see an increase or decrease [in lipid levels], that can be informative.” Looking at ratios of lipids might be more useful than looking only at a change in a single measure. “If you see trends in a variety of measures that track with one another, it might be more of a sign that something is potentially wrong.” 

Whether the patient should first try a lifestyle intervention or might need medication is a “personalized clinical decision, depending on the individual, their risk factors, and how their levels are going,” said Dr. Mills. 

Dr. Mills, Dr. Hansen, and Dr. Naidoo declared no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

The relationship between lipid levels and the development of dementia is an evolving but confusing landscape.

“This is an incredibly complex area, and there really isn’t a clear consensus on this subject because different lipid classes reflect different things,” according to Betsy Mills, PhD, assistant director of aging and Alzheimer’s prevention at the Alzheimer’s Drug Discovery Foundation.

Some studies suggest that excessive lipid levels may increase the risk of developing dementia and Alzheimer’s disease (AD). Others imply that elevated low-density lipoprotein (LDL) cholesterol or even triglycerides may offer some protection against subsequent dementia whereas higher levels of high-density lipoprotein (HDL) cholesterol, hitherto thought to be protective, may have a deleterious effect.

“It depends on what lipids you’re measuring, what you’re using to measure those lipids, what age the person is, and multiple other factors,” Dr. Mills told this news organization.

Teasing out the variables and potential mechanisms for the association between lipids and dementia risk necessitates understanding the role that lipids play in the healthy brain, the negative impact of brain lipid dysregulation, and the interplay between cholesterol in the central nervous system (CNS) and the cholesterol in the rest of the body.

 

Beyond Amyloid

The role of lipids in AD risk has historically been “overlooked,” says Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida.

“The common narrative is that amyloid is the culprit in AD and certainly that’s the case in familial AD,” he told this news organization. “It’s been assumed that because amyloid deposits are also found in the brains of people with late-onset AD — which is the vast majority of cases — amyloid is the cause, but that’s not clear at all.”

The “limited clinical success” of aducanumab, its “extremely small efficacy” — despite its obvious success in eradicating the amyloid plaques — suggests there’s “much more to the story than amyloid.”

He and a growing community of scientists recognize the role of inflammation and lipids. “The major finding of my lab is that cholesterol actually drives the synthesis of amyloid via inflammation. In other words, amyloid is downstream of cholesterol. Cholesterol drives the inflammation, and the inflammation drives amyloid,” he said.
 

‘Lipid Invasion Model’

Because the brain is an incredibly lipid-rich organ, Dr. Mills said that “any dysregulation in lipid homeostasis will impact the brain because cholesterol is needed for the myelin sheaths, cell membranes, and other functions.”

A healthy brain relies upon healthy lipid regulation, and “since the first description of AD over 100 years ago, the disease has been associated with altered lipids in the brain,” Dr. Hansen noted.

He cited the “ lipid invasion model” as a way of understanding brain lipid dysregulation. This hypothesis posits that AD is driven by external lipids that enter the brain as a result of damage to the blood-brain barrier (BBB).

“Cholesterol in the brain and cholesterol in the periphery — meaning, in the rest of the body, outside the brain — are separate,” Dr. Hansen explained. “The brain produces its own cholesterol and keeps tight control of it.”

Under normal circumstances, cholesterol from the diet doesn’t enter the brain. “Each pool of cholesterol — in the brain and in the periphery — has its own distinct regulatory mechanisms, target cells, and transport mechanisms.”

When the BBB has been compromised, it becomes permeable, allowing LDL cholesterol to enter the brain, said Dr. Hansen. Then the brain’s own lipoproteins transport the invading cholesterol, allowing it to be taken up by neurons. In turn, this causes neuronal amyloid levels to rise, ultimately leading to the creation of amyloid-b plaques. It also plays a role in tau phosphorylation. Both are key features of AD pathology.

Elevated levels of cholesterol and other lipids have been found in amyloid plaques, Dr. Hansen noted. Moreover, studies of brains of patients with AD have pointed to BBB damage.

And the risk factors for AD overlap with the risk factors for damage to the BBB (such as, aging, brain trauma, hypertension, stress, sleep deprivation, smoking, excess alcohol, obesity, diabetes, and APOE4 genotype), according to the lipid invasion model paper cited by Dr. Hansen.
 

‘Chicken and Egg’

“There is a strong link between the brain and the heart, and we know that cardiovascular risk factors have an overlap with dementia risk factors — especially vascular dementia,” said Dr. Mills. 

She explained that an atherogenic lipid profile results in narrowing of the arteries, with less blood reaching the brain. “This can lead to stress in the brain, which drives inflammation and pathology.”

