Clinical Endocrinology News

A former pain medicine physician received a sentence of 20 years in prison for selling opioids and writing prescriptions for patients who were abusing or diverting the medications.

Patrick Titus, 58, operated Lighthouse Internal Medicine in Milford, Delaware, from 2005-2014.

Federal prosecutors said Mr. Titus unlawfully distributed or dispensed opioids including fentanyl, morphine, methadone, OxyContin, and oxycodone outside the scope of practice and often prescribed them in combination with each other or in other dangerous combinations. Mr. Titus distributed over 1 million pills, said the government.

In a 2018 indictment, the government said that Mr. Titus would, “at the first and nearly every follow-up visit” prescribe opioids in high dosages, often without conducting an exam or reviewing any urine test results. He would also write prescriptions for opioids without getting patients’s prior medical records or reviewing test results and rarely referred patients to alternative pain treatments such as physical therapy, psychotherapy, or massage.

According to the indictment, he ignored “red flags,” including that patients would come from long distances, sometimes from out of state, and would pay cash, despite having Medicaid coverage.

“Today’s sentencing makes clear that medical professionals who recklessly prescribe opioids and endanger the safety and health of patients will be held accountable,” said Anne Milgram, a Drug Enforcement Administration administrator.

“This sentence is a reminder that the Department of Justice will hold accountable those doctors who are illegitimately prescribing opioids and fueling the country’s opioid crisis,” said Assistant Attorney General Kenneth A. Polite Jr., of the Justice Department’s Criminal Division, in the same statement. “Doctors who commit these unlawful acts exploit their roles as stewards of their patients’s care for their own profit,” he added.

The sentence follows Mr. Titus’s 2-week jury trial in 2021, when he was convicted of 13 counts of unlawful distribution and dispensing of controlled substances and one count of maintaining his practice primarily as a location to sell drugs. Mr. Titus faced a maximum of 20 years per count.

At the time of his conviction, Mr. Titus’s attorney said he planned to appeal, according to Delaware Online.

Delaware suspended Mr. Titus’s registration to prescribe controlled substances for 1 year in 2011. At the time, the state said it had determined that his continued prescribing “poses [an] imminent danger to the public health or safety.”

The state found that from January to November 2011, Mr. Titus issued 3,941 prescriptions for almost 750,000 pills for 17 different controlled substances, all sent to a single pharmacy.

The state also alleged that he wrote prescriptions for controlled substances to patients with felony convictions for drug trafficking and to at least one patient who his staff told him was selling the opioid that Mr. Titus had prescribed. It later determined that Mr. Titus continued prescribing even after it had suspended his DEA registration.

According to a 2014 consent agreement, the state subsequently ordered another 1-year suspension of his DEA registration, to be followed by a 3-year probation period.

Meanwhile, the same year, the state Board of Medical Licensure put Mr. Titus’s medical license on probation for 2 years and ordered him to complete 15 continuing medical education credits in medical recordkeeping, ethics, how to detect diversion and abuse, and in some other areas, and to pay a $7,500 fine.

In 2016, the medical board revoked Mr. Titus’s license, after finding that he continued to prescribe pain medications to patients he did not screen or monitor and for a multitude of other infractions.

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

A former pain medicine physician received a sentence of 20 years in prison for selling opioids and writing prescriptions for patients who were abusing or diverting the medications.

Patrick Titus, 58, operated Lighthouse Internal Medicine in Milford, Delaware, from 2005-2014.

Federal prosecutors said Mr. Titus unlawfully distributed or dispensed opioids including fentanyl, morphine, methadone, OxyContin, and oxycodone outside the scope of practice and often prescribed them in combination with each other or in other dangerous combinations. Mr. Titus distributed over 1 million pills, said the government.

In a 2018 indictment, the government said that Mr. Titus would, “at the first and nearly every follow-up visit” prescribe opioids in high dosages, often without conducting an exam or reviewing any urine test results. He would also write prescriptions for opioids without getting patients’s prior medical records or reviewing test results and rarely referred patients to alternative pain treatments such as physical therapy, psychotherapy, or massage.

According to the indictment, he ignored “red flags,” including that patients would come from long distances, sometimes from out of state, and would pay cash, despite having Medicaid coverage.

“Today’s sentencing makes clear that medical professionals who recklessly prescribe opioids and endanger the safety and health of patients will be held accountable,” said Anne Milgram, a Drug Enforcement Administration administrator.

“This sentence is a reminder that the Department of Justice will hold accountable those doctors who are illegitimately prescribing opioids and fueling the country’s opioid crisis,” said Assistant Attorney General Kenneth A. Polite Jr., of the Justice Department’s Criminal Division, in the same statement. “Doctors who commit these unlawful acts exploit their roles as stewards of their patients’s care for their own profit,” he added.

The sentence follows Mr. Titus’s 2-week jury trial in 2021, when he was convicted of 13 counts of unlawful distribution and dispensing of controlled substances and one count of maintaining his practice primarily as a location to sell drugs. Mr. Titus faced a maximum of 20 years per count.

At the time of his conviction, Mr. Titus’s attorney said he planned to appeal, according to Delaware Online.

Delaware suspended Mr. Titus’s registration to prescribe controlled substances for 1 year in 2011. At the time, the state said it had determined that his continued prescribing “poses [an] imminent danger to the public health or safety.”

The state found that from January to November 2011, Mr. Titus issued 3,941 prescriptions for almost 750,000 pills for 17 different controlled substances, all sent to a single pharmacy.

The state also alleged that he wrote prescriptions for controlled substances to patients with felony convictions for drug trafficking and to at least one patient who his staff told him was selling the opioid that Mr. Titus had prescribed. It later determined that Mr. Titus continued prescribing even after it had suspended his DEA registration.

According to a 2014 consent agreement, the state subsequently ordered another 1-year suspension of his DEA registration, to be followed by a 3-year probation period.

Meanwhile, the same year, the state Board of Medical Licensure put Mr. Titus’s medical license on probation for 2 years and ordered him to complete 15 continuing medical education credits in medical recordkeeping, ethics, how to detect diversion and abuse, and in some other areas, and to pay a $7,500 fine.

In 2016, the medical board revoked Mr. Titus’s license, after finding that he continued to prescribe pain medications to patients he did not screen or monitor and for a multitude of other infractions.

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

A former pain medicine physician received a sentence of 20 years in prison for selling opioids and writing prescriptions for patients who were abusing or diverting the medications.

Patrick Titus, 58, operated Lighthouse Internal Medicine in Milford, Delaware, from 2005-2014.

Federal prosecutors said Mr. Titus unlawfully distributed or dispensed opioids including fentanyl, morphine, methadone, OxyContin, and oxycodone outside the scope of practice and often prescribed them in combination with each other or in other dangerous combinations. Mr. Titus distributed over 1 million pills, said the government.

In a 2018 indictment, the government said that Mr. Titus would, “at the first and nearly every follow-up visit” prescribe opioids in high dosages, often without conducting an exam or reviewing any urine test results. He would also write prescriptions for opioids without getting patients’s prior medical records or reviewing test results and rarely referred patients to alternative pain treatments such as physical therapy, psychotherapy, or massage.

According to the indictment, he ignored “red flags,” including that patients would come from long distances, sometimes from out of state, and would pay cash, despite having Medicaid coverage.

“Today’s sentencing makes clear that medical professionals who recklessly prescribe opioids and endanger the safety and health of patients will be held accountable,” said Anne Milgram, a Drug Enforcement Administration administrator.

“This sentence is a reminder that the Department of Justice will hold accountable those doctors who are illegitimately prescribing opioids and fueling the country’s opioid crisis,” said Assistant Attorney General Kenneth A. Polite Jr., of the Justice Department’s Criminal Division, in the same statement. “Doctors who commit these unlawful acts exploit their roles as stewards of their patients’s care for their own profit,” he added.

The sentence follows Mr. Titus’s 2-week jury trial in 2021, when he was convicted of 13 counts of unlawful distribution and dispensing of controlled substances and one count of maintaining his practice primarily as a location to sell drugs. Mr. Titus faced a maximum of 20 years per count.

At the time of his conviction, Mr. Titus’s attorney said he planned to appeal, according to Delaware Online.

Delaware suspended Mr. Titus’s registration to prescribe controlled substances for 1 year in 2011. At the time, the state said it had determined that his continued prescribing “poses [an] imminent danger to the public health or safety.”

The state found that from January to November 2011, Mr. Titus issued 3,941 prescriptions for almost 750,000 pills for 17 different controlled substances, all sent to a single pharmacy.

The state also alleged that he wrote prescriptions for controlled substances to patients with felony convictions for drug trafficking and to at least one patient who his staff told him was selling the opioid that Mr. Titus had prescribed. It later determined that Mr. Titus continued prescribing even after it had suspended his DEA registration.

According to a 2014 consent agreement, the state subsequently ordered another 1-year suspension of his DEA registration, to be followed by a 3-year probation period.

Meanwhile, the same year, the state Board of Medical Licensure put Mr. Titus’s medical license on probation for 2 years and ordered him to complete 15 continuing medical education credits in medical recordkeeping, ethics, how to detect diversion and abuse, and in some other areas, and to pay a $7,500 fine.

In 2016, the medical board revoked Mr. Titus’s license, after finding that he continued to prescribe pain medications to patients he did not screen or monitor and for a multitude of other infractions.

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

“Adipose tissue is an underappreciated and misunderstood organ.” It’s with these words that Aaron M. Cypess, MD, PhD, begins his recent review published in the New England Journal of Medicine.

As obesity rates steadily rise, “the riskiest approach to human adipose tissue is to dismiss its importance,” he adds, especially because there has been “an explosive growth” in our understanding of white and brown adipose tissue over the past 5 to 10 years.

This news organization asked Dr. Cypess, a National Institutes of Health (NIH) scientist whose research focuses on brown fat, to discuss some of the main points in his review, titled, “Reassessing Human Adipose Tissue,” and clear up some misconceptions about fat.

You write that, for people who struggle to lose weight, “fat is often a source of misery, not marvel.” Why is fat a marvel?

When I started medical school in 1992, fat was just a thing that stored calories. You had to get it out of the way when you operated on the stomach or intestines. Now we know it’s not just one cell, it’s multiple types of cells, including immune cells and some blood cells. There’s cell turnover, and cells can get bigger or smaller, so it’s a dynamic tissue. It impacts the immune system and affects insulin sensitivity.

Why use the term “adipose tissue” and not just “fat”?

People think of fat cells and that’s it. However, adipose tissue (fat) has multiple cell types, and they each matter. There are adipocytes (fat cells) – which can be white, brown, beige, or pink – as well as immune cells, fibroblasts, blood vessels, and parts of nerve cells.

The main function of white adipose tissue is to store energy in the form of triglycerides. Brown adipose tissue consumes glucose and triglycerides, generating heat. Brown fat cells within depots of white fat are termed brite cells (a portmanteau of brown and white) or beige cells. Pink fat cells have been found in breast tissue in mice.

What do we now know about white fat and brown fat? Can brown fat change to white fat or vice versa?

White adipose tissue is commonly separated into visceral fat and subcutaneous fat, which have negative and neutral or positive metabolic effects, respectively. It is capable of more than doubling in mass and then returning to baseline.

White adipocyte-derived hormones include leptin, which is low in starvation, and adiponectin, which regulates glucose and lipid metabolism. White adipose tissue is essential for the proper function of the reproductive system, including secretion of hormones and lactation.

Brown adipose tissue protects newborns from cold as they develop the ability to shiver, and in adults it is found in depots in the neck, shoulders, posterior thorax, and abdomen. The amount of brown adipose tissue varies according to sex and lowers with increasing age and increasing body mass index.

There is much more white fat in the body than brown fat. It appears that activating brown fat leads to beneficial effects on metabolism, though we don’t know yet all the steps for how that happens.

In mice, you’ve got white fat depots and brown fat depots, and some brown fat can be found in the white fat.

With humans it’s much more complicated, and I’ve seen this in the operating room myself, and on slides. Where you find brown fat cells you also find a certain proportion of white fat cells, not an exclusive brown fat depot like you see in a mouse.

It is hotly debated right now whether brown fat can change to white fat and vice versa (transdifferentiation). The beige fat cells are supposed to be the kind that can shuttle between more white-like or brown-like. They can sometimes be white or sometimes brown. It can be very contentious in [scientific] papers and meetings.

Are humans born with all the fat cells they will ever have?

No. New fat cells are made throughout our lives. When the white adipocytes store too much triglyceride, they get really big and they get “sick” and die faster. It’s the rate at which the white cells take up the fat to store it and then get rid of it that can impact whether someone gains a lot of weight and whether they can successfully lose it after reasonable effort.

The average lifespan of a white fat cell is 15 years. We have no idea yet of the lifespan of a brown fat cell.

Is there a single “fat gene”? What role do fat genes play in the likelihood of developing metabolic diseases and type 2 diabetes?

Genes are very important for influencing the development of obesity and probably influence 50%-70% of obesity, based on studies in populations of predominantly European origin. But that high percentage reflects the impact of hundreds of genes. For most people, there is no one gene that exerts all of the effects. There are extremely rare diseases where one gene is responsible. Currently, only 20% of the entire phenotypic variation in obesity can be explained by the thousands of loci identified so far.

Why is it “correct but too simplistic” to attribute the increasing rates of obesity to excessive triglyceride storage in white adipose tissue?

Saying obesity is caused by too much triglyceride storage ignores the reasons how and why the triglycerides got there. There are likely to be multiple contributing factors to drive obesity, and those have billions of dollars of policy implications. Is obesity resulting from portion sizes? Then we should work on educating the public on how to estimate their caloric intake. Is it the types of foods, such as ultra-processed foods? Then we can discourage eating certain food groups while promoting others. Is it about physical activity? Then we should prioritize exercise programs.

Why is obesity “not simply a failure of will power”?

Genetic factors in adipose tissue impact how easy it is to store triglycerides, how easy it is to get fat out of the tissue and burn it up, and what kinds of hormones are released by the tissue to regulate appetite, insulin resistance, and inflammation. Ten different people can all overeat the same amount of the same foods, yet there will be differences in the amount of weight gain and metabolic complications experienced. And at the brain level, some people will feel “full” sooner than others.

How can excess adipose tissue lead to disease? Do some people have “metabolically healthy obesity”?

Excess adipose tissue leads to chronic inflammation that can then cause insulin resistance, hypertension, fatty liver disease, and other complications. It appears that there are metabolically healthy obese people, but it is not clear if that is only a temporary state.

Could long-term brown adipose tissue activation help treat obesity or related metabolic disease?

Our research group at the NIH and others have shown that long-term brown adipose tissue activation produces metabolic benefit such as improved insulin resistance, lower plasma glucose, and higher HDL [good] cholesterol. However, there is no evidence yet that it will lead to actual weight loss.

We are trying to use brown adipose tissue activation to treat obesity-related metabolic disease to see if it could lead to reduction in inflammation, improvement in the cholesterol profile, and decrease in blood pressure.

A large observational study published Jan. 4, 2021, in Nature Medicine by Paul Cohen’s group at Rockefeller University, in tens of thousands of people at Memorial Sloan Kettering Cancer Center, showed that people who had brown fat were generally healthier and had less high blood pressure and less cardiovascular disease. This study could not show causation, but at every BMI, people were healthier if they had more brown fat than if they had less. So, there’s something going on. We’re still trying to figure that out.

Dr. Cypess has no reported no relevant financial relationships.

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

“Adipose tissue is an underappreciated and misunderstood organ.” It’s with these words that Aaron M. Cypess, MD, PhD, begins his recent review published in the New England Journal of Medicine.

As obesity rates steadily rise, “the riskiest approach to human adipose tissue is to dismiss its importance,” he adds, especially because there has been “an explosive growth” in our understanding of white and brown adipose tissue over the past 5 to 10 years.

This news organization asked Dr. Cypess, a National Institutes of Health (NIH) scientist whose research focuses on brown fat, to discuss some of the main points in his review, titled, “Reassessing Human Adipose Tissue,” and clear up some misconceptions about fat.

You write that, for people who struggle to lose weight, “fat is often a source of misery, not marvel.” Why is fat a marvel?

When I started medical school in 1992, fat was just a thing that stored calories. You had to get it out of the way when you operated on the stomach or intestines. Now we know it’s not just one cell, it’s multiple types of cells, including immune cells and some blood cells. There’s cell turnover, and cells can get bigger or smaller, so it’s a dynamic tissue. It impacts the immune system and affects insulin sensitivity.

Why use the term “adipose tissue” and not just “fat”?

People think of fat cells and that’s it. However, adipose tissue (fat) has multiple cell types, and they each matter. There are adipocytes (fat cells) – which can be white, brown, beige, or pink – as well as immune cells, fibroblasts, blood vessels, and parts of nerve cells.

The main function of white adipose tissue is to store energy in the form of triglycerides. Brown adipose tissue consumes glucose and triglycerides, generating heat. Brown fat cells within depots of white fat are termed brite cells (a portmanteau of brown and white) or beige cells. Pink fat cells have been found in breast tissue in mice.

What do we now know about white fat and brown fat? Can brown fat change to white fat or vice versa?

White adipose tissue is commonly separated into visceral fat and subcutaneous fat, which have negative and neutral or positive metabolic effects, respectively. It is capable of more than doubling in mass and then returning to baseline.

White adipocyte-derived hormones include leptin, which is low in starvation, and adiponectin, which regulates glucose and lipid metabolism. White adipose tissue is essential for the proper function of the reproductive system, including secretion of hormones and lactation.

Brown adipose tissue protects newborns from cold as they develop the ability to shiver, and in adults it is found in depots in the neck, shoulders, posterior thorax, and abdomen. The amount of brown adipose tissue varies according to sex and lowers with increasing age and increasing body mass index.

There is much more white fat in the body than brown fat. It appears that activating brown fat leads to beneficial effects on metabolism, though we don’t know yet all the steps for how that happens.

In mice, you’ve got white fat depots and brown fat depots, and some brown fat can be found in the white fat.

With humans it’s much more complicated, and I’ve seen this in the operating room myself, and on slides. Where you find brown fat cells you also find a certain proportion of white fat cells, not an exclusive brown fat depot like you see in a mouse.

It is hotly debated right now whether brown fat can change to white fat and vice versa (transdifferentiation). The beige fat cells are supposed to be the kind that can shuttle between more white-like or brown-like. They can sometimes be white or sometimes brown. It can be very contentious in [scientific] papers and meetings.

Are humans born with all the fat cells they will ever have?

No. New fat cells are made throughout our lives. When the white adipocytes store too much triglyceride, they get really big and they get “sick” and die faster. It’s the rate at which the white cells take up the fat to store it and then get rid of it that can impact whether someone gains a lot of weight and whether they can successfully lose it after reasonable effort.

The average lifespan of a white fat cell is 15 years. We have no idea yet of the lifespan of a brown fat cell.

Is there a single “fat gene”? What role do fat genes play in the likelihood of developing metabolic diseases and type 2 diabetes?

Genes are very important for influencing the development of obesity and probably influence 50%-70% of obesity, based on studies in populations of predominantly European origin. But that high percentage reflects the impact of hundreds of genes. For most people, there is no one gene that exerts all of the effects. There are extremely rare diseases where one gene is responsible. Currently, only 20% of the entire phenotypic variation in obesity can be explained by the thousands of loci identified so far.

Why is it “correct but too simplistic” to attribute the increasing rates of obesity to excessive triglyceride storage in white adipose tissue?

Saying obesity is caused by too much triglyceride storage ignores the reasons how and why the triglycerides got there. There are likely to be multiple contributing factors to drive obesity, and those have billions of dollars of policy implications. Is obesity resulting from portion sizes? Then we should work on educating the public on how to estimate their caloric intake. Is it the types of foods, such as ultra-processed foods? Then we can discourage eating certain food groups while promoting others. Is it about physical activity? Then we should prioritize exercise programs.

Why is obesity “not simply a failure of will power”?

Genetic factors in adipose tissue impact how easy it is to store triglycerides, how easy it is to get fat out of the tissue and burn it up, and what kinds of hormones are released by the tissue to regulate appetite, insulin resistance, and inflammation. Ten different people can all overeat the same amount of the same foods, yet there will be differences in the amount of weight gain and metabolic complications experienced. And at the brain level, some people will feel “full” sooner than others.

How can excess adipose tissue lead to disease? Do some people have “metabolically healthy obesity”?

Excess adipose tissue leads to chronic inflammation that can then cause insulin resistance, hypertension, fatty liver disease, and other complications. It appears that there are metabolically healthy obese people, but it is not clear if that is only a temporary state.

Could long-term brown adipose tissue activation help treat obesity or related metabolic disease?

Our research group at the NIH and others have shown that long-term brown adipose tissue activation produces metabolic benefit such as improved insulin resistance, lower plasma glucose, and higher HDL [good] cholesterol. However, there is no evidence yet that it will lead to actual weight loss.

We are trying to use brown adipose tissue activation to treat obesity-related metabolic disease to see if it could lead to reduction in inflammation, improvement in the cholesterol profile, and decrease in blood pressure.

A large observational study published Jan. 4, 2021, in Nature Medicine by Paul Cohen’s group at Rockefeller University, in tens of thousands of people at Memorial Sloan Kettering Cancer Center, showed that people who had brown fat were generally healthier and had less high blood pressure and less cardiovascular disease. This study could not show causation, but at every BMI, people were healthier if they had more brown fat than if they had less. So, there’s something going on. We’re still trying to figure that out.

Dr. Cypess has no reported no relevant financial relationships.

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

“Adipose tissue is an underappreciated and misunderstood organ.” It’s with these words that Aaron M. Cypess, MD, PhD, begins his recent review published in the New England Journal of Medicine.

As obesity rates steadily rise, “the riskiest approach to human adipose tissue is to dismiss its importance,” he adds, especially because there has been “an explosive growth” in our understanding of white and brown adipose tissue over the past 5 to 10 years.

This news organization asked Dr. Cypess, a National Institutes of Health (NIH) scientist whose research focuses on brown fat, to discuss some of the main points in his review, titled, “Reassessing Human Adipose Tissue,” and clear up some misconceptions about fat.

You write that, for people who struggle to lose weight, “fat is often a source of misery, not marvel.” Why is fat a marvel?

When I started medical school in 1992, fat was just a thing that stored calories. You had to get it out of the way when you operated on the stomach or intestines. Now we know it’s not just one cell, it’s multiple types of cells, including immune cells and some blood cells. There’s cell turnover, and cells can get bigger or smaller, so it’s a dynamic tissue. It impacts the immune system and affects insulin sensitivity.

Why use the term “adipose tissue” and not just “fat”?

People think of fat cells and that’s it. However, adipose tissue (fat) has multiple cell types, and they each matter. There are adipocytes (fat cells) – which can be white, brown, beige, or pink – as well as immune cells, fibroblasts, blood vessels, and parts of nerve cells.

The main function of white adipose tissue is to store energy in the form of triglycerides. Brown adipose tissue consumes glucose and triglycerides, generating heat. Brown fat cells within depots of white fat are termed brite cells (a portmanteau of brown and white) or beige cells. Pink fat cells have been found in breast tissue in mice.

What do we now know about white fat and brown fat? Can brown fat change to white fat or vice versa?

White adipose tissue is commonly separated into visceral fat and subcutaneous fat, which have negative and neutral or positive metabolic effects, respectively. It is capable of more than doubling in mass and then returning to baseline.

White adipocyte-derived hormones include leptin, which is low in starvation, and adiponectin, which regulates glucose and lipid metabolism. White adipose tissue is essential for the proper function of the reproductive system, including secretion of hormones and lactation.

Brown adipose tissue protects newborns from cold as they develop the ability to shiver, and in adults it is found in depots in the neck, shoulders, posterior thorax, and abdomen. The amount of brown adipose tissue varies according to sex and lowers with increasing age and increasing body mass index.

There is much more white fat in the body than brown fat. It appears that activating brown fat leads to beneficial effects on metabolism, though we don’t know yet all the steps for how that happens.

In mice, you’ve got white fat depots and brown fat depots, and some brown fat can be found in the white fat.

With humans it’s much more complicated, and I’ve seen this in the operating room myself, and on slides. Where you find brown fat cells you also find a certain proportion of white fat cells, not an exclusive brown fat depot like you see in a mouse.

It is hotly debated right now whether brown fat can change to white fat and vice versa (transdifferentiation). The beige fat cells are supposed to be the kind that can shuttle between more white-like or brown-like. They can sometimes be white or sometimes brown. It can be very contentious in [scientific] papers and meetings.

Are humans born with all the fat cells they will ever have?

No. New fat cells are made throughout our lives. When the white adipocytes store too much triglyceride, they get really big and they get “sick” and die faster. It’s the rate at which the white cells take up the fat to store it and then get rid of it that can impact whether someone gains a lot of weight and whether they can successfully lose it after reasonable effort.

The average lifespan of a white fat cell is 15 years. We have no idea yet of the lifespan of a brown fat cell.

Is there a single “fat gene”? What role do fat genes play in the likelihood of developing metabolic diseases and type 2 diabetes?

Genes are very important for influencing the development of obesity and probably influence 50%-70% of obesity, based on studies in populations of predominantly European origin. But that high percentage reflects the impact of hundreds of genes. For most people, there is no one gene that exerts all of the effects. There are extremely rare diseases where one gene is responsible. Currently, only 20% of the entire phenotypic variation in obesity can be explained by the thousands of loci identified so far.

Why is it “correct but too simplistic” to attribute the increasing rates of obesity to excessive triglyceride storage in white adipose tissue?

Saying obesity is caused by too much triglyceride storage ignores the reasons how and why the triglycerides got there. There are likely to be multiple contributing factors to drive obesity, and those have billions of dollars of policy implications. Is obesity resulting from portion sizes? Then we should work on educating the public on how to estimate their caloric intake. Is it the types of foods, such as ultra-processed foods? Then we can discourage eating certain food groups while promoting others. Is it about physical activity? Then we should prioritize exercise programs.

Why is obesity “not simply a failure of will power”?

Genetic factors in adipose tissue impact how easy it is to store triglycerides, how easy it is to get fat out of the tissue and burn it up, and what kinds of hormones are released by the tissue to regulate appetite, insulin resistance, and inflammation. Ten different people can all overeat the same amount of the same foods, yet there will be differences in the amount of weight gain and metabolic complications experienced. And at the brain level, some people will feel “full” sooner than others.

How can excess adipose tissue lead to disease? Do some people have “metabolically healthy obesity”?

Excess adipose tissue leads to chronic inflammation that can then cause insulin resistance, hypertension, fatty liver disease, and other complications. It appears that there are metabolically healthy obese people, but it is not clear if that is only a temporary state.

Could long-term brown adipose tissue activation help treat obesity or related metabolic disease?

Our research group at the NIH and others have shown that long-term brown adipose tissue activation produces metabolic benefit such as improved insulin resistance, lower plasma glucose, and higher HDL [good] cholesterol. However, there is no evidence yet that it will lead to actual weight loss.

We are trying to use brown adipose tissue activation to treat obesity-related metabolic disease to see if it could lead to reduction in inflammation, improvement in the cholesterol profile, and decrease in blood pressure.

A large observational study published Jan. 4, 2021, in Nature Medicine by Paul Cohen’s group at Rockefeller University, in tens of thousands of people at Memorial Sloan Kettering Cancer Center, showed that people who had brown fat were generally healthier and had less high blood pressure and less cardiovascular disease. This study could not show causation, but at every BMI, people were healthier if they had more brown fat than if they had less. So, there’s something going on. We’re still trying to figure that out.

Dr. Cypess has no reported no relevant financial relationships.

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

Pregnant women with a history of spontaneous abortion had a significantly increased risk of gestational diabetes in subsequent pregnancies, based on data from more than 100,000 women.

Gestational diabetes is associated not only with adverse perinatal outcomes, but also with an increased risk of long-term cardiovascular and metabolic health issues in mothers and children, wrote Yan Zhao, PhD, of Tongji University, Shanghai, and colleagues.

Previous studies also have shown that spontaneous abortion (SAB) is associated with later maternal risk of cardiovascular disease and venous thromboembolism, the researchers said. The same mechanisms might contribute to the development of gestational diabetes, but the association between abortion history and gestational diabetes risk in subsequent pregnancies remains unclear, they added.

In a study published in JAMA Network Open, the researchers identified 102,259 pregnant women seen for routine prenatal care at a single hospital in Shanghai between January 2014 and December 2019. The mean age of the women was 29.8 years.

During the study period, 14,579 women experienced SAB (14.3%), 17,935 experienced induced abortion (17.5%), and 4,017 experienced both (11.9%).

In all, 12,153 cases of gestational diabetes were identified, for a prevalence of 11.9%. The relative risk of gestational diabetes was 1.25 for women who experienced SAB and 1.15 for those who experienced both SAB and induced abortion, and the association between SAB and gestational diabetes increased in a number-dependent manner, the researchers said. The increase in relative risk for gestational diabetes in pregnant women with one SAB, two SABs, and three or more SABs was 18%, 41%, and 43%, compared to pregnant women with no SAB history.

However, no association appeared between a history of induced abortion and gestational diabetes, the researchers said. “To date, no study has reported the association of prior induced abortion with gestational diabetes,” they wrote.

The study findings were limited by several factors including the reliance on self-reports for history of SAB and therefore possible underreporting, the researchers noted. Other limitations included the lack of data on the timing of SABs; therefore, the time between SAB and gestational diabetes diagnosis could not be included in the analysis, they said. Unknown variables and the inclusion only of women from a single city in China might limit the generalizability of the results, they added.

More research is needed to understand the biological mechanisms behind the association between SAB and gestational diabetes, an association that has potential public health implications, they noted. However, the results suggest that “pregnant women with a history of SAB, especially those with a history of recurrent SAB, should attend more antenatal visits to monitor their blood glucose and implement early prevention and intervention,” such as healthful eating and regular exercise, they wrote.
 

Findings confirm, not surprise

The diagnosis of gestational diabetes in the current study “was made with a slightly different test than we typically use in the United States – a 1-hour nonfasting glucola followed by a confirmatory 3-hour fasting glucola,” Sarah W. Prager, MD, of the University of Washington, Seattle, said in an interview. The current study of both SAB and gestational diabetes is important because both conditions are very common and have been the focus of increased attention in the popular media and in scientific study, she said.

Dr. Prager said she was not surprised by the findings of a link between a history of gestational diabetes and a history of SAB, “but the association is likely that people at risk for gestational diabetes or who have undiagnosed diabetes/glucose intolerance are more likely to experience SAB,” she noted. “I would be surprised if the direction of the association is that SAB puts people at risk for gestational diabetes; more likely undiagnosed diabetes is a risk factor for SAB,” she added. “Perhaps we should be screening for glucose intolerance and other metabolic disorders more frequently in people who have especially recurrent SAB, as the more miscarriages someone had, the more likely they were in this study to be diagnosed with gestational diabetes;” or perhaps those with a history of SAB/recurrent SAB should be screened closer to 24 weeks’ than 28 weeks’ gestation to enable earlier intervention in those more likely to have gestational diabetes, Dr. Prager said.

The study was supported by the Key Program of the National Natural Science Foundation of China, the National Natural Science Foundation of China, the National Key Research and Development Program of China, the Shanghai Municipal Medical and Health Discipline Construction Projects, and the Shanghai Rising-Star Program. The researchers and Dr. Prager had no financial conflicts to disclose. Dr. Prager serves on the editorial advisory board of Ob.Gyn. News.

Pregnant women with a history of spontaneous abortion had a significantly increased risk of gestational diabetes in subsequent pregnancies, based on data from more than 100,000 women.

Gestational diabetes is associated not only with adverse perinatal outcomes, but also with an increased risk of long-term cardiovascular and metabolic health issues in mothers and children, wrote Yan Zhao, PhD, of Tongji University, Shanghai, and colleagues.

Previous studies also have shown that spontaneous abortion (SAB) is associated with later maternal risk of cardiovascular disease and venous thromboembolism, the researchers said. The same mechanisms might contribute to the development of gestational diabetes, but the association between abortion history and gestational diabetes risk in subsequent pregnancies remains unclear, they added.

In a study published in JAMA Network Open, the researchers identified 102,259 pregnant women seen for routine prenatal care at a single hospital in Shanghai between January 2014 and December 2019. The mean age of the women was 29.8 years.

During the study period, 14,579 women experienced SAB (14.3%), 17,935 experienced induced abortion (17.5%), and 4,017 experienced both (11.9%).

In all, 12,153 cases of gestational diabetes were identified, for a prevalence of 11.9%. The relative risk of gestational diabetes was 1.25 for women who experienced SAB and 1.15 for those who experienced both SAB and induced abortion, and the association between SAB and gestational diabetes increased in a number-dependent manner, the researchers said. The increase in relative risk for gestational diabetes in pregnant women with one SAB, two SABs, and three or more SABs was 18%, 41%, and 43%, compared to pregnant women with no SAB history.

However, no association appeared between a history of induced abortion and gestational diabetes, the researchers said. “To date, no study has reported the association of prior induced abortion with gestational diabetes,” they wrote.

The study findings were limited by several factors including the reliance on self-reports for history of SAB and therefore possible underreporting, the researchers noted. Other limitations included the lack of data on the timing of SABs; therefore, the time between SAB and gestational diabetes diagnosis could not be included in the analysis, they said. Unknown variables and the inclusion only of women from a single city in China might limit the generalizability of the results, they added.

More research is needed to understand the biological mechanisms behind the association between SAB and gestational diabetes, an association that has potential public health implications, they noted. However, the results suggest that “pregnant women with a history of SAB, especially those with a history of recurrent SAB, should attend more antenatal visits to monitor their blood glucose and implement early prevention and intervention,” such as healthful eating and regular exercise, they wrote.
 

Findings confirm, not surprise

The diagnosis of gestational diabetes in the current study “was made with a slightly different test than we typically use in the United States – a 1-hour nonfasting glucola followed by a confirmatory 3-hour fasting glucola,” Sarah W. Prager, MD, of the University of Washington, Seattle, said in an interview. The current study of both SAB and gestational diabetes is important because both conditions are very common and have been the focus of increased attention in the popular media and in scientific study, she said.

Dr. Prager said she was not surprised by the findings of a link between a history of gestational diabetes and a history of SAB, “but the association is likely that people at risk for gestational diabetes or who have undiagnosed diabetes/glucose intolerance are more likely to experience SAB,” she noted. “I would be surprised if the direction of the association is that SAB puts people at risk for gestational diabetes; more likely undiagnosed diabetes is a risk factor for SAB,” she added. “Perhaps we should be screening for glucose intolerance and other metabolic disorders more frequently in people who have especially recurrent SAB, as the more miscarriages someone had, the more likely they were in this study to be diagnosed with gestational diabetes;” or perhaps those with a history of SAB/recurrent SAB should be screened closer to 24 weeks’ than 28 weeks’ gestation to enable earlier intervention in those more likely to have gestational diabetes, Dr. Prager said.

The study was supported by the Key Program of the National Natural Science Foundation of China, the National Natural Science Foundation of China, the National Key Research and Development Program of China, the Shanghai Municipal Medical and Health Discipline Construction Projects, and the Shanghai Rising-Star Program. The researchers and Dr. Prager had no financial conflicts to disclose. Dr. Prager serves on the editorial advisory board of Ob.Gyn. News.

Pregnant women with a history of spontaneous abortion had a significantly increased risk of gestational diabetes in subsequent pregnancies, based on data from more than 100,000 women.

Gestational diabetes is associated not only with adverse perinatal outcomes, but also with an increased risk of long-term cardiovascular and metabolic health issues in mothers and children, wrote Yan Zhao, PhD, of Tongji University, Shanghai, and colleagues.

Previous studies also have shown that spontaneous abortion (SAB) is associated with later maternal risk of cardiovascular disease and venous thromboembolism, the researchers said. The same mechanisms might contribute to the development of gestational diabetes, but the association between abortion history and gestational diabetes risk in subsequent pregnancies remains unclear, they added.

In a study published in JAMA Network Open, the researchers identified 102,259 pregnant women seen for routine prenatal care at a single hospital in Shanghai between January 2014 and December 2019. The mean age of the women was 29.8 years.

During the study period, 14,579 women experienced SAB (14.3%), 17,935 experienced induced abortion (17.5%), and 4,017 experienced both (11.9%).