But cholesterol itself plays an important role in inflammation, Dr. Hansen said. In the periphery, it is “part of an integral response to tissue damage and infection.”

In the brain, once cholesterol is synthesized by the astrocytes, it is transported to neurons via the apolipoprotein E (APOE) protein, which plays a role in brain cholesterol homeostasis, Dr. Mills explained. Those with the ε4 allele of APOE (APOE4) tend to have faultier transport and storage of lipids in the brain, relative to the other APOE variants.

It’s known that individuals with APOE4 are particularly vulnerable to late-onset AD, Dr. Hansen observed. By contrast, APOE2 has a more protective effect. “Most people have APOE3, which is ‘in between,’ ” he said.

When there is neuronal uptake of “invading cholesterol,” not only is amyloid produced but also neuroinflammatory cytokines, further driving inflammation. A vicious cycle ensues: Cholesterol induces cytokine release; and cytokine release, in turn, induces cholesterol synthesis — which “suggests an autocatalytic function of cholesterol in the escalation of inflammation,” Dr. Hansen suggested. He noted that permeability of the BBB also allows inflammatory cytokines from elsewhere in the body to invade the brain, further driving inflammation.

Dr. Mills elaborated: “We know that generally, in dementia, there appear to be some changes in cholesterol metabolism in the brain, but it’s a chicken-and-egg question. We know that as the disease progresses, neurons are dying and getting remodeled. Do these changes have to do with the degenerative process, or are the changes in the cholesterol metabolism actually driving the degenerative disease process? It’s probably a combination, but it’s unclear at this point.”
 

Lipids in Plasma vs CSF

Dr. Mills explained that HDL particles in the brain differ from those in the periphery. “In the CNS, you have ‘HDL-like particles,’ which are similar in size and composition [to HDL in the periphery] but aren’t the same particles.” The brain itself generates HDL-like lipoproteins, which are produced by astrocytes and other glial cells and found in cerebrospinal fluid (CSF).

Dyslipidemia in the periphery can be a marker for cardiovascular pathology. In the brain, “it can be an indication that there is active damage going on, depending on which compartment you’re looking at.”

She noted that plasma lipid levels and brain CSF lipid levels are “very different.” Research suggests that HDL in the CSF exhibits similar heterogeneity to plasma HDL, but these CSF lipoproteins present at 100-fold lower concentrations, compared to plasma HDL and have unique combinations of protein subpopulations. Lipidomics analysis studies show that these compartments “get very different readings, in terms of the predominant lipid disease state, and they are regulated differently from the way lipids in the periphery are regulated.” 

In the brain, the cholesterol “needs to get shuttled from glial cells to neurons,” so defects in the transport process can disrupt overall brain homeostasis, said Dr. Mills. But since the brain system is separate from the peripheral system, measuring plasma lipids is more likely to point to cardiovascular risks, while changes reflected in CSF lipids are “more indicative of alteration in lipid homeostasis in the brain.”
 

HDL and Triglycerides: A Complicated Story

Dr. Mills noted that HDL in the periphery is “very complicated,” and the idea that HDL, as a measure on its own, is “necessarily ‘good’ isn’t particularly informative.” Rather, HDL is “extremely heterogeneous, very diverse, has different lipid compositions, different classes, and different modifications.” For example, like oxidized LDL, oxidized HDL is also “bad,” preventing the HDL from having protective functions.

Similarly, the apolipoproteins associated with HDL can affect the function of the HDL. “Our understanding of the HDL-like particles in the CNS is limited, but we do understand the APOE4 link,” Dr. Mills said. “It seems that the HDL-like particles containing APOE2 or APOE3 are larger and are more effective at transferring the lipids and cholesterol linked to them relative to APOE4-containing particles.” 

Because HDL is more complex than simply being “good,” measuring HDL doesn’t “give you the full story,” said Dr. Mills. She speculates that this may be why there are studies suggesting that high levels of HDL might not have protective benefits and might even be detrimental. This makes it difficult to look at population studies, where the different subclasses of HDL are not necessarily captured in depth. 

Dr. Mills pointed to another confounding factor, which is that much of the risk for the development of AD appears to be related to the interaction of HDL, LDL, and triglycerides. “When you look at each of these individually, you get a lot of heterogeneity, and it’s unclear what’s driving what,” she said.

An advantage of observational studies is that they give information about which of these markers are associated with trends and disease risks in specific groups vs others. 

“For example, higher levels of triglycerides are associated with cardiovascular risk more in women, relative to men,” she said. And the triglyceride-to-HDL ratio seems “particularly robust” as a measure of cardiovascular health and risk. 

The interpretation of associations with triglycerides can be “tricky” and “confusing” because results differ so much between studies, she said. “There are differences between middle age and older age, which have to do with age-related changes in metabolism and lipid metabolism and not necessarily that the markers are indicating something different,” she said.