In all, 12,153 cases of gestational diabetes were identified, for a prevalence of 11.9%. The relative risk of gestational diabetes was 1.25 for women who experienced SAB and 1.15 for those who experienced both SAB and induced abortion, and the association between SAB and gestational diabetes increased in a number-dependent manner, the researchers said. The increase in relative risk for gestational diabetes in pregnant women with one SAB, two SABs, and three or more SABs was 18%, 41%, and 43%, compared to pregnant women with no SAB history.

However, no association appeared between a history of induced abortion and gestational diabetes, the researchers said. “To date, no study has reported the association of prior induced abortion with gestational diabetes,” they wrote.

The study findings were limited by several factors including the reliance on self-reports for history of SAB and therefore possible underreporting, the researchers noted. Other limitations included the lack of data on the timing of SABs; therefore, the time between SAB and gestational diabetes diagnosis could not be included in the analysis, they said. Unknown variables and the inclusion only of women from a single city in China might limit the generalizability of the results, they added.

More research is needed to understand the biological mechanisms behind the association between SAB and gestational diabetes, an association that has potential public health implications, they noted. However, the results suggest that “pregnant women with a history of SAB, especially those with a history of recurrent SAB, should attend more antenatal visits to monitor their blood glucose and implement early prevention and intervention,” such as healthful eating and regular exercise, they wrote.
 

Findings confirm, not surprise

The diagnosis of gestational diabetes in the current study “was made with a slightly different test than we typically use in the United States – a 1-hour nonfasting glucola followed by a confirmatory 3-hour fasting glucola,” Sarah W. Prager, MD, of the University of Washington, Seattle, said in an interview. The current study of both SAB and gestational diabetes is important because both conditions are very common and have been the focus of increased attention in the popular media and in scientific study, she said.

Dr. Prager said she was not surprised by the findings of a link between a history of gestational diabetes and a history of SAB, “but the association is likely that people at risk for gestational diabetes or who have undiagnosed diabetes/glucose intolerance are more likely to experience SAB,” she noted. “I would be surprised if the direction of the association is that SAB puts people at risk for gestational diabetes; more likely undiagnosed diabetes is a risk factor for SAB,” she added. “Perhaps we should be screening for glucose intolerance and other metabolic disorders more frequently in people who have especially recurrent SAB, as the more miscarriages someone had, the more likely they were in this study to be diagnosed with gestational diabetes;” or perhaps those with a history of SAB/recurrent SAB should be screened closer to 24 weeks’ than 28 weeks’ gestation to enable earlier intervention in those more likely to have gestational diabetes, Dr. Prager said.

The study was supported by the Key Program of the National Natural Science Foundation of China, the National Natural Science Foundation of China, the National Key Research and Development Program of China, the Shanghai Municipal Medical and Health Discipline Construction Projects, and the Shanghai Rising-Star Program. The researchers and Dr. Prager had no financial conflicts to disclose. Dr. Prager serves on the editorial advisory board of Ob.Gyn. News.

Increasingly active patterns of physical activity were linked with reduced rates of overall mortality and cardiovascular disease (CVD), but early rather than later in late life, in a 20-year follow-up cohort study.

In this population of people older than 65 years, researchers found that physical activity overall was associated with lower rates of incident CVD, particularly among men, and the association was strongest in people 70 to 75 years of age, rather than in older age groups.

They also looked at “trajectories,” or changes in activity over time, and found that a stable-high trajectory of activity was associated with a significantly lower risk for cardiovascular outcomes in men than in those with a stable-low trajectory. For women, more physical activity was consistently associated with lower CVD outcomes, although not statistically significantly so, except for overall mortality, which did reach significance.

Notably, the greatest reduction in cardiovascular risk was reported in people who did more than 20 minutes of physical exercise each day, and it was more pronounced in those 70 years of age.

Physical activity was also associated with a lower incidence of heart failure and coronary heart disease in older people, again especially early on in late life, reported Claudio Barbiellini Amidei, MD, University of Padua, Italy, and colleagues.

The data suggest that physical activity is more effective in preventing CVD onset when implemented early rather than later in life, noted Dr. Amidei in an email.

“The findings of our study are suggestive of a protective effect of physical activity in late-life on cardiovascular health. WHO recommendations for adults and older adults are to practice at least 20 minutes of moderate to vigorous physical activity per day. I believe this is a realistic target, and policy makers should raise awareness on the importance of achieving this goal at all ages, including in late-life,” Dr. Amidei said.

The study was published online Feb. 14 in Heart.

Previous research has demonstrated that the most benefit of high physical activity, compared with low, begins at about 60 years of age, and that is because younger people are at much lower risk, noted Carl “Chip” Lavie MD, FACC, medical director of cardiac rehabilitation and prevention, Ochsner Clinical School–The University of Queensland School of Medicine, New Orleans, who was not involved in the study.

“At quite old ages, for example over age 80, resistance exercise or weight training and balance training may be even more important than aerobic training,” he added.

Activity ‘trajectories’

The benefits of physical activity on cardiovascular risk are well established, the researchers note. Less clear is the role that trajectories of activity over time play, although research to date suggests a reduction in risk with increasing activity from mid-life to early old age, they write.

For the current analysis, the researchers assessed 3,099 Italian participants. Mean age was about 75 years, and baseline data were collected from 1995 to 1997.

Follow-up visits were conducted after 4 years and again after 7 years. Using hospital medical records and mortality data, the researchers were able to collect surveillance data through 2018. Hospital records, surveys, and clinical assessments helped them identify incident and prevalent cardiovascular diseases, such as stroke, coronary heart disease, and heart failure.

Participants’ physical activity patterns were classified as stable-high, low-increasing, high-decreasing, and stable-low. Exposure was evaluated at 70, 75, 80, and 85 years of age.

“In our analyses, we focused on moderate to vigorous physical activity, and these include a broad range of exercises, such as walking very briskly, playing tennis, [and] jogging, but comprise also other activities, such as gardening or doing household chores,” said Dr. Amidei.

Patterns of stable-low physical activity were linked to a significantly greater risk for cardiovascular outcomes in men than patterns of stable-high physical activity (hazard ratio, 0.48; 95% confidence interval, 0.27-0.86; P for trend = .002).

No significant relation was found between physical activity and stroke, the researchers note.

“The benefits of physical activity seem to lessen above the age of 75 years and seem more important in men,” noted Dr. Lavie. “This may be partly due to the higher risk of CVD in men. Women typically lag 13 to 15 years behind men for CVD but start catching up in older years.”

Limitations of the study include lack of information regarding physical activity during mid-life, the limited number of stroke events, the relatively few participants older than 85 years, and potential recall bias, the researchers note.

Another limitation was that the physical activity data were based on patient surveys collected 3 years apart and did not involve the use of an accelerometer, the researchers add.

“Future observational studies are required to confirm our findings and pathophysiological studies are warranted to examine the underlying biological mechanisms. Physical activity is likely to be beneficial at any age, but to summarize our findings, we could say that when it comes to being physically active, the sooner the better,” concluded Dr. Amidei.

Dr. Amidei reports no relevant financial relationships.

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

Increasingly active patterns of physical activity were linked with reduced rates of overall mortality and cardiovascular disease (CVD), but early rather than later in late life, in a 20-year follow-up cohort study.

In this population of people older than 65 years, researchers found that physical activity overall was associated with lower rates of incident CVD, particularly among men, and the association was strongest in people 70 to 75 years of age, rather than in older age groups.

They also looked at “trajectories,” or changes in activity over time, and found that a stable-high trajectory of activity was associated with a significantly lower risk for cardiovascular outcomes in men than in those with a stable-low trajectory. For women, more physical activity was consistently associated with lower CVD outcomes, although not statistically significantly so, except for overall mortality, which did reach significance.

Notably, the greatest reduction in cardiovascular risk was reported in people who did more than 20 minutes of physical exercise each day, and it was more pronounced in those 70 years of age.

Physical activity was also associated with a lower incidence of heart failure and coronary heart disease in older people, again especially early on in late life, reported Claudio Barbiellini Amidei, MD, University of Padua, Italy, and colleagues.

The data suggest that physical activity is more effective in preventing CVD onset when implemented early rather than later in life, noted Dr. Amidei in an email.

“The findings of our study are suggestive of a protective effect of physical activity in late-life on cardiovascular health. WHO recommendations for adults and older adults are to practice at least 20 minutes of moderate to vigorous physical activity per day. I believe this is a realistic target, and policy makers should raise awareness on the importance of achieving this goal at all ages, including in late-life,” Dr. Amidei said.

The study was published online Feb. 14 in Heart.

Previous research has demonstrated that the most benefit of high physical activity, compared with low, begins at about 60 years of age, and that is because younger people are at much lower risk, noted Carl “Chip” Lavie MD, FACC, medical director of cardiac rehabilitation and prevention, Ochsner Clinical School–The University of Queensland School of Medicine, New Orleans, who was not involved in the study.

“At quite old ages, for example over age 80, resistance exercise or weight training and balance training may be even more important than aerobic training,” he added.

Activity ‘trajectories’

The benefits of physical activity on cardiovascular risk are well established, the researchers note. Less clear is the role that trajectories of activity over time play, although research to date suggests a reduction in risk with increasing activity from mid-life to early old age, they write.

For the current analysis, the researchers assessed 3,099 Italian participants. Mean age was about 75 years, and baseline data were collected from 1995 to 1997.

Follow-up visits were conducted after 4 years and again after 7 years. Using hospital medical records and mortality data, the researchers were able to collect surveillance data through 2018. Hospital records, surveys, and clinical assessments helped them identify incident and prevalent cardiovascular diseases, such as stroke, coronary heart disease, and heart failure.

Participants’ physical activity patterns were classified as stable-high, low-increasing, high-decreasing, and stable-low. Exposure was evaluated at 70, 75, 80, and 85 years of age.

“In our analyses, we focused on moderate to vigorous physical activity, and these include a broad range of exercises, such as walking very briskly, playing tennis, [and] jogging, but comprise also other activities, such as gardening or doing household chores,” said Dr. Amidei.

Patterns of stable-low physical activity were linked to a significantly greater risk for cardiovascular outcomes in men than patterns of stable-high physical activity (hazard ratio, 0.48; 95% confidence interval, 0.27-0.86; P for trend = .002).

No significant relation was found between physical activity and stroke, the researchers note.

“The benefits of physical activity seem to lessen above the age of 75 years and seem more important in men,” noted Dr. Lavie. “This may be partly due to the higher risk of CVD in men. Women typically lag 13 to 15 years behind men for CVD but start catching up in older years.”

Limitations of the study include lack of information regarding physical activity during mid-life, the limited number of stroke events, the relatively few participants older than 85 years, and potential recall bias, the researchers note.

Another limitation was that the physical activity data were based on patient surveys collected 3 years apart and did not involve the use of an accelerometer, the researchers add.

“Future observational studies are required to confirm our findings and pathophysiological studies are warranted to examine the underlying biological mechanisms. Physical activity is likely to be beneficial at any age, but to summarize our findings, we could say that when it comes to being physically active, the sooner the better,” concluded Dr. Amidei.

Dr. Amidei reports no relevant financial relationships.

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

Increasingly active patterns of physical activity were linked with reduced rates of overall mortality and cardiovascular disease (CVD), but early rather than later in late life, in a 20-year follow-up cohort study.

In this population of people older than 65 years, researchers found that physical activity overall was associated with lower rates of incident CVD, particularly among men, and the association was strongest in people 70 to 75 years of age, rather than in older age groups.

They also looked at “trajectories,” or changes in activity over time, and found that a stable-high trajectory of activity was associated with a significantly lower risk for cardiovascular outcomes in men than in those with a stable-low trajectory. For women, more physical activity was consistently associated with lower CVD outcomes, although not statistically significantly so, except for overall mortality, which did reach significance.

Notably, the greatest reduction in cardiovascular risk was reported in people who did more than 20 minutes of physical exercise each day, and it was more pronounced in those 70 years of age.

Physical activity was also associated with a lower incidence of heart failure and coronary heart disease in older people, again especially early on in late life, reported Claudio Barbiellini Amidei, MD, University of Padua, Italy, and colleagues.

The data suggest that physical activity is more effective in preventing CVD onset when implemented early rather than later in life, noted Dr. Amidei in an email.

“The findings of our study are suggestive of a protective effect of physical activity in late-life on cardiovascular health. WHO recommendations for adults and older adults are to practice at least 20 minutes of moderate to vigorous physical activity per day. I believe this is a realistic target, and policy makers should raise awareness on the importance of achieving this goal at all ages, including in late-life,” Dr. Amidei said.

The study was published online Feb. 14 in Heart.

Previous research has demonstrated that the most benefit of high physical activity, compared with low, begins at about 60 years of age, and that is because younger people are at much lower risk, noted Carl “Chip” Lavie MD, FACC, medical director of cardiac rehabilitation and prevention, Ochsner Clinical School–The University of Queensland School of Medicine, New Orleans, who was not involved in the study.

“At quite old ages, for example over age 80, resistance exercise or weight training and balance training may be even more important than aerobic training,” he added.

Activity ‘trajectories’

The benefits of physical activity on cardiovascular risk are well established, the researchers note. Less clear is the role that trajectories of activity over time play, although research to date suggests a reduction in risk with increasing activity from mid-life to early old age, they write.

For the current analysis, the researchers assessed 3,099 Italian participants. Mean age was about 75 years, and baseline data were collected from 1995 to 1997.

Follow-up visits were conducted after 4 years and again after 7 years. Using hospital medical records and mortality data, the researchers were able to collect surveillance data through 2018. Hospital records, surveys, and clinical assessments helped them identify incident and prevalent cardiovascular diseases, such as stroke, coronary heart disease, and heart failure.

Participants’ physical activity patterns were classified as stable-high, low-increasing, high-decreasing, and stable-low. Exposure was evaluated at 70, 75, 80, and 85 years of age.

“In our analyses, we focused on moderate to vigorous physical activity, and these include a broad range of exercises, such as walking very briskly, playing tennis, [and] jogging, but comprise also other activities, such as gardening or doing household chores,” said Dr. Amidei.

Patterns of stable-low physical activity were linked to a significantly greater risk for cardiovascular outcomes in men than patterns of stable-high physical activity (hazard ratio, 0.48; 95% confidence interval, 0.27-0.86; P for trend = .002).

No significant relation was found between physical activity and stroke, the researchers note.

“The benefits of physical activity seem to lessen above the age of 75 years and seem more important in men,” noted Dr. Lavie. “This may be partly due to the higher risk of CVD in men. Women typically lag 13 to 15 years behind men for CVD but start catching up in older years.”

Limitations of the study include lack of information regarding physical activity during mid-life, the limited number of stroke events, the relatively few participants older than 85 years, and potential recall bias, the researchers note.

Another limitation was that the physical activity data were based on patient surveys collected 3 years apart and did not involve the use of an accelerometer, the researchers add.

“Future observational studies are required to confirm our findings and pathophysiological studies are warranted to examine the underlying biological mechanisms. Physical activity is likely to be beneficial at any age, but to summarize our findings, we could say that when it comes to being physically active, the sooner the better,” concluded Dr. Amidei.

Dr. Amidei reports no relevant financial relationships.

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

Earlier menopause appears to be associated with a higher risk of dementia, and earlier onset of dementia, compared with menopause at normal age or later, according to a large study.

“Being aware of this increased risk can help women practice strategies to prevent dementia and to work with their physicians to closely monitor their cognitive status as they age,” study investigator Wenting Hao, MD, with Shandong University, Jinan, China, says in a news release.

The findings were presented in an e-poster March 1 at the Epidemiology, Prevention, Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.
 

UK Biobank data

Dr. Hao and colleagues examined health data for 153,291 women who were 60 years old on average when they became participants in the UK Biobank.

Age at menopause was categorized as premature (younger than age 40), early (40 to 44 years), reference (45 to 51), 52 to 55 years, and 55+ years.

Compared with women who entered menopause around age 50 years (reference), women who experienced premature menopause were 35% more likely to develop some type of dementia later in life (hazard ratio, 1.35; 95% confidence interval, 1.22 to 1.91).

Women with early menopause were also more likely to develop early-onset dementia, that is, before age 65 (HR, 1.31; 95% confidence interval, 1.07 to 1.72).

Women who entered menopause later (at age 52+) had dementia risk similar to women who entered menopause at the average age of 50 to 51 years.

The results were adjusted for relevant cofactors, including age at last exam, race, educational level, cigarette and alcohol use, body mass index, cardiovascular disease, diabetes, income, and leisure and physical activities.

Blame it on estrogen?

Reduced estrogen levels may be a factor in the possible connection between early menopause and dementia, Dr. Hao and her colleagues say.

Estradiol plays a key role in a range of neurological functions, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative disease and speed up progression of dementia, they explain.

“We know that the lack of estrogen over the long term enhances oxidative stress, which may increase brain aging and lead to cognitive impairment,” Dr. Hao adds.

Limitations of the study include reliance on self-reported information about age at menopause onset.

Also, the researchers did not evaluate dementia rates in women who had a naturally occurring early menopause separate from the women with surgery-induced menopause, which may affect the results.

Finally, the data used for this study included mostly White women living in the U.K. and may not generalize to other populations.
 

Supportive evidence, critical area of research

The U.K. study supports results of a previously reported Kaiser Permanente study, which showed women who entered menopause at age 45 or younger were at 28% greater dementia risk, compared with women who experienced menopause after age 45.

Reached for comment, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, noted that nearly two-thirds of Americans with Alzheimer’s are women.

“We know Alzheimer’s and other dementias impact a greater number of women than men, but we don’t know why,” she told this news organization.

“Lifelong differences in women may affect their risk or affect what is contributing to their underlying biology of the disease, and we need more research to better understand what may be these contributing factors,” said Dr. Snyder.

“Reproductive history is one critical area being studied. The physical and hormonal changes that occur during menopause – as well as other hormonal changes throughout life – are considerable, and it’s important to understand what impact, if any, these changes may have on the brain,” Dr. Snyder added.

“The potential link between reproduction history and brain health is intriguing, but much more research in this area is needed to understand these links,” she said.

The study was funded by the Start-up Foundation for Scientific Research at Shandong University. Dr. Hao and Dr. Snyder have disclosed no relevant financial relationships.

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

Earlier menopause appears to be associated with a higher risk of dementia, and earlier onset of dementia, compared with menopause at normal age or later, according to a large study.

“Being aware of this increased risk can help women practice strategies to prevent dementia and to work with their physicians to closely monitor their cognitive status as they age,” study investigator Wenting Hao, MD, with Shandong University, Jinan, China, says in a news release.

The findings were presented in an e-poster March 1 at the Epidemiology, Prevention, Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.
 

UK Biobank data

Dr. Hao and colleagues examined health data for 153,291 women who were 60 years old on average when they became participants in the UK Biobank.

Age at menopause was categorized as premature (younger than age 40), early (40 to 44 years), reference (45 to 51), 52 to 55 years, and 55+ years.

Compared with women who entered menopause around age 50 years (reference), women who experienced premature menopause were 35% more likely to develop some type of dementia later in life (hazard ratio, 1.35; 95% confidence interval, 1.22 to 1.91).

Women with early menopause were also more likely to develop early-onset dementia, that is, before age 65 (HR, 1.31; 95% confidence interval, 1.07 to 1.72).

Women who entered menopause later (at age 52+) had dementia risk similar to women who entered menopause at the average age of 50 to 51 years.

The results were adjusted for relevant cofactors, including age at last exam, race, educational level, cigarette and alcohol use, body mass index, cardiovascular disease, diabetes, income, and leisure and physical activities.

Blame it on estrogen?

Reduced estrogen levels may be a factor in the possible connection between early menopause and dementia, Dr. Hao and her colleagues say.

Estradiol plays a key role in a range of neurological functions, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative disease and speed up progression of dementia, they explain.

“We know that the lack of estrogen over the long term enhances oxidative stress, which may increase brain aging and lead to cognitive impairment,” Dr. Hao adds.

Limitations of the study include reliance on self-reported information about age at menopause onset.

Also, the researchers did not evaluate dementia rates in women who had a naturally occurring early menopause separate from the women with surgery-induced menopause, which may affect the results.

Finally, the data used for this study included mostly White women living in the U.K. and may not generalize to other populations.
 

Supportive evidence, critical area of research

The U.K. study supports results of a previously reported Kaiser Permanente study, which showed women who entered menopause at age 45 or younger were at 28% greater dementia risk, compared with women who experienced menopause after age 45.

Reached for comment, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, noted that nearly two-thirds of Americans with Alzheimer’s are women.

“We know Alzheimer’s and other dementias impact a greater number of women than men, but we don’t know why,” she told this news organization.

“Lifelong differences in women may affect their risk or affect what is contributing to their underlying biology of the disease, and we need more research to better understand what may be these contributing factors,” said Dr. Snyder.

“Reproductive history is one critical area being studied. The physical and hormonal changes that occur during menopause – as well as other hormonal changes throughout life – are considerable, and it’s important to understand what impact, if any, these changes may have on the brain,” Dr. Snyder added.

“The potential link between reproduction history and brain health is intriguing, but much more research in this area is needed to understand these links,” she said.

The study was funded by the Start-up Foundation for Scientific Research at Shandong University. Dr. Hao and Dr. Snyder have disclosed no relevant financial relationships.

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

Earlier menopause appears to be associated with a higher risk of dementia, and earlier onset of dementia, compared with menopause at normal age or later, according to a large study.

“Being aware of this increased risk can help women practice strategies to prevent dementia and to work with their physicians to closely monitor their cognitive status as they age,” study investigator Wenting Hao, MD, with Shandong University, Jinan, China, says in a news release.

The findings were presented in an e-poster March 1 at the Epidemiology, Prevention, Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.
 

UK Biobank data

Dr. Hao and colleagues examined health data for 153,291 women who were 60 years old on average when they became participants in the UK Biobank.

Age at menopause was categorized as premature (younger than age 40), early (40 to 44 years), reference (45 to 51), 52 to 55 years, and 55+ years.

Compared with women who entered menopause around age 50 years (reference), women who experienced premature menopause were 35% more likely to develop some type of dementia later in life (hazard ratio, 1.35; 95% confidence interval, 1.22 to 1.91).

Women with early menopause were also more likely to develop early-onset dementia, that is, before age 65 (HR, 1.31; 95% confidence interval, 1.07 to 1.72).

Women who entered menopause later (at age 52+) had dementia risk similar to women who entered menopause at the average age of 50 to 51 years.

The results were adjusted for relevant cofactors, including age at last exam, race, educational level, cigarette and alcohol use, body mass index, cardiovascular disease, diabetes, income, and leisure and physical activities.

Blame it on estrogen?

Reduced estrogen levels may be a factor in the possible connection between early menopause and dementia, Dr. Hao and her colleagues say.

Estradiol plays a key role in a range of neurological functions, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative disease and speed up progression of dementia, they explain.

“We know that the lack of estrogen over the long term enhances oxidative stress, which may increase brain aging and lead to cognitive impairment,” Dr. Hao adds.

Limitations of the study include reliance on self-reported information about age at menopause onset.

Also, the researchers did not evaluate dementia rates in women who had a naturally occurring early menopause separate from the women with surgery-induced menopause, which may affect the results.

Finally, the data used for this study included mostly White women living in the U.K. and may not generalize to other populations.
 

Supportive evidence, critical area of research

The U.K. study supports results of a previously reported Kaiser Permanente study, which showed women who entered menopause at age 45 or younger were at 28% greater dementia risk, compared with women who experienced menopause after age 45.

Reached for comment, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, noted that nearly two-thirds of Americans with Alzheimer’s are women.

“We know Alzheimer’s and other dementias impact a greater number of women than men, but we don’t know why,” she told this news organization.

“Lifelong differences in women may affect their risk or affect what is contributing to their underlying biology of the disease, and we need more research to better understand what may be these contributing factors,” said Dr. Snyder.

“Reproductive history is one critical area being studied. The physical and hormonal changes that occur during menopause – as well as other hormonal changes throughout life – are considerable, and it’s important to understand what impact, if any, these changes may have on the brain,” Dr. Snyder added.

“The potential link between reproduction history and brain health is intriguing, but much more research in this area is needed to understand these links,” she said.

The study was funded by the Start-up Foundation for Scientific Research at Shandong University. Dr. Hao and Dr. Snyder have disclosed no relevant financial relationships.

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

Patients with familial hypercholesterolemia (FH) who start lipid-lowering treatment earlier in life may reduce their cardiovascular risk, compared with those who don’t begin treatment early, according to results of a recent meta-analysis.

They showed a difference in the carotid intima-media thickness (IMT) between patients with and without FH that increased with age, but there was also a difference in IMT seen among patients with FH who started treatment early, compared with untreated patients with FH, Kika van Bergen en Henegouwen, of the departments of pediatrics and epidemiology and data science at Amsterdam University Medical Center, and colleagues wrote in their report, published in the Journal of Clinical Lipidology.

“The fact that the difference in IMT increases with age between FH patients and unaffected controls, and is more pronounced in studies with untreated FH patients than in studies with treated patients, suggests that starting treatment already at a young age in patients with FH is preferred,” the researchers wrote. “However, despite treatment, IMT in treated FH patients is still thicker in comparison to subjects without FH.”

The researchers identified 42 studies with among patients with FH and healthy control groups across the MEDLINE, EMBASE and Trials.gov databases up to a cutoff date of April 2020, with 39 studies specifically examining carotid IMT, 2 studies evaluating carotid and femoral IMT, and 1 study evaluating femoral IMT alone. Overall, the researchers examined IMT measurements in 3,796 patients with FH and 2,363 control group participants.

Although data on age and gender for FH and control groups were not available in 6 studies, the mean age ranged from 9 to 57 years for patients with FH and from 8 to 61 years in the control group. Men comprised just under half of both the FH and control groups.

The mean between-group difference in carotid IMT in 34 studies was 0.11 mm (95% confidence interval, 0.06-0.15 mm; P < .001) for patients with FH, compared with the control group, while the mean difference in femoral IMT in three studies was 0.47 mm (95% CI, 0.19-0.74 mm; P < .001) between FH and control groups.

In 13 studies in which data on differences between partly treated and untreated FH were available, there was a significant between-group difference in carotid IMT with partly treated patients with FH, compared with the control group (0.05 mm; 95% CI, 0.03-0.08 mm; P < .001), but a larger mean between-group difference in carotid IMT among untreated patients with FH, compared with a control group (0.12 mm; 95% CI, 0.03-0.21 mm; P = .009).

The researchers also analyzed how age impacts carotid IMT, and they found patients with FH had a mean increase of 0.0018 mm (95% CI, –0.0007 to 0.0042 mm) over a control group in 34 studies. For patients with partly treated FH, compared with patients with untreated FH, the mean between-group increase per year was smaller (0.0023 mm; 95% CI, 0.0021-0.0025 mm), compared with the control group (0.0104 mm; 95% CI, 0.0100-0.0108 mm).

“This sign of residual risk might suggest that more robust cholesterol-lowering treatment and achieving treatment targets, or earlier treatment initiation, is needed to reduce IMT progression to non-FH conditions,” the researchers said. “Therefore, we must find and diagnose these patients, and treat them according to current guidelines.”

Limitations of the authors’ meta-analyses include heterogeneity among studies, differences in IMT measurement protocols, and inclusion of studies with an open-label design. Although randomized clinical trials would be preferable to compare treatment effect, “since statin therapy is indicated in FH patients to reduce [cardiovascular disease], it would be unethical to have a placebo group,” they said.

The authors reported no relevant financial disclosures.

Patients with familial hypercholesterolemia (FH) who start lipid-lowering treatment earlier in life may reduce their cardiovascular risk, compared with those who don’t begin treatment early, according to results of a recent meta-analysis.

They showed a difference in the carotid intima-media thickness (IMT) between patients with and without FH that increased with age, but there was also a difference in IMT seen among patients with FH who started treatment early, compared with untreated patients with FH, Kika van Bergen en Henegouwen, of the departments of pediatrics and epidemiology and data science at Amsterdam University Medical Center, and colleagues wrote in their report, published in the Journal of Clinical Lipidology.

“The fact that the difference in IMT increases with age between FH patients and unaffected controls, and is more pronounced in studies with untreated FH patients than in studies with treated patients, suggests that starting treatment already at a young age in patients with FH is preferred,” the researchers wrote. “However, despite treatment, IMT in treated FH patients is still thicker in comparison to subjects without FH.”

The researchers identified 42 studies with among patients with FH and healthy control groups across the MEDLINE, EMBASE and Trials.gov databases up to a cutoff date of April 2020, with 39 studies specifically examining carotid IMT, 2 studies evaluating carotid and femoral IMT, and 1 study evaluating femoral IMT alone. Overall, the researchers examined IMT measurements in 3,796 patients with FH and 2,363 control group participants.

Although data on age and gender for FH and control groups were not available in 6 studies, the mean age ranged from 9 to 57 years for patients with FH and from 8 to 61 years in the control group. Men comprised just under half of both the FH and control groups.

The mean between-group difference in carotid IMT in 34 studies was 0.11 mm (95% confidence interval, 0.06-0.15 mm; P < .001) for patients with FH, compared with the control group, while the mean difference in femoral IMT in three studies was 0.47 mm (95% CI, 0.19-0.74 mm; P < .001) between FH and control groups.

In 13 studies in which data on differences between partly treated and untreated FH were available, there was a significant between-group difference in carotid IMT with partly treated patients with FH, compared with the control group (0.05 mm; 95% CI, 0.03-0.08 mm; P < .001), but a larger mean between-group difference in carotid IMT among untreated patients with FH, compared with a control group (0.12 mm; 95% CI, 0.03-0.21 mm; P = .009).

The researchers also analyzed how age impacts carotid IMT, and they found patients with FH had a mean increase of 0.0018 mm (95% CI, –0.0007 to 0.0042 mm) over a control group in 34 studies. For patients with partly treated FH, compared with patients with untreated FH, the mean between-group increase per year was smaller (0.0023 mm; 95% CI, 0.0021-0.0025 mm), compared with the control group (0.0104 mm; 95% CI, 0.0100-0.0108 mm).

“This sign of residual risk might suggest that more robust cholesterol-lowering treatment and achieving treatment targets, or earlier treatment initiation, is needed to reduce IMT progression to non-FH conditions,” the researchers said. “Therefore, we must find and diagnose these patients, and treat them according to current guidelines.”

Limitations of the authors’ meta-analyses include heterogeneity among studies, differences in IMT measurement protocols, and inclusion of studies with an open-label design. Although randomized clinical trials would be preferable to compare treatment effect, “since statin therapy is indicated in FH patients to reduce [cardiovascular disease], it would be unethical to have a placebo group,” they said.

The authors reported no relevant financial disclosures.

Patients with familial hypercholesterolemia (FH) who start lipid-lowering treatment earlier in life may reduce their cardiovascular risk, compared with those who don’t begin treatment early, according to results of a recent meta-analysis.

They showed a difference in the carotid intima-media thickness (IMT) between patients with and without FH that increased with age, but there was also a difference in IMT seen among patients with FH who started treatment early, compared with untreated patients with FH, Kika van Bergen en Henegouwen, of the departments of pediatrics and epidemiology and data science at Amsterdam University Medical Center, and colleagues wrote in their report, published in the Journal of Clinical Lipidology.

“The fact that the difference in IMT increases with age between FH patients and unaffected controls, and is more pronounced in studies with untreated FH patients than in studies with treated patients, suggests that starting treatment already at a young age in patients with FH is preferred,” the researchers wrote. “However, despite treatment, IMT in treated FH patients is still thicker in comparison to subjects without FH.”

The researchers identified 42 studies with among patients with FH and healthy control groups across the MEDLINE, EMBASE and Trials.gov databases up to a cutoff date of April 2020, with 39 studies specifically examining carotid IMT, 2 studies evaluating carotid and femoral IMT, and 1 study evaluating femoral IMT alone. Overall, the researchers examined IMT measurements in 3,796 patients with FH and 2,363 control group participants.

Although data on age and gender for FH and control groups were not available in 6 studies, the mean age ranged from 9 to 57 years for patients with FH and from 8 to 61 years in the control group. Men comprised just under half of both the FH and control groups.

The mean between-group difference in carotid IMT in 34 studies was 0.11 mm (95% confidence interval, 0.06-0.15 mm; P < .001) for patients with FH, compared with the control group, while the mean difference in femoral IMT in three studies was 0.47 mm (95% CI, 0.19-0.74 mm; P < .001) between FH and control groups.

In 13 studies in which data on differences between partly treated and untreated FH were available, there was a significant between-group difference in carotid IMT with partly treated patients with FH, compared with the control group (0.05 mm; 95% CI, 0.03-0.08 mm; P < .001), but a larger mean between-group difference in carotid IMT among untreated patients with FH, compared with a control group (0.12 mm; 95% CI, 0.03-0.21 mm; P = .009).

The researchers also analyzed how age impacts carotid IMT, and they found patients with FH had a mean increase of 0.0018 mm (95% CI, –0.0007 to 0.0042 mm) over a control group in 34 studies. For patients with partly treated FH, compared with patients with untreated FH, the mean between-group increase per year was smaller (0.0023 mm; 95% CI, 0.0021-0.0025 mm), compared with the control group (0.0104 mm; 95% CI, 0.0100-0.0108 mm).

“This sign of residual risk might suggest that more robust cholesterol-lowering treatment and achieving treatment targets, or earlier treatment initiation, is needed to reduce IMT progression to non-FH conditions,” the researchers said. “Therefore, we must find and diagnose these patients, and treat them according to current guidelines.”

Limitations of the authors’ meta-analyses include heterogeneity among studies, differences in IMT measurement protocols, and inclusion of studies with an open-label design. Although randomized clinical trials would be preferable to compare treatment effect, “since statin therapy is indicated in FH patients to reduce [cardiovascular disease], it would be unethical to have a placebo group,” they said.

The authors reported no relevant financial disclosures.

The prevalence of metabolic syndrome varies according to how it is defined, but approximately 30% of psoriatic arthritis (PsA) patients met the criteria in a cohort study of 724 individuals, as did approximately 23%-63% of patients across multiple studies, investigators from Spain report.

Previous studies of people with PsA in particular suggest they are at an increased risk of cardiovascular disease and have a higher prevalence of metabolic syndrome, prompting recommendations on cardiovascular risk management for patients with PsA, wrote the authors, Ana Urruticoechea-Arana, MD, of the department of rheumatology, Hospital Can Misses, Ibiza, Spain, and colleagues.

However, assessing the prevalence of metabolic syndrome remains a challenge because the definition varies across studies, they noted.

For a more thorough assessment of the prevalence of metabolic syndrome in this population, the researchers conducted a study using two sources: a systematic literature review of 18 studies published up to March 2019, and data on patients with PsA enrolled in the CARMA (Spanish Cardiovascular in Rheumatology) project, a longitudinal cohort observational study of adults with inflammatory diseases in Spain. The findings were published March 1 in the Journal of Clinical Rheumatology.

The literature review included a total of a total of 2,452 patients with PsA, with a mean age between 42 and 59 years, and a mean disease duration ranging from 3 to 14 years.

The definitions of metabolic syndrome varied; the most common was the definition from the National Cholesterol Education Program (NECP ATP III). Other definitions used in the studies included those issued by the International Diabetes Federation, the World Health Organization, and the American Heart Association.

Across these studies, the rate of metabolic syndrome ranged from 23.5% to 62.9%. Prevalence was similar between men and women. One study that included patients with a PsA disease duration of only 3 years showed a prevalence of 38%, similar to the average prevalence overall. Another study showed a significantly higher prevalence of metabolic syndrome in patients with PsA and cutaneous psoriasis, compared with those without psoriasis (40.8% vs. 13.16%; P = .006).

The CARMA study included 724 patients with PsA; 45.4% were women and 21.8% were smokers. The mean age of the population in this study was 51 years, and the mean disease duration was 9 years. Overall, 222 patients (30.7%) met at least three criteria for metabolic syndrome, based on the NCEP ATP III definition. The most common abnormal findings for traditional cardiovascular risk factors in the CARMA cohort were high blood pressure (66.8%), hyperglycemia (42.6%), and hypertriglyceridemia (30.6%).

Despite the variation in prevalence of metabolic syndrome, depending on the definition used, the authors wrote, “It can be stated that the rate of [metabolic syndrome] in patients with PsA is in general very high, especially if we take into account the mean age of patients included in the studies.”