Some research has suggested that triglycerides may have a protective effect against dementia, noted Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and director of nutritional psychiatry at MGH Academy.

This may be because the brain “runs mostly on energy from burning triglycerides,” suggested Dr. Naidoo, author of the books Calm Your Mind With Food and This Is Your Brain on Food.

In addition, having higher levels of triglycerides may be linked with having overall healthier behaviors, Dr. Naidoo told this news organization.

Dr. Mills said that in middle-aged individuals, high levels of LDL-C and triglycerides are “often indicative of more atherogenic particles and risk to cardiovascular health, which is a generally negative trajectory. But in older individuals, things become more complicated because there are differences in terms of clearance of some of these particles, tissue clearance and distribution, and nutrient status. So for older individuals, it seems that fluctuations in either direction—either too high or too low—tend to be more informative that some overall dysregulation is going on the system.” 

She emphasized that, in this “emerging area, looking at only one or two studies is confusing. But if you look at the spectrum of studies, you can see a pattern, which is that the regulation gets ‘off,’ as people age.”

 

The Potential Role of Statins

Dr. Mills speculated that there may be “neuroprotective benefits for some of the statins which appear to be related to cardiovascular benefits. But at this point, we don’t have any clear data whether statins actually directly impact brain cholesterol, since it’s a separate pool.”

They could help “by increasing blood flow and reducing narrowing of the arteries, but any direct impact on the brain is still under investigation.”

Dr. Hansen pointed to research suggesting statins taken at midlife appear to be cardioprotective and may be protective of brain health as well, whereas statins initiated in older age do not appear to have these benefits.

He speculated that one reason statins seem less helpful when initiated later in life is that the BBB has already been damaged by systemic inflammation in the periphery, and the neuroinflammatory process resulting in neuronal destruction is already underway. “I think statins aren’t going to fix that problem, so although lowering cholesterol can be helpful in some respects, it might be too late to affect cognition because the nerves have already died and won’t grow back.”
 

Can Dietary Approaches Help?

Dr. Naidoo said that when looking at neurologic and psychiatric disease, “it’s important to think about the ‘long game’ — how can we improve our blood and cardiovascular health earlier in life to help potentiate healthy aging?”

From a nutritional psychiatry standpoint, Dr. Naidoo focuses on nourishing the gut microbiome and decreasing inflammation. “A healthy and balanced microbiome supports cognition, while the composition of gut bacteria is actually drastically different in patients with neurological diseases, such as AD.” 

She recommends a nutrient-dense, anti-inflammatory diet including probiotic-rich foods (such as kimchi, sauerkraut, plain yogurt, and miso). Moreover, “the quality and structure of our fatty acids may be relevant as well: Increasing our intake of polyunsaturated fatty acids and avoiding processed fats like trans fats and hydrogenated oils may benefit our overall brain health.”

Dr. Naidoo recommends extra-virgin olive oil as a source of healthy fat. Its consumption is linked to lower incidence of AD by way of encouraging autophagy, which she calls “our own process of “cellular cleanup.’”

Dr. Naidoo believes that clinicians’ guidance to patients should “focus on healthy nutrition and other lifestyle practices, such as exercise, outdoor time, good sleep, and stress reduction.” 

Dr. Mills notes the importance of omega-3 fatty acids, such as docosahexaenoic acid (DHA) , for brain health. “DHA is a major lipid component of neuronal membranes,” she said. “Because of inefficiencies in metabolism with APOE4, people tend to metabolize more of the lipids on the membranes themselves, so they have higher lipid membrane turnover and a greater need to supplement. Supplementing particularly through diet, with foods such as fatty fish rich in omega-3, can help boost the levels to help keep neuronal membranes intact.”
 

What This Means for the Clinician

“At this point, we see all of these associations between lipids and dementia, but we haven’t worked out exactly what it means on the individual level for an individual patient,” said Dr. Mills. Certainly, the picture is complex, and the understanding is growing and shifting. “The clinical applications remain unclear.”

One potential clinical take-home is that clinicians might consider tracking lipid levels over time. “If you follow a patient and see an increase or decrease [in lipid levels], that can be informative.” Looking at ratios of lipids might be more useful than looking only at a change in a single measure. “If you see trends in a variety of measures that track with one another, it might be more of a sign that something is potentially wrong.” 

Whether the patient should first try a lifestyle intervention or might need medication is a “personalized clinical decision, depending on the individual, their risk factors, and how their levels are going,” said Dr. Mills. 

Dr. Mills, Dr. Hansen, and Dr. Naidoo declared no relevant financial relationships.
 

A version of this article appeared on Medscape.com.