“These findings support the hypotheses that this increase in the inflammatory pathway in PsA may contribute a higher risk of cardiovascular events and [metabolic syndrome] in patients with PsA than patients with psoriasis alone, the risk being even higher in severe PsA,” and that insulin resistance, metabolic syndrome, and atherosclerotic events “may have a common inflammatory basis,” the researchers wrote in their discussion of the results.

The study findings were limited by several factors, most importantly the variation in definitions of metabolic syndrome in the literature review, which limits the generalizability of the results, the researchers said. Limitations of the CARMA study include the focus only on patients who were being cared for in hospitals, which might yield an overestimation of metabolic syndrome, they added.

However, the results support findings from previous studies and highlight the need for proper assessment of body weight and cardiovascular risk factors in patients with PsA at the onset of disease, they said.

“Furthermore, it is necessary to conduct more research to standardize (and modify as appropriate) the definition of [metabolic syndrome] and establish the best strategy for managing it in these patients,” they concluded.

The study was funded by an independent grant from UCB Pharma. One author disclosed receiving grants from Pfizer, Abbvie, Novartis, Roche, UCB, Sanofi, BMS, Lilly, MSD, and Janssen. Lead author Dr. Urruticoechea-Arana and the other authors had no disclosures.

The prevalence of metabolic syndrome varies according to how it is defined, but approximately 30% of psoriatic arthritis (PsA) patients met the criteria in a cohort study of 724 individuals, as did approximately 23%-63% of patients across multiple studies, investigators from Spain report.

Previous studies of people with PsA in particular suggest they are at an increased risk of cardiovascular disease and have a higher prevalence of metabolic syndrome, prompting recommendations on cardiovascular risk management for patients with PsA, wrote the authors, Ana Urruticoechea-Arana, MD, of the department of rheumatology, Hospital Can Misses, Ibiza, Spain, and colleagues.

However, assessing the prevalence of metabolic syndrome remains a challenge because the definition varies across studies, they noted.

For a more thorough assessment of the prevalence of metabolic syndrome in this population, the researchers conducted a study using two sources: a systematic literature review of 18 studies published up to March 2019, and data on patients with PsA enrolled in the CARMA (Spanish Cardiovascular in Rheumatology) project, a longitudinal cohort observational study of adults with inflammatory diseases in Spain. The findings were published March 1 in the Journal of Clinical Rheumatology.

The literature review included a total of a total of 2,452 patients with PsA, with a mean age between 42 and 59 years, and a mean disease duration ranging from 3 to 14 years.

The definitions of metabolic syndrome varied; the most common was the definition from the National Cholesterol Education Program (NECP ATP III). Other definitions used in the studies included those issued by the International Diabetes Federation, the World Health Organization, and the American Heart Association.

Across these studies, the rate of metabolic syndrome ranged from 23.5% to 62.9%. Prevalence was similar between men and women. One study that included patients with a PsA disease duration of only 3 years showed a prevalence of 38%, similar to the average prevalence overall. Another study showed a significantly higher prevalence of metabolic syndrome in patients with PsA and cutaneous psoriasis, compared with those without psoriasis (40.8% vs. 13.16%; P = .006).

The CARMA study included 724 patients with PsA; 45.4% were women and 21.8% were smokers. The mean age of the population in this study was 51 years, and the mean disease duration was 9 years. Overall, 222 patients (30.7%) met at least three criteria for metabolic syndrome, based on the NCEP ATP III definition. The most common abnormal findings for traditional cardiovascular risk factors in the CARMA cohort were high blood pressure (66.8%), hyperglycemia (42.6%), and hypertriglyceridemia (30.6%).

Despite the variation in prevalence of metabolic syndrome, depending on the definition used, the authors wrote, “It can be stated that the rate of [metabolic syndrome] in patients with PsA is in general very high, especially if we take into account the mean age of patients included in the studies.”

“These findings support the hypotheses that this increase in the inflammatory pathway in PsA may contribute a higher risk of cardiovascular events and [metabolic syndrome] in patients with PsA than patients with psoriasis alone, the risk being even higher in severe PsA,” and that insulin resistance, metabolic syndrome, and atherosclerotic events “may have a common inflammatory basis,” the researchers wrote in their discussion of the results.

The study findings were limited by several factors, most importantly the variation in definitions of metabolic syndrome in the literature review, which limits the generalizability of the results, the researchers said. Limitations of the CARMA study include the focus only on patients who were being cared for in hospitals, which might yield an overestimation of metabolic syndrome, they added.

However, the results support findings from previous studies and highlight the need for proper assessment of body weight and cardiovascular risk factors in patients with PsA at the onset of disease, they said.

“Furthermore, it is necessary to conduct more research to standardize (and modify as appropriate) the definition of [metabolic syndrome] and establish the best strategy for managing it in these patients,” they concluded.

The study was funded by an independent grant from UCB Pharma. One author disclosed receiving grants from Pfizer, Abbvie, Novartis, Roche, UCB, Sanofi, BMS, Lilly, MSD, and Janssen. Lead author Dr. Urruticoechea-Arana and the other authors had no disclosures.

The prevalence of metabolic syndrome varies according to how it is defined, but approximately 30% of psoriatic arthritis (PsA) patients met the criteria in a cohort study of 724 individuals, as did approximately 23%-63% of patients across multiple studies, investigators from Spain report.

Previous studies of people with PsA in particular suggest they are at an increased risk of cardiovascular disease and have a higher prevalence of metabolic syndrome, prompting recommendations on cardiovascular risk management for patients with PsA, wrote the authors, Ana Urruticoechea-Arana, MD, of the department of rheumatology, Hospital Can Misses, Ibiza, Spain, and colleagues.

However, assessing the prevalence of metabolic syndrome remains a challenge because the definition varies across studies, they noted.

For a more thorough assessment of the prevalence of metabolic syndrome in this population, the researchers conducted a study using two sources: a systematic literature review of 18 studies published up to March 2019, and data on patients with PsA enrolled in the CARMA (Spanish Cardiovascular in Rheumatology) project, a longitudinal cohort observational study of adults with inflammatory diseases in Spain. The findings were published March 1 in the Journal of Clinical Rheumatology.

The literature review included a total of a total of 2,452 patients with PsA, with a mean age between 42 and 59 years, and a mean disease duration ranging from 3 to 14 years.

The definitions of metabolic syndrome varied; the most common was the definition from the National Cholesterol Education Program (NECP ATP III). Other definitions used in the studies included those issued by the International Diabetes Federation, the World Health Organization, and the American Heart Association.

Across these studies, the rate of metabolic syndrome ranged from 23.5% to 62.9%. Prevalence was similar between men and women. One study that included patients with a PsA disease duration of only 3 years showed a prevalence of 38%, similar to the average prevalence overall. Another study showed a significantly higher prevalence of metabolic syndrome in patients with PsA and cutaneous psoriasis, compared with those without psoriasis (40.8% vs. 13.16%; P = .006).

The CARMA study included 724 patients with PsA; 45.4% were women and 21.8% were smokers. The mean age of the population in this study was 51 years, and the mean disease duration was 9 years. Overall, 222 patients (30.7%) met at least three criteria for metabolic syndrome, based on the NCEP ATP III definition. The most common abnormal findings for traditional cardiovascular risk factors in the CARMA cohort were high blood pressure (66.8%), hyperglycemia (42.6%), and hypertriglyceridemia (30.6%).

Despite the variation in prevalence of metabolic syndrome, depending on the definition used, the authors wrote, “It can be stated that the rate of [metabolic syndrome] in patients with PsA is in general very high, especially if we take into account the mean age of patients included in the studies.”

“These findings support the hypotheses that this increase in the inflammatory pathway in PsA may contribute a higher risk of cardiovascular events and [metabolic syndrome] in patients with PsA than patients with psoriasis alone, the risk being even higher in severe PsA,” and that insulin resistance, metabolic syndrome, and atherosclerotic events “may have a common inflammatory basis,” the researchers wrote in their discussion of the results.

The study findings were limited by several factors, most importantly the variation in definitions of metabolic syndrome in the literature review, which limits the generalizability of the results, the researchers said. Limitations of the CARMA study include the focus only on patients who were being cared for in hospitals, which might yield an overestimation of metabolic syndrome, they added.

However, the results support findings from previous studies and highlight the need for proper assessment of body weight and cardiovascular risk factors in patients with PsA at the onset of disease, they said.

“Furthermore, it is necessary to conduct more research to standardize (and modify as appropriate) the definition of [metabolic syndrome] and establish the best strategy for managing it in these patients,” they concluded.

The study was funded by an independent grant from UCB Pharma. One author disclosed receiving grants from Pfizer, Abbvie, Novartis, Roche, UCB, Sanofi, BMS, Lilly, MSD, and Janssen. Lead author Dr. Urruticoechea-Arana and the other authors had no disclosures.

“Living with diabetes is not smooth sailing…From the onset of the disease in a child or adolescent through all the days that follow, there is nothing ordinary about it,” according to Aide aux Jeunes Diabétiques (AJD), a French association providing support for children and adolescents with diabetes. What is the psychological impact of the disease on patients and their loved ones? When we look at the life of a person with diabetes, are there key stages that call for more focused attention?

Nadine Hoffmeister, a psychologist at AJD, offers support to patients with diabetes and their parents as they navigate and deal with in-patient treatment for the disease. She recently spoke with this news organization.

Q: Are psychological issues more prevalent in patients with type 1 diabetes (T1D) than in the general population?

Dr. Hoffmeister: Having a chronic disease is not something that should be viewed as automatically making the person more susceptible to psychological issues. When we think about kids with T1D, it’s important to keep in mind that the risk for depression and the risk for eating disorders are, in general, higher in adolescence.

Of course, it can’t be denied that having diabetes can make one more vulnerable to experiencing mental distress. Clearly, the risk for eating disorders is there, given the constant focus on managing one’s diet. And there’s a greater risk for depression, because life with diabetes can really be trying. That said, how much impact the disease has depends in large part on the environment, the monitoring, and the collaboration of everyone involved.
 

Q: Are there key stages in the life of patients with T1D that call for targeted psychological support? 

Dr. Hoffmeister: The thing about T1D is that it can affect anyone at any age – a small child, a teenager, a young adult. So, in that sense, all ‘firsts’ are key stages. They start, of course, with the first ‘first’: diagnosis. For children diagnosed at an early age, there’s the first day of nursery school or kindergarten, the first piece of birthday cake. Then we get to kids starting middle school and high school, places where they’re now left to their own devices. This is when, for the first time, they’ll have an opportunity to take a trip without their parents and siblings, to go to a party.

And then, there’s the first time using a particular treatment. For example, switching from injections to a pump requires not only an adjustment in terms of physically operating a new device, but a reorientation in terms of mentally settling into a new routine, a new way of administering medication, and so on. They have to learn how to get along with this machine that’s attached to them all the time. They have to view it as being a part of them, view it as a partner, a teammate, a friend. It’s not that easy.

Later on, one of the major stages is, of course, adolescence. Critical developments in the separation–individuation process are taking place. They start to feel the need to break free, to become autonomous, as they seek to fully come to terms with their disease.

Parents usually worry about this stage, adolescence. They’re scared that their child won’t be as vigilant, that they’ll be scatterbrained or careless when it comes to staying on top of all those things that need to be done to keep T1D under control. Most of the time, this stage goes better than they thought. Still, the fact remains that it’s difficult to find a happy medium between adolescence and diabetes. Indeed, there’s a bit of a paradox here. On the one hand, we have adolescence which, by definition, is a time of spontaneity, independence, of trying new things. On the other hand, we have diabetes and its limits and constraints, its care and treatment, day in and day out. We have to pay close attention to how the child navigates and makes their way through this stage of their life.

During adolescence, there’s also a heightened awareness and concern about how others look at you, see you – everywhere, not only in classrooms and hallways. If the way someone looks at them seems aggressive or intrusive, the child may start to feel scared. The risk then becomes that they’ll start feeling awkward or ashamed or embarrassed. We have to keep this in mind and help lead the child away from those feelings. Otherwise, they can end up with low self-esteem, they can start to withdraw.

It can sometimes get to the point where they choose to neglect their treatment so as to conform to the way others see them. Adults can easily lose sight of these kinds of things. So, it’s imperative that we talk to the child. If they’re having trouble following their treatment plan, maybe there’s something going on at school. So, let’s ask them: “How do you like your classes and teachers?” “How are you doing with your injections? Are you finding that they’re getting easier and easier to do?” And always keeping in mind the real possibility that the child may be feeling awkward, ashamed, embarrassed.
 

Q: Is enough being done to pick up on and address these children’s needs?

Dr. Hoffmeister: I think that these efforts are becoming more and more widespread. Still, there are disparities. When it comes to patients with chronic diseases, it’s not always easy to implement mental health care into the treatment plan. In some cases, there might not be a hospital nearby. And as we know, there are no spots available in medical and psychiatric centers. Of course, outside of hospital settings, we’re seeing the unfortunate situation of fewer and fewer middle schools and high schools having nurses on site.

And then, what options there are for getting support vary greatly from hospital to hospital. Some don’t have psychologists. Others have full schedules and not enough staff. That said, more and more teams are trying to set up regular appointments right from the time of diagnosis. This is a really good approach to take, even though the circumstances may not be ideal. After all, the person has just been told that they have diabetes; they’re not really in the best state of mind to have any kind of discussion.
 

Q: And so, it makes sense that AJD would offer the kind of mental health support that you’re now providing there.

Dr. Hoffmeister: Exactly. My position was created 4 years ago. I’m not at the hospital. I’m an external. The goal is to be able to offer this psychological support to everyone. I do consultations over the phone so that no matter where a person is in France, they’ll have access to this support. There’s great demand, and the requests are only increasing. I think this has to do with the fact that people are being diagnosed younger and younger. It’s a very complicated situation for the parents. No matter how young their child is, they want to get that support underway as soon as possible.

Q: You speak about the patients getting support. But doesn’t some kind of help have to be given to their parents and loved ones as well?

Dr. Hoffmeister: Yes. I’d say that 60% to 70% of the work I do at AJD is for parents. I also have some older adolescents and some younger kids whom I call to keep up with. But children aren’t very interested in discussing plans over the phone. For parents, the thing about diabetes is that they find themselves in these situations where their child is in the hospital for, say, a week, then is discharged, and all of a sudden, they find themselves at home as the ones in charge of their child’s treatment.

When it’s a little kid, the parents are the ones who are taking care of all the steps, the injections, the pumps. They’re dealing with the distress of a child going through episodes of nocturnal hypoglycemia. They’re experiencing varying degrees of anxiety in carrying out all of these responsibilities and, at the same time, the bond they have with their child is becoming stronger and stronger. So, there’s that anxiety. In this situation, parents may also feel a need for control. And they’re also feeling exhausted; the mental load of dealing with diabetes is very, very intense. To work through all this, many parents reach out for psychological support.

Then later on, when the child has gotten a little older, the parents find it difficult to get to the point of being able to just let go. But once the parents get to know their child better, get to know how their child experiences diabetes, they’ll get to that point. What they come to learn is that the child can take care of things, the child can feel what’s going on in their body, the child can be trusted.
 

Q: How can we help and support children with diabetes?

Dr. Hoffmeister: One of the most important things is to teach the child to come to terms with the disease and how it affects their body. In other words, the idea here is to adapt diabetes to one’s life, not the other way around. The goal is to not let diabetes take over.

When faced with standardized medical protocols, during a session with a psychologist, the child can talk about their life, give an idea of what a day in their life looks like. For example, the school cafeteria is a place where children get the opportunity to socialize and interact with their peers. We want to have that lunch period be as normal as possible for the child with diabetes. In some schools, lunchtime becomes a challenge. So, not seeing any other solution, mom stops working so the child can come home to eat. These are the kinds of situations where efforts to make the child feel included have failed. They’re tough to deal with, all around. And so this is why we do all we can to keep things as normal as possible for these children.
 

Q: What would you say is the one initiative out there that’s giving young patients with T1D the most help and support?

Dr. Hoffmeister: AJD offers stays at Care Management and Rehabilitation (SSR) sites. For kids and teenagers with diabetes, these places are like summer camps where every aspect of treatment is taken care of.

There’s a medical team monitoring their disease and a team of counselors always on hand. It’s a time when children may very well bring up things that are on their mind. All in all, the children have a safe and welcoming environment where treatment is provided and they can feel free to open up and talk.

If a problem crops up, I’m always on call to jump online. And throughout the stay, the medical team is keeping in touch to discuss the child’s care.

AJD is also an interdisciplinary association. We regularly organize practice exchange groups that bring together health care professionals and families from all over France. In this way, we’re able to collaborate and come up with resources, such as information packets and kits – for the newly diagnosed, for those starting intensive insulin therapy, and so on. These resources take into account medical protocols related to diabetes. They’re also designed with family life in mind. And having this set of resources works toward standardizing treatments.

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

“Living with diabetes is not smooth sailing…From the onset of the disease in a child or adolescent through all the days that follow, there is nothing ordinary about it,” according to Aide aux Jeunes Diabétiques (AJD), a French association providing support for children and adolescents with diabetes. What is the psychological impact of the disease on patients and their loved ones? When we look at the life of a person with diabetes, are there key stages that call for more focused attention?

Nadine Hoffmeister, a psychologist at AJD, offers support to patients with diabetes and their parents as they navigate and deal with in-patient treatment for the disease. She recently spoke with this news organization.

Q: Are psychological issues more prevalent in patients with type 1 diabetes (T1D) than in the general population?

Dr. Hoffmeister: Having a chronic disease is not something that should be viewed as automatically making the person more susceptible to psychological issues. When we think about kids with T1D, it’s important to keep in mind that the risk for depression and the risk for eating disorders are, in general, higher in adolescence.

Of course, it can’t be denied that having diabetes can make one more vulnerable to experiencing mental distress. Clearly, the risk for eating disorders is there, given the constant focus on managing one’s diet. And there’s a greater risk for depression, because life with diabetes can really be trying. That said, how much impact the disease has depends in large part on the environment, the monitoring, and the collaboration of everyone involved.
 

Q: Are there key stages in the life of patients with T1D that call for targeted psychological support? 

Dr. Hoffmeister: The thing about T1D is that it can affect anyone at any age – a small child, a teenager, a young adult. So, in that sense, all ‘firsts’ are key stages. They start, of course, with the first ‘first’: diagnosis. For children diagnosed at an early age, there’s the first day of nursery school or kindergarten, the first piece of birthday cake. Then we get to kids starting middle school and high school, places where they’re now left to their own devices. This is when, for the first time, they’ll have an opportunity to take a trip without their parents and siblings, to go to a party.

And then, there’s the first time using a particular treatment. For example, switching from injections to a pump requires not only an adjustment in terms of physically operating a new device, but a reorientation in terms of mentally settling into a new routine, a new way of administering medication, and so on. They have to learn how to get along with this machine that’s attached to them all the time. They have to view it as being a part of them, view it as a partner, a teammate, a friend. It’s not that easy.

Later on, one of the major stages is, of course, adolescence. Critical developments in the separation–individuation process are taking place. They start to feel the need to break free, to become autonomous, as they seek to fully come to terms with their disease.

Parents usually worry about this stage, adolescence. They’re scared that their child won’t be as vigilant, that they’ll be scatterbrained or careless when it comes to staying on top of all those things that need to be done to keep T1D under control. Most of the time, this stage goes better than they thought. Still, the fact remains that it’s difficult to find a happy medium between adolescence and diabetes. Indeed, there’s a bit of a paradox here. On the one hand, we have adolescence which, by definition, is a time of spontaneity, independence, of trying new things. On the other hand, we have diabetes and its limits and constraints, its care and treatment, day in and day out. We have to pay close attention to how the child navigates and makes their way through this stage of their life.

During adolescence, there’s also a heightened awareness and concern about how others look at you, see you – everywhere, not only in classrooms and hallways. If the way someone looks at them seems aggressive or intrusive, the child may start to feel scared. The risk then becomes that they’ll start feeling awkward or ashamed or embarrassed. We have to keep this in mind and help lead the child away from those feelings. Otherwise, they can end up with low self-esteem, they can start to withdraw.

It can sometimes get to the point where they choose to neglect their treatment so as to conform to the way others see them. Adults can easily lose sight of these kinds of things. So, it’s imperative that we talk to the child. If they’re having trouble following their treatment plan, maybe there’s something going on at school. So, let’s ask them: “How do you like your classes and teachers?” “How are you doing with your injections? Are you finding that they’re getting easier and easier to do?” And always keeping in mind the real possibility that the child may be feeling awkward, ashamed, embarrassed.
 

Q: Is enough being done to pick up on and address these children’s needs?

Dr. Hoffmeister: I think that these efforts are becoming more and more widespread. Still, there are disparities. When it comes to patients with chronic diseases, it’s not always easy to implement mental health care into the treatment plan. In some cases, there might not be a hospital nearby. And as we know, there are no spots available in medical and psychiatric centers. Of course, outside of hospital settings, we’re seeing the unfortunate situation of fewer and fewer middle schools and high schools having nurses on site.

And then, what options there are for getting support vary greatly from hospital to hospital. Some don’t have psychologists. Others have full schedules and not enough staff. That said, more and more teams are trying to set up regular appointments right from the time of diagnosis. This is a really good approach to take, even though the circumstances may not be ideal. After all, the person has just been told that they have diabetes; they’re not really in the best state of mind to have any kind of discussion.
 

Q: And so, it makes sense that AJD would offer the kind of mental health support that you’re now providing there.

Dr. Hoffmeister: Exactly. My position was created 4 years ago. I’m not at the hospital. I’m an external. The goal is to be able to offer this psychological support to everyone. I do consultations over the phone so that no matter where a person is in France, they’ll have access to this support. There’s great demand, and the requests are only increasing. I think this has to do with the fact that people are being diagnosed younger and younger. It’s a very complicated situation for the parents. No matter how young their child is, they want to get that support underway as soon as possible.

Q: You speak about the patients getting support. But doesn’t some kind of help have to be given to their parents and loved ones as well?

Dr. Hoffmeister: Yes. I’d say that 60% to 70% of the work I do at AJD is for parents. I also have some older adolescents and some younger kids whom I call to keep up with. But children aren’t very interested in discussing plans over the phone. For parents, the thing about diabetes is that they find themselves in these situations where their child is in the hospital for, say, a week, then is discharged, and all of a sudden, they find themselves at home as the ones in charge of their child’s treatment.

When it’s a little kid, the parents are the ones who are taking care of all the steps, the injections, the pumps. They’re dealing with the distress of a child going through episodes of nocturnal hypoglycemia. They’re experiencing varying degrees of anxiety in carrying out all of these responsibilities and, at the same time, the bond they have with their child is becoming stronger and stronger. So, there’s that anxiety. In this situation, parents may also feel a need for control. And they’re also feeling exhausted; the mental load of dealing with diabetes is very, very intense. To work through all this, many parents reach out for psychological support.

Then later on, when the child has gotten a little older, the parents find it difficult to get to the point of being able to just let go. But once the parents get to know their child better, get to know how their child experiences diabetes, they’ll get to that point. What they come to learn is that the child can take care of things, the child can feel what’s going on in their body, the child can be trusted.
 

Q: How can we help and support children with diabetes?

Dr. Hoffmeister: One of the most important things is to teach the child to come to terms with the disease and how it affects their body. In other words, the idea here is to adapt diabetes to one’s life, not the other way around. The goal is to not let diabetes take over.

When faced with standardized medical protocols, during a session with a psychologist, the child can talk about their life, give an idea of what a day in their life looks like. For example, the school cafeteria is a place where children get the opportunity to socialize and interact with their peers. We want to have that lunch period be as normal as possible for the child with diabetes. In some schools, lunchtime becomes a challenge. So, not seeing any other solution, mom stops working so the child can come home to eat. These are the kinds of situations where efforts to make the child feel included have failed. They’re tough to deal with, all around. And so this is why we do all we can to keep things as normal as possible for these children.
 

Q: What would you say is the one initiative out there that’s giving young patients with T1D the most help and support?

Dr. Hoffmeister: AJD offers stays at Care Management and Rehabilitation (SSR) sites. For kids and teenagers with diabetes, these places are like summer camps where every aspect of treatment is taken care of.

There’s a medical team monitoring their disease and a team of counselors always on hand. It’s a time when children may very well bring up things that are on their mind. All in all, the children have a safe and welcoming environment where treatment is provided and they can feel free to open up and talk.

If a problem crops up, I’m always on call to jump online. And throughout the stay, the medical team is keeping in touch to discuss the child’s care.

AJD is also an interdisciplinary association. We regularly organize practice exchange groups that bring together health care professionals and families from all over France. In this way, we’re able to collaborate and come up with resources, such as information packets and kits – for the newly diagnosed, for those starting intensive insulin therapy, and so on. These resources take into account medical protocols related to diabetes. They’re also designed with family life in mind. And having this set of resources works toward standardizing treatments.

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

“Living with diabetes is not smooth sailing…From the onset of the disease in a child or adolescent through all the days that follow, there is nothing ordinary about it,” according to Aide aux Jeunes Diabétiques (AJD), a French association providing support for children and adolescents with diabetes. What is the psychological impact of the disease on patients and their loved ones? When we look at the life of a person with diabetes, are there key stages that call for more focused attention?

Nadine Hoffmeister, a psychologist at AJD, offers support to patients with diabetes and their parents as they navigate and deal with in-patient treatment for the disease. She recently spoke with this news organization.

Q: Are psychological issues more prevalent in patients with type 1 diabetes (T1D) than in the general population?

Dr. Hoffmeister: Having a chronic disease is not something that should be viewed as automatically making the person more susceptible to psychological issues. When we think about kids with T1D, it’s important to keep in mind that the risk for depression and the risk for eating disorders are, in general, higher in adolescence.

Of course, it can’t be denied that having diabetes can make one more vulnerable to experiencing mental distress. Clearly, the risk for eating disorders is there, given the constant focus on managing one’s diet. And there’s a greater risk for depression, because life with diabetes can really be trying. That said, how much impact the disease has depends in large part on the environment, the monitoring, and the collaboration of everyone involved.
 

Q: Are there key stages in the life of patients with T1D that call for targeted psychological support? 

Dr. Hoffmeister: The thing about T1D is that it can affect anyone at any age – a small child, a teenager, a young adult. So, in that sense, all ‘firsts’ are key stages. They start, of course, with the first ‘first’: diagnosis. For children diagnosed at an early age, there’s the first day of nursery school or kindergarten, the first piece of birthday cake. Then we get to kids starting middle school and high school, places where they’re now left to their own devices. This is when, for the first time, they’ll have an opportunity to take a trip without their parents and siblings, to go to a party.

And then, there’s the first time using a particular treatment. For example, switching from injections to a pump requires not only an adjustment in terms of physically operating a new device, but a reorientation in terms of mentally settling into a new routine, a new way of administering medication, and so on. They have to learn how to get along with this machine that’s attached to them all the time. They have to view it as being a part of them, view it as a partner, a teammate, a friend. It’s not that easy.

Later on, one of the major stages is, of course, adolescence. Critical developments in the separation–individuation process are taking place. They start to feel the need to break free, to become autonomous, as they seek to fully come to terms with their disease.

Parents usually worry about this stage, adolescence. They’re scared that their child won’t be as vigilant, that they’ll be scatterbrained or careless when it comes to staying on top of all those things that need to be done to keep T1D under control. Most of the time, this stage goes better than they thought. Still, the fact remains that it’s difficult to find a happy medium between adolescence and diabetes. Indeed, there’s a bit of a paradox here. On the one hand, we have adolescence which, by definition, is a time of spontaneity, independence, of trying new things. On the other hand, we have diabetes and its limits and constraints, its care and treatment, day in and day out. We have to pay close attention to how the child navigates and makes their way through this stage of their life.

During adolescence, there’s also a heightened awareness and concern about how others look at you, see you – everywhere, not only in classrooms and hallways. If the way someone looks at them seems aggressive or intrusive, the child may start to feel scared. The risk then becomes that they’ll start feeling awkward or ashamed or embarrassed. We have to keep this in mind and help lead the child away from those feelings. Otherwise, they can end up with low self-esteem, they can start to withdraw.

It can sometimes get to the point where they choose to neglect their treatment so as to conform to the way others see them. Adults can easily lose sight of these kinds of things. So, it’s imperative that we talk to the child. If they’re having trouble following their treatment plan, maybe there’s something going on at school. So, let’s ask them: “How do you like your classes and teachers?” “How are you doing with your injections? Are you finding that they’re getting easier and easier to do?” And always keeping in mind the real possibility that the child may be feeling awkward, ashamed, embarrassed.
 

Q: Is enough being done to pick up on and address these children’s needs?

Dr. Hoffmeister: I think that these efforts are becoming more and more widespread. Still, there are disparities. When it comes to patients with chronic diseases, it’s not always easy to implement mental health care into the treatment plan. In some cases, there might not be a hospital nearby. And as we know, there are no spots available in medical and psychiatric centers. Of course, outside of hospital settings, we’re seeing the unfortunate situation of fewer and fewer middle schools and high schools having nurses on site.

And then, what options there are for getting support vary greatly from hospital to hospital. Some don’t have psychologists. Others have full schedules and not enough staff. That said, more and more teams are trying to set up regular appointments right from the time of diagnosis. This is a really good approach to take, even though the circumstances may not be ideal. After all, the person has just been told that they have diabetes; they’re not really in the best state of mind to have any kind of discussion.
 

Q: And so, it makes sense that AJD would offer the kind of mental health support that you’re now providing there.

Dr. Hoffmeister: Exactly. My position was created 4 years ago. I’m not at the hospital. I’m an external. The goal is to be able to offer this psychological support to everyone. I do consultations over the phone so that no matter where a person is in France, they’ll have access to this support. There’s great demand, and the requests are only increasing. I think this has to do with the fact that people are being diagnosed younger and younger. It’s a very complicated situation for the parents. No matter how young their child is, they want to get that support underway as soon as possible.

Q: You speak about the patients getting support. But doesn’t some kind of help have to be given to their parents and loved ones as well?

Dr. Hoffmeister: Yes. I’d say that 60% to 70% of the work I do at AJD is for parents. I also have some older adolescents and some younger kids whom I call to keep up with. But children aren’t very interested in discussing plans over the phone. For parents, the thing about diabetes is that they find themselves in these situations where their child is in the hospital for, say, a week, then is discharged, and all of a sudden, they find themselves at home as the ones in charge of their child’s treatment.

When it’s a little kid, the parents are the ones who are taking care of all the steps, the injections, the pumps. They’re dealing with the distress of a child going through episodes of nocturnal hypoglycemia. They’re experiencing varying degrees of anxiety in carrying out all of these responsibilities and, at the same time, the bond they have with their child is becoming stronger and stronger. So, there’s that anxiety. In this situation, parents may also feel a need for control. And they’re also feeling exhausted; the mental load of dealing with diabetes is very, very intense. To work through all this, many parents reach out for psychological support.

Then later on, when the child has gotten a little older, the parents find it difficult to get to the point of being able to just let go. But once the parents get to know their child better, get to know how their child experiences diabetes, they’ll get to that point. What they come to learn is that the child can take care of things, the child can feel what’s going on in their body, the child can be trusted.
 

Q: How can we help and support children with diabetes?

Dr. Hoffmeister: One of the most important things is to teach the child to come to terms with the disease and how it affects their body. In other words, the idea here is to adapt diabetes to one’s life, not the other way around. The goal is to not let diabetes take over.

When faced with standardized medical protocols, during a session with a psychologist, the child can talk about their life, give an idea of what a day in their life looks like. For example, the school cafeteria is a place where children get the opportunity to socialize and interact with their peers. We want to have that lunch period be as normal as possible for the child with diabetes. In some schools, lunchtime becomes a challenge. So, not seeing any other solution, mom stops working so the child can come home to eat. These are the kinds of situations where efforts to make the child feel included have failed. They’re tough to deal with, all around. And so this is why we do all we can to keep things as normal as possible for these children.
 

Q: What would you say is the one initiative out there that’s giving young patients with T1D the most help and support?

Dr. Hoffmeister: AJD offers stays at Care Management and Rehabilitation (SSR) sites. For kids and teenagers with diabetes, these places are like summer camps where every aspect of treatment is taken care of.

There’s a medical team monitoring their disease and a team of counselors always on hand. It’s a time when children may very well bring up things that are on their mind. All in all, the children have a safe and welcoming environment where treatment is provided and they can feel free to open up and talk.

If a problem crops up, I’m always on call to jump online. And throughout the stay, the medical team is keeping in touch to discuss the child’s care.

AJD is also an interdisciplinary association. We regularly organize practice exchange groups that bring together health care professionals and families from all over France. In this way, we’re able to collaborate and come up with resources, such as information packets and kits – for the newly diagnosed, for those starting intensive insulin therapy, and so on. These resources take into account medical protocols related to diabetes. They’re also designed with family life in mind. And having this set of resources works toward standardizing treatments.

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

The debate on whether the popular class of antihypertensive drugs, angiotensin receptor blockers (ARBs), may be associated with an increased risk for cancer has been reopened with the publication of a new meta-analysis.

The analysis found an increasing risk for cancer, and specifically lung cancer, with increasing cumulative exposure to these drugs.

The findings are reported in a study published online in PLOS ONE.

The author of this new meta-analysis is Ilke Sipahi, MD, a cardiologist from Acibadem University Medical School, Istanbul, who previously raised this issue in an initial meta-analysis published in 2010.

“The new meta-analysis is important because it is the first study to investigate whether there is a dose response in the association between ARBs and cancer,” Dr. Sipahi told this news organization.

“I found a clear signal of increased risk of cancer as exposure to ARBs increased, and the association started to become significant when the maximum dose was taken for 3 years,” he added.

Dr. Sipahi explained that in the first meta-analysis published in Lancet Oncology, he and his colleagues reported an increased cancer risk with ARBs based on observations from high-exposure trials – those that included higher doses of ARBs with a long duration of follow-up.

Following this publication, an investigation by the U.S. Food and Drug Administration refuted the risk, and a collaboration of ARB trial investigators also performed an analysis published in the Journal of Hypertension (2011. doi: 10.1097/HJH.0b013e328344a7de), which again did not show an increased risk for cancer with use of ARBs.

Dr. Sipahi claims that those analyses by the FDA and the ARB Trialists Collaboration, which were all trial-level meta-analyses, diluted the “high exposure” data (including higher doses taken for longer periods of time) with a large amount of other data on much lower exposures (lower doses and/or shorter time periods).

“The overall risk would then inevitably become nonsignificant. These analyses also did not look at different exposure levels,” he says.

“For cancer, the degree of exposure is obviously very important. The risk associated with smoking 2 or 3 cigarettes a day for a year is very different from that of smoking 2 packs a day for 40 years. The same principle applies to taking a medication,” Dr. Sipahi asserts.

From these latest data, he estimates that 120 patients needed to be treated with the maximal daily dose of an ARB for 4.7 years for one excess cancer diagnosis, and 464 patients needed to be treated for one excess lung cancer.

“Given that at least 200 million individuals are being treated with an ARB globally, approximately 1.7 million excess cancers (and 430,000 lung cancers) in 4.6 years could be potentially caused by this class of drugs,” he suggests.

For the current analysis, Dr. Sipahi used trial-level data taken from the paper by the ARB Trialists Collaboration and investigated the effect of exposure to ARBs – including both the dose taken and the length of treatment – on risk for cancer. He performed metaregression analyses that he says has not been done before.

“I mathematically quantitated the degree of exposure in each trial. And when the degree of exposure was correlated with risk of cancer, there was a significant association.”

The new meta-analysis includes 15 randomized controlled trials. The two coprimary outcomes were the relationship between cumulative exposure to ARBs and risk for all cancers combined and the relationship between cumulative exposure and risk for lung cancer.

In the trials, 74,021 patients were randomly assigned to an ARB, resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent), and 61,197 patients were randomly assigned to control.

Results showed a highly significant correlation between the degree of cumulative exposure to ARBs and risk for all cancers combined (slope = 0.07; 95% confidence interval, 0.03-0.11; P < .001) and also lung cancer (slope = 0.16; 95% CI, 0.05-0.27; P = .003).

In trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk for all cancers combined (risk ratio, 1.11; 95% CI, 1.03-1.19; P = .006).

There was also a statistically significant increase in risk for lung cancers in trials where the cumulative exposure was greater than 2.5 years (RR, 1.21; 95% CI, 1.02-1.44; P = .03).

In trials with lower cumulative exposure to ARBs, there was no increased risk either for all cancers combined or lung cancer.

Dr. Sipahi reports that the cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme (ACE) inhibitor treatment or the type of control (placebo or nonplacebo control).

But he acknowledges that since this is a trial-level analysis, the effects of patient characteristics such as age and smoking status could not be examined because of lack of patient-level data.

Dr. Sipahi says he does not know the mechanism behind these findings, but he draws attention to the recent withdrawal of several thousand lots of ARB formulations because of the presence of potentially carcinogenic impurities that have been suggested to be a byproduct of ARB synthesis.

He also claims that unlike some other classes of antihypertensives, ARBs have not been shown to reduce the risk for MI, leading him to conclude that “other classes of antihypertensives with good safety and efficacy data (such as ACE-inhibitors, calcium-channel blockers or others) should become the preferred first-line agents in the treatment of hypertension.”

Dr. Sipahi wants the FDA to reinvestigate the issue of ARBs and cancer risk using individual patient data. “They already have the patient-level data from the trials. They should look at it more carefully and look at exposure levels and how they relate to cancer risk,” he said. “And the fact that there have been studies linking high ARB exposure levels to increased cancer risk should at least get a warning on the drug labels.”
 

A ‘clear increase’ in risk

Dr. Sipahi also points out that a link between ARBs and cancer has been found in another meta-analysis performed in 2013 by senior FDA analyst Thomas Marciniak, MD.

“Because he worked at the FDA, [Dr.] Marciniak had access to individual patent data. This is the best type of analysis and generally produces more accurate results than a trial-level meta-analysis,” Dr. Sipahi commented.

Dr. Marciniak’s analysis, which is available on the FDA website as part of another document, was not officially published elsewhere, and no further action has been taken on the issue.

Contacted by this news organization, Dr. Marciniak, who has now retired from the FDA, said he not only conducted a patient-level meta-analysis but also followed up adverse effects reported in the trials that could have been a symptom of cancer to establish further whether the patient was later diagnosed with cancer or not.

“I used every scrap of information sent in, including serious adverse event reports. I saw a clear increase in lung cancer risk with the ARBs,” Dr. Marciniak said. He did not, however, perform a dose-response relationship analysis.

Asked why his analysis and those from Dr. Sipahi reach different conclusions to those from the ARB Trialists Collaboration and the official FDA investigations, Dr. Marciniak said: “It may be that there were too many low-exposure trials that just washed out the difference. But trial data generally do not capture adverse events such as cancer, which takes a long time to develop, very well, and if you’re not really looking for it, you’re probably not going to find it.”

Dr. Marciniak said that Dr. Sipahi’s current findings are in line with his results. “Finding a dose response, to me, is extremely compelling, and I think the signal here is real,” he commented. “I think this new paper from Dr. Sipahi verifies what I found. I think the FDA should now release all individual patient data it has.”

Contacted for comment, an FDA spokesperson said, “Generally the FDA does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

They added: “The FDA has ongoing assessment, surveillance, compliance, and pharmaceutical quality efforts across every product area, and we will continue to work with drug manufacturers to ensure safe, effective, and high-quality drugs for the American public. When we identify new and previously unrecognized risks to safety and quality, we react swiftly to resolve the problem, as we have done in responding to the recent findings of nitrosamines in certain medicines.”
 

Analysis ‘should be taken seriously’

Commenting on this new study, Steve Nissen, MD, a key figure in analyzing such complex data and who has himself uncovered problems with high-profile drugs in the past, says the current analysis should be taken seriously. 

Dr. Nissen, who was Dr. Sipahi’s senior during his post-doc position at the Cleveland Clinic, wrote an editorial accompanying Dr. Sipahi’s first paper and calling for urgent regulatory review of the evidence.

He says the new findings add to previous evidence suggesting a possible risk for cancer with ARBs.

“[Dr.] Sipahi is a capable researcher, and this analysis needs to be taken seriously, but it needs to be verified. It is not possible to draw a strong conclusion on this analysis, as it is not based on individual patient data, but I don’t think it should be ignored,” Dr. Nissen stated.

“I will say again what I said 12 years ago – that the regulatory agencies need to carefully review all their data in a very detailed way. The FDA and EMA have access to the individual patient data and are both very capable of doing the required analyses.”
 

Limitations of trial-level analysis

Asked to evaluate the statistics in the current paper, Andrew Althouse, PhD, an assistant professor of medicine at the University of Pittsburgh, and a clinical trial statistician, explained that the best way to do a thorough analysis of the relationship between ARB exposure and risk for incident cancer would involve the use of patient-level data.

“As such data were not available to Dr. Sipahi, I believe he is doing as well as he can. But without full access to individual patient-level data from the respective trials, it is difficult to support any firm conclusions,” Dr. Althouse said in an interview.

He suggested that the meta-regression analyses used in the paper were unable to properly estimate the relationship between ARB exposure and risk for incident cancer. 

“Taken at face value, the current analysis suggests that [in] trials with longer follow-up duration (and therefore greater cumulative exposure to ARB for the treatment group), the risk of developing cancer for patients in the ARB group versus the non-ARB group was progressively higher. But this study doesn’t take into account the actual amount of follow-up time for individual patients or potential differences in the amount of follow-up time between the two groups in each trial,” he noted.

Dr. Althouse says this raises the possibility of “competing risks” or the idea that if ARBs reduce cardiovascular disease and cardiovascular death, then there would be more patients remaining in that arm who could go on to develop cancer. “So a crude count of the number of cancer cases may look as though patients receiving ARBs are ‘more likely’ to develop cancer, but this is a mirage.”

He added: “When there are some patients dying during the study, the only way to tell whether the intervention actually increased the risk of other health-related complications is to have an analysis that properly accounts for each patient’s time-at-risk of the outcome. Unfortunately, properly analyzing this requires the use of patient-level data.”
 

Cardiologists skeptical?

Cardiology experts asked for thoughts on the new meta-analysis were also cautious to read too much into the findings.

Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “Perhaps one would simply ignore this rambling, cherrypicking-based condemnation of ARBs if it were not for the powerful negative connotation of the word cancer. Thus, the meta-analysis of Dr. Sipahi purporting that ARBs could be increasing the development of cancers in a cumulative way is of concern to both physicians and patients.”

But, raising a similar point to Dr. Althouse about competing risks, Dr. Messerli said: “We have to consider that as one gets older, the cardiovascular disease state and cancer state will compete with each other for the outcome of death. The better that therapies protect against cardiovascular death, the more they will increase life expectancy and thus the risk of cancer.”

He also added that “in head-to-head comparisons with ACE inhibitors, ARBs showed similar efficacy in terms of death, CV mortality, MI, stroke, and end-stage kidney disease, so can we agree that the attempt of Dr. Sipahi to disparage ARBs as a class is much ado about nothing?”

Dr. Nissen, however, said he views the idea of competing risk as “a bit of a stretch” in this case. “Although ARBs are effective antihypertensive drugs, I would say there is very little evidence that they would prolong survival versus other antihypertensives.”

Dr. Sipahi also claims that this argument is not relevant to the current analysis. “ARBs did not increase survival in any of the high-exposure trials that showed an excess in cancers. Therefore, competing outcomes, or ‘survival bias’ to be more specific, is not a possibility here,” he says.

George Bakris, MD, professor of medicine at the University of Chicago Medicine, noted that while the current study shows a slight increase in cancer incidence, especially lung cancer, among those taking ARBs for more than 3 years, it “totally ignores the overwhelming cardiovascular risk reduction seen in the trials.”

“Moreover,” he adds, “the author notes that the findings were independent of ACE-inhibitors, but he can’t rule out smoking and age as factors, two major risk factors for cancer and lung cancer, specifically. Thus, as typical of these types of analyses, the associations are probably true/true unrelated or, at best, partially related.”

Dr. Bakris referred to the potentially carcinogenic nitrosamine and azido compounds found in several ARB formulations that have resulted in recalls.

“At any stage of drug synthesis throughout each product’s lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions,” he said. “Drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products. The studies noted in the author’s analysis were done well before these guidelines were implemented. Hence, many of the issues raised by the authors using trials from 10-20 years ago are not of significant concern.”

Still, the cardiology experts all agreed on one thing – that patients should continue to take ARBs as prescribed.  

Noting that worldwide authorities are now addressing the issue of possible carcinogen contamination, Dr. Bakris stressed that patients “should not panic and should not stop their meds.”

Dr. Nissen added: “What we don’t want is for patents who are taking ARBs to stop taking these medications – hypertension is a deadly disorder, and these drugs have proven cardiovascular benefits.”

Dr. Sipahi received no specific funding for this work. He reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, Sanofi, Sandoz, Bristol-Myers Squibb, Bayer, Pfizer, Ranbaxy, Servier, and ARIS and served on advisory boards for Novartis, Sanofi, Servier, Bristol-Myers Squibb, Pfizer, Bayer and I.E. Ulagay. The other commenters do not report any relevant disclosures.

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

The debate on whether the popular class of antihypertensive drugs, angiotensin receptor blockers (ARBs), may be associated with an increased risk for cancer has been reopened with the publication of a new meta-analysis.

The analysis found an increasing risk for cancer, and specifically lung cancer, with increasing cumulative exposure to these drugs.

The findings are reported in a study published online in PLOS ONE.

The author of this new meta-analysis is Ilke Sipahi, MD, a cardiologist from Acibadem University Medical School, Istanbul, who previously raised this issue in an initial meta-analysis published in 2010.

“The new meta-analysis is important because it is the first study to investigate whether there is a dose response in the association between ARBs and cancer,” Dr. Sipahi told this news organization.

“I found a clear signal of increased risk of cancer as exposure to ARBs increased, and the association started to become significant when the maximum dose was taken for 3 years,” he added.

Dr. Sipahi explained that in the first meta-analysis published in Lancet Oncology, he and his colleagues reported an increased cancer risk with ARBs based on observations from high-exposure trials – those that included higher doses of ARBs with a long duration of follow-up.

Following this publication, an investigation by the U.S. Food and Drug Administration refuted the risk, and a collaboration of ARB trial investigators also performed an analysis published in the Journal of Hypertension (2011. doi: 10.1097/HJH.0b013e328344a7de), which again did not show an increased risk for cancer with use of ARBs.

Dr. Sipahi claims that those analyses by the FDA and the ARB Trialists Collaboration, which were all trial-level meta-analyses, diluted the “high exposure” data (including higher doses taken for longer periods of time) with a large amount of other data on much lower exposures (lower doses and/or shorter time periods).

“The overall risk would then inevitably become nonsignificant. These analyses also did not look at different exposure levels,” he says.

“For cancer, the degree of exposure is obviously very important. The risk associated with smoking 2 or 3 cigarettes a day for a year is very different from that of smoking 2 packs a day for 40 years. The same principle applies to taking a medication,” Dr. Sipahi asserts.

From these latest data, he estimates that 120 patients needed to be treated with the maximal daily dose of an ARB for 4.7 years for one excess cancer diagnosis, and 464 patients needed to be treated for one excess lung cancer.

“Given that at least 200 million individuals are being treated with an ARB globally, approximately 1.7 million excess cancers (and 430,000 lung cancers) in 4.6 years could be potentially caused by this class of drugs,” he suggests.

For the current analysis, Dr. Sipahi used trial-level data taken from the paper by the ARB Trialists Collaboration and investigated the effect of exposure to ARBs – including both the dose taken and the length of treatment – on risk for cancer. He performed metaregression analyses that he says has not been done before.

“I mathematically quantitated the degree of exposure in each trial. And when the degree of exposure was correlated with risk of cancer, there was a significant association.”

The new meta-analysis includes 15 randomized controlled trials. The two coprimary outcomes were the relationship between cumulative exposure to ARBs and risk for all cancers combined and the relationship between cumulative exposure and risk for lung cancer.

In the trials, 74,021 patients were randomly assigned to an ARB, resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent), and 61,197 patients were randomly assigned to control.

Results showed a highly significant correlation between the degree of cumulative exposure to ARBs and risk for all cancers combined (slope = 0.07; 95% confidence interval, 0.03-0.11; P < .001) and also lung cancer (slope = 0.16; 95% CI, 0.05-0.27; P = .003).

In trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk for all cancers combined (risk ratio, 1.11; 95% CI, 1.03-1.19; P = .006).

There was also a statistically significant increase in risk for lung cancers in trials where the cumulative exposure was greater than 2.5 years (RR, 1.21; 95% CI, 1.02-1.44; P = .03).

In trials with lower cumulative exposure to ARBs, there was no increased risk either for all cancers combined or lung cancer.

Dr. Sipahi reports that the cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme (ACE) inhibitor treatment or the type of control (placebo or nonplacebo control).

But he acknowledges that since this is a trial-level analysis, the effects of patient characteristics such as age and smoking status could not be examined because of lack of patient-level data.

Dr. Sipahi says he does not know the mechanism behind these findings, but he draws attention to the recent withdrawal of several thousand lots of ARB formulations because of the presence of potentially carcinogenic impurities that have been suggested to be a byproduct of ARB synthesis.

He also claims that unlike some other classes of antihypertensives, ARBs have not been shown to reduce the risk for MI, leading him to conclude that “other classes of antihypertensives with good safety and efficacy data (such as ACE-inhibitors, calcium-channel blockers or others) should become the preferred first-line agents in the treatment of hypertension.”

Dr. Sipahi wants the FDA to reinvestigate the issue of ARBs and cancer risk using individual patient data. “They already have the patient-level data from the trials. They should look at it more carefully and look at exposure levels and how they relate to cancer risk,” he said. “And the fact that there have been studies linking high ARB exposure levels to increased cancer risk should at least get a warning on the drug labels.”
 

A ‘clear increase’ in risk

Dr. Sipahi also points out that a link between ARBs and cancer has been found in another meta-analysis performed in 2013 by senior FDA analyst Thomas Marciniak, MD.

“Because he worked at the FDA, [Dr.] Marciniak had access to individual patent data. This is the best type of analysis and generally produces more accurate results than a trial-level meta-analysis,” Dr. Sipahi commented.

Dr. Marciniak’s analysis, which is available on the FDA website as part of another document, was not officially published elsewhere, and no further action has been taken on the issue.

Contacted by this news organization, Dr. Marciniak, who has now retired from the FDA, said he not only conducted a patient-level meta-analysis but also followed up adverse effects reported in the trials that could have been a symptom of cancer to establish further whether the patient was later diagnosed with cancer or not.

“I used every scrap of information sent in, including serious adverse event reports. I saw a clear increase in lung cancer risk with the ARBs,” Dr. Marciniak said. He did not, however, perform a dose-response relationship analysis.

Asked why his analysis and those from Dr. Sipahi reach different conclusions to those from the ARB Trialists Collaboration and the official FDA investigations, Dr. Marciniak said: “It may be that there were too many low-exposure trials that just washed out the difference. But trial data generally do not capture adverse events such as cancer, which takes a long time to develop, very well, and if you’re not really looking for it, you’re probably not going to find it.”

Dr. Marciniak said that Dr. Sipahi’s current findings are in line with his results. “Finding a dose response, to me, is extremely compelling, and I think the signal here is real,” he commented. “I think this new paper from Dr. Sipahi verifies what I found. I think the FDA should now release all individual patient data it has.”

Contacted for comment, an FDA spokesperson said, “Generally the FDA does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

They added: “The FDA has ongoing assessment, surveillance, compliance, and pharmaceutical quality efforts across every product area, and we will continue to work with drug manufacturers to ensure safe, effective, and high-quality drugs for the American public. When we identify new and previously unrecognized risks to safety and quality, we react swiftly to resolve the problem, as we have done in responding to the recent findings of nitrosamines in certain medicines.”
 

Analysis ‘should be taken seriously’

Commenting on this new study, Steve Nissen, MD, a key figure in analyzing such complex data and who has himself uncovered problems with high-profile drugs in the past, says the current analysis should be taken seriously. 

Dr. Nissen, who was Dr. Sipahi’s senior during his post-doc position at the Cleveland Clinic, wrote an editorial accompanying Dr. Sipahi’s first paper and calling for urgent regulatory review of the evidence.

He says the new findings add to previous evidence suggesting a possible risk for cancer with ARBs.

“[Dr.] Sipahi is a capable researcher, and this analysis needs to be taken seriously, but it needs to be verified. It is not possible to draw a strong conclusion on this analysis, as it is not based on individual patient data, but I don’t think it should be ignored,” Dr. Nissen stated.

“I will say again what I said 12 years ago – that the regulatory agencies need to carefully review all their data in a very detailed way. The FDA and EMA have access to the individual patient data and are both very capable of doing the required analyses.”
 

Limitations of trial-level analysis

Asked to evaluate the statistics in the current paper, Andrew Althouse, PhD, an assistant professor of medicine at the University of Pittsburgh, and a clinical trial statistician, explained that the best way to do a thorough analysis of the relationship between ARB exposure and risk for incident cancer would involve the use of patient-level data.

“As such data were not available to Dr. Sipahi, I believe he is doing as well as he can. But without full access to individual patient-level data from the respective trials, it is difficult to support any firm conclusions,” Dr. Althouse said in an interview.

He suggested that the meta-regression analyses used in the paper were unable to properly estimate the relationship between ARB exposure and risk for incident cancer. 

“Taken at face value, the current analysis suggests that [in] trials with longer follow-up duration (and therefore greater cumulative exposure to ARB for the treatment group), the risk of developing cancer for patients in the ARB group versus the non-ARB group was progressively higher. But this study doesn’t take into account the actual amount of follow-up time for individual patients or potential differences in the amount of follow-up time between the two groups in each trial,” he noted.

Dr. Althouse says this raises the possibility of “competing risks” or the idea that if ARBs reduce cardiovascular disease and cardiovascular death, then there would be more patients remaining in that arm who could go on to develop cancer. “So a crude count of the number of cancer cases may look as though patients receiving ARBs are ‘more likely’ to develop cancer, but this is a mirage.”

He added: “When there are some patients dying during the study, the only way to tell whether the intervention actually increased the risk of other health-related complications is to have an analysis that properly accounts for each patient’s time-at-risk of the outcome. Unfortunately, properly analyzing this requires the use of patient-level data.”
 

Cardiologists skeptical?

Cardiology experts asked for thoughts on the new meta-analysis were also cautious to read too much into the findings.

Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “Perhaps one would simply ignore this rambling, cherrypicking-based condemnation of ARBs if it were not for the powerful negative connotation of the word cancer. Thus, the meta-analysis of Dr. Sipahi purporting that ARBs could be increasing the development of cancers in a cumulative way is of concern to both physicians and patients.”

But, raising a similar point to Dr. Althouse about competing risks, Dr. Messerli said: “We have to consider that as one gets older, the cardiovascular disease state and cancer state will compete with each other for the outcome of death. The better that therapies protect against cardiovascular death, the more they will increase life expectancy and thus the risk of cancer.”

He also added that “in head-to-head comparisons with ACE inhibitors, ARBs showed similar efficacy in terms of death, CV mortality, MI, stroke, and end-stage kidney disease, so can we agree that the attempt of Dr. Sipahi to disparage ARBs as a class is much ado about nothing?”

Dr. Nissen, however, said he views the idea of competing risk as “a bit of a stretch” in this case. “Although ARBs are effective antihypertensive drugs, I would say there is very little evidence that they would prolong survival versus other antihypertensives.”

Dr. Sipahi also claims that this argument is not relevant to the current analysis. “ARBs did not increase survival in any of the high-exposure trials that showed an excess in cancers. Therefore, competing outcomes, or ‘survival bias’ to be more specific, is not a possibility here,” he says.

George Bakris, MD, professor of medicine at the University of Chicago Medicine, noted that while the current study shows a slight increase in cancer incidence, especially lung cancer, among those taking ARBs for more than 3 years, it “totally ignores the overwhelming cardiovascular risk reduction seen in the trials.”

“Moreover,” he adds, “the author notes that the findings were independent of ACE-inhibitors, but he can’t rule out smoking and age as factors, two major risk factors for cancer and lung cancer, specifically. Thus, as typical of these types of analyses, the associations are probably true/true unrelated or, at best, partially related.”

Dr. Bakris referred to the potentially carcinogenic nitrosamine and azido compounds found in several ARB formulations that have resulted in recalls.

“At any stage of drug synthesis throughout each product’s lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions,” he said. “Drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products. The studies noted in the author’s analysis were done well before these guidelines were implemented. Hence, many of the issues raised by the authors using trials from 10-20 years ago are not of significant concern.”

Still, the cardiology experts all agreed on one thing – that patients should continue to take ARBs as prescribed.  

Noting that worldwide authorities are now addressing the issue of possible carcinogen contamination, Dr. Bakris stressed that patients “should not panic and should not stop their meds.”

Dr. Nissen added: “What we don’t want is for patents who are taking ARBs to stop taking these medications – hypertension is a deadly disorder, and these drugs have proven cardiovascular benefits.”

Dr. Sipahi received no specific funding for this work. He reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, Sanofi, Sandoz, Bristol-Myers Squibb, Bayer, Pfizer, Ranbaxy, Servier, and ARIS and served on advisory boards for Novartis, Sanofi, Servier, Bristol-Myers Squibb, Pfizer, Bayer and I.E. Ulagay. The other commenters do not report any relevant disclosures.

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

The debate on whether the popular class of antihypertensive drugs, angiotensin receptor blockers (ARBs), may be associated with an increased risk for cancer has been reopened with the publication of a new meta-analysis.

The analysis found an increasing risk for cancer, and specifically lung cancer, with increasing cumulative exposure to these drugs.

The findings are reported in a study published online in PLOS ONE.

The author of this new meta-analysis is Ilke Sipahi, MD, a cardiologist from Acibadem University Medical School, Istanbul, who previously raised this issue in an initial meta-analysis published in 2010.

“The new meta-analysis is important because it is the first study to investigate whether there is a dose response in the association between ARBs and cancer,” Dr. Sipahi told this news organization.

“I found a clear signal of increased risk of cancer as exposure to ARBs increased, and the association started to become significant when the maximum dose was taken for 3 years,” he added.

Dr. Sipahi explained that in the first meta-analysis published in Lancet Oncology, he and his colleagues reported an increased cancer risk with ARBs based on observations from high-exposure trials – those that included higher doses of ARBs with a long duration of follow-up.

Following this publication, an investigation by the U.S. Food and Drug Administration refuted the risk, and a collaboration of ARB trial investigators also performed an analysis published in the Journal of Hypertension (2011. doi: 10.1097/HJH.0b013e328344a7de), which again did not show an increased risk for cancer with use of ARBs.

Dr. Sipahi claims that those analyses by the FDA and the ARB Trialists Collaboration, which were all trial-level meta-analyses, diluted the “high exposure” data (including higher doses taken for longer periods of time) with a large amount of other data on much lower exposures (lower doses and/or shorter time periods).

“The overall risk would then inevitably become nonsignificant. These analyses also did not look at different exposure levels,” he says.

“For cancer, the degree of exposure is obviously very important. The risk associated with smoking 2 or 3 cigarettes a day for a year is very different from that of smoking 2 packs a day for 40 years. The same principle applies to taking a medication,” Dr. Sipahi asserts.

From these latest data, he estimates that 120 patients needed to be treated with the maximal daily dose of an ARB for 4.7 years for one excess cancer diagnosis, and 464 patients needed to be treated for one excess lung cancer.

“Given that at least 200 million individuals are being treated with an ARB globally, approximately 1.7 million excess cancers (and 430,000 lung cancers) in 4.6 years could be potentially caused by this class of drugs,” he suggests.

For the current analysis, Dr. Sipahi used trial-level data taken from the paper by the ARB Trialists Collaboration and investigated the effect of exposure to ARBs – including both the dose taken and the length of treatment – on risk for cancer. He performed metaregression analyses that he says has not been done before.

“I mathematically quantitated the degree of exposure in each trial. And when the degree of exposure was correlated with risk of cancer, there was a significant association.”

The new meta-analysis includes 15 randomized controlled trials. The two coprimary outcomes were the relationship between cumulative exposure to ARBs and risk for all cancers combined and the relationship between cumulative exposure and risk for lung cancer.

In the trials, 74,021 patients were randomly assigned to an ARB, resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent), and 61,197 patients were randomly assigned to control.

Results showed a highly significant correlation between the degree of cumulative exposure to ARBs and risk for all cancers combined (slope = 0.07; 95% confidence interval, 0.03-0.11; P < .001) and also lung cancer (slope = 0.16; 95% CI, 0.05-0.27; P = .003).

In trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk for all cancers combined (risk ratio, 1.11; 95% CI, 1.03-1.19; P = .006).

There was also a statistically significant increase in risk for lung cancers in trials where the cumulative exposure was greater than 2.5 years (RR, 1.21; 95% CI, 1.02-1.44; P = .03).

In trials with lower cumulative exposure to ARBs, there was no increased risk either for all cancers combined or lung cancer.

Dr. Sipahi reports that the cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme (ACE) inhibitor treatment or the type of control (placebo or nonplacebo control).

But he acknowledges that since this is a trial-level analysis, the effects of patient characteristics such as age and smoking status could not be examined because of lack of patient-level data.

Dr. Sipahi says he does not know the mechanism behind these findings, but he draws attention to the recent withdrawal of several thousand lots of ARB formulations because of the presence of potentially carcinogenic impurities that have been suggested to be a byproduct of ARB synthesis.

He also claims that unlike some other classes of antihypertensives, ARBs have not been shown to reduce the risk for MI, leading him to conclude that “other classes of antihypertensives with good safety and efficacy data (such as ACE-inhibitors, calcium-channel blockers or others) should become the preferred first-line agents in the treatment of hypertension.”

Dr. Sipahi wants the FDA to reinvestigate the issue of ARBs and cancer risk using individual patient data. “They already have the patient-level data from the trials. They should look at it more carefully and look at exposure levels and how they relate to cancer risk,” he said. “And the fact that there have been studies linking high ARB exposure levels to increased cancer risk should at least get a warning on the drug labels.”
 

A ‘clear increase’ in risk

Dr. Sipahi also points out that a link between ARBs and cancer has been found in another meta-analysis performed in 2013 by senior FDA analyst Thomas Marciniak, MD.

“Because he worked at the FDA, [Dr.] Marciniak had access to individual patent data. This is the best type of analysis and generally produces more accurate results than a trial-level meta-analysis,” Dr. Sipahi commented.

Dr. Marciniak’s analysis, which is available on the FDA website as part of another document, was not officially published elsewhere, and no further action has been taken on the issue.

Contacted by this news organization, Dr. Marciniak, who has now retired from the FDA, said he not only conducted a patient-level meta-analysis but also followed up adverse effects reported in the trials that could have been a symptom of cancer to establish further whether the patient was later diagnosed with cancer or not.

“I used every scrap of information sent in, including serious adverse event reports. I saw a clear increase in lung cancer risk with the ARBs,” Dr. Marciniak said. He did not, however, perform a dose-response relationship analysis.

Asked why his analysis and those from Dr. Sipahi reach different conclusions to those from the ARB Trialists Collaboration and the official FDA investigations, Dr. Marciniak said: “It may be that there were too many low-exposure trials that just washed out the difference. But trial data generally do not capture adverse events such as cancer, which takes a long time to develop, very well, and if you’re not really looking for it, you’re probably not going to find it.”

Dr. Marciniak said that Dr. Sipahi’s current findings are in line with his results. “Finding a dose response, to me, is extremely compelling, and I think the signal here is real,” he commented. “I think this new paper from Dr. Sipahi verifies what I found. I think the FDA should now release all individual patient data it has.”

Contacted for comment, an FDA spokesperson said, “Generally the FDA does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

They added: “The FDA has ongoing assessment, surveillance, compliance, and pharmaceutical quality efforts across every product area, and we will continue to work with drug manufacturers to ensure safe, effective, and high-quality drugs for the American public. When we identify new and previously unrecognized risks to safety and quality, we react swiftly to resolve the problem, as we have done in responding to the recent findings of nitrosamines in certain medicines.”
 

Analysis ‘should be taken seriously’

Commenting on this new study, Steve Nissen, MD, a key figure in analyzing such complex data and who has himself uncovered problems with high-profile drugs in the past, says the current analysis should be taken seriously. 

Dr. Nissen, who was Dr. Sipahi’s senior during his post-doc position at the Cleveland Clinic, wrote an editorial accompanying Dr. Sipahi’s first paper and calling for urgent regulatory review of the evidence.

He says the new findings add to previous evidence suggesting a possible risk for cancer with ARBs.

“[Dr.] Sipahi is a capable researcher, and this analysis needs to be taken seriously, but it needs to be verified. It is not possible to draw a strong conclusion on this analysis, as it is not based on individual patient data, but I don’t think it should be ignored,” Dr. Nissen stated.

“I will say again what I said 12 years ago – that the regulatory agencies need to carefully review all their data in a very detailed way. The FDA and EMA have access to the individual patient data and are both very capable of doing the required analyses.”
 

Limitations of trial-level analysis

Asked to evaluate the statistics in the current paper, Andrew Althouse, PhD, an assistant professor of medicine at the University of Pittsburgh, and a clinical trial statistician, explained that the best way to do a thorough analysis of the relationship between ARB exposure and risk for incident cancer would involve the use of patient-level data.

“As such data were not available to Dr. Sipahi, I believe he is doing as well as he can. But without full access to individual patient-level data from the respective trials, it is difficult to support any firm conclusions,” Dr. Althouse said in an interview.

He suggested that the meta-regression analyses used in the paper were unable to properly estimate the relationship between ARB exposure and risk for incident cancer. 

“Taken at face value, the current analysis suggests that [in] trials with longer follow-up duration (and therefore greater cumulative exposure to ARB for the treatment group), the risk of developing cancer for patients in the ARB group versus the non-ARB group was progressively higher. But this study doesn’t take into account the actual amount of follow-up time for individual patients or potential differences in the amount of follow-up time between the two groups in each trial,” he noted.

Dr. Althouse says this raises the possibility of “competing risks” or the idea that if ARBs reduce cardiovascular disease and cardiovascular death, then there would be more patients remaining in that arm who could go on to develop cancer. “So a crude count of the number of cancer cases may look as though patients receiving ARBs are ‘more likely’ to develop cancer, but this is a mirage.”

He added: “When there are some patients dying during the study, the only way to tell whether the intervention actually increased the risk of other health-related complications is to have an analysis that properly accounts for each patient’s time-at-risk of the outcome. Unfortunately, properly analyzing this requires the use of patient-level data.”
 

Cardiologists skeptical?

Cardiology experts asked for thoughts on the new meta-analysis were also cautious to read too much into the findings.

Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “Perhaps one would simply ignore this rambling, cherrypicking-based condemnation of ARBs if it were not for the powerful negative connotation of the word cancer. Thus, the meta-analysis of Dr. Sipahi purporting that ARBs could be increasing the development of cancers in a cumulative way is of concern to both physicians and patients.”

But, raising a similar point to Dr. Althouse about competing risks, Dr. Messerli said: “We have to consider that as one gets older, the cardiovascular disease state and cancer state will compete with each other for the outcome of death. The better that therapies protect against cardiovascular death, the more they will increase life expectancy and thus the risk of cancer.”

He also added that “in head-to-head comparisons with ACE inhibitors, ARBs showed similar efficacy in terms of death, CV mortality, MI, stroke, and end-stage kidney disease, so can we agree that the attempt of Dr. Sipahi to disparage ARBs as a class is much ado about nothing?”

Dr. Nissen, however, said he views the idea of competing risk as “a bit of a stretch” in this case. “Although ARBs are effective antihypertensive drugs, I would say there is very little evidence that they would prolong survival versus other antihypertensives.”

Dr. Sipahi also claims that this argument is not relevant to the current analysis. “ARBs did not increase survival in any of the high-exposure trials that showed an excess in cancers. Therefore, competing outcomes, or ‘survival bias’ to be more specific, is not a possibility here,” he says.

George Bakris, MD, professor of medicine at the University of Chicago Medicine, noted that while the current study shows a slight increase in cancer incidence, especially lung cancer, among those taking ARBs for more than 3 years, it “totally ignores the overwhelming cardiovascular risk reduction seen in the trials.”

“Moreover,” he adds, “the author notes that the findings were independent of ACE-inhibitors, but he can’t rule out smoking and age as factors, two major risk factors for cancer and lung cancer, specifically. Thus, as typical of these types of analyses, the associations are probably true/true unrelated or, at best, partially related.”

Dr. Bakris referred to the potentially carcinogenic nitrosamine and azido compounds found in several ARB formulations that have resulted in recalls.

“At any stage of drug synthesis throughout each product’s lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions,” he said. “Drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products. The studies noted in the author’s analysis were done well before these guidelines were implemented. Hence, many of the issues raised by the authors using trials from 10-20 years ago are not of significant concern.”

Still, the cardiology experts all agreed on one thing – that patients should continue to take ARBs as prescribed.  

Noting that worldwide authorities are now addressing the issue of possible carcinogen contamination, Dr. Bakris stressed that patients “should not panic and should not stop their meds.”

Dr. Nissen added: “What we don’t want is for patents who are taking ARBs to stop taking these medications – hypertension is a deadly disorder, and these drugs have proven cardiovascular benefits.”

Dr. Sipahi received no specific funding for this work. He reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, Sanofi, Sandoz, Bristol-Myers Squibb, Bayer, Pfizer, Ranbaxy, Servier, and ARIS and served on advisory boards for Novartis, Sanofi, Servier, Bristol-Myers Squibb, Pfizer, Bayer and I.E. Ulagay. The other commenters do not report any relevant disclosures.

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

Getting a COVID-19 mRNA vaccine did not affect pregnancy rates for women trying to conceive with in vitro fertilization or ovarian response to treatment, findings of a new study indicate.

The study was led by Sarit Avraham, MD, with the IVF unit, department of obstetrics and gynecology, Shamir Medical Center in Tzrifi, Israel. The findings were published online in Fertility and Sterility in a preproof version.

“Women should be vaccinated for COVID-19 prior to attempting to conceive via IVF treatments, given the higher risk of severe illness in pregnant women,” the authors wrote.

Doubts arose from “the theoretical concept of the supposed similarity between the SARS-CoV-2 spike protein and the syncytin protein that is speculated to take part in the fertilization process and the formation of the placenta,” the authors wrote.

Some then assumed that the COVID vaccine might kick off an immune response that could affect implantation and pregnancy. But this study and others before it found otherwise.

Researchers included 200 vaccinated women trying to conceive with IVF treatments in the retrospective study, and compared them with 200 unvaccinated patients of similar age (average age in both groups, 36 years) who were not previously infected with COVID-19. All the women were undergoing IVF from January to April 2021 and all the vaccinated women completed two doses of the BNT162b2 (Pfizer/BioNTech) vaccine at least 2 weeks before ovarian stimulation.

Researchers compared the average number of oocytes retrieved and clinical pregnancy rates between the two groups.
 

No difference between groups

Two hundred patients underwent oocyte retrieval 14-68 days after receiving a COVID shot; there was no significant difference by vaccination status in the number retrieved per cycle (10.63 in the vaccinated group vs. 10.72 in the unvaccinated group; P = .93).

There was also no difference in the clinical pregnancy rates after fresh embryo transfers. The rate among 128 vaccinated patients was 32.8% versus 33.1% in the 133 unvaccinated patients (P = .96), with 42 and 44 clinical pregnancies, respectively.

A total of 113 patients (66 in the study group and 47 in the controls) underwent freeze-all cycles to preserve fertility and fertilization rates were similar between vaccinated and unvaccinated (55.43% vaccinated vs. 54.29% unvaccinated; P = .73). The average number of cryopreserved embryos was 3.59 (vaccinated) versus 3.28 (unvaccinated) (P = .80).

In a subanalysis of outcomes by age, researchers found vaccination status had no effect on number of oocytes or pregnancy rates in the 39-and-older group. That’s important because it shows the vaccine did not affect outcomes even in a population with reduced ovarian reserves, the authors wrote.

The authors noted one of the study’s limitations is that it didn’t include information about vaccination or past infection status of the male partners.
 

Question should be put to rest

Sarah Cross, MD, a maternal-fetal medicine specialist at the University of Minnesota, Minneapolis, said the study is the biggest she’s seen that concludes COVID vaccinations are safe and highly encouraged for women before trying to conceive, but other smaller studies have come to the same conclusion.

She pointed to research including a study from 2021 with similar findings that concluded: “Physicians and public health personnel can counsel women of reproductive age that neither previous illness with COVID-19 nor antibodies produced from vaccination to COVID-19 will cause sterility.”

She said she thinks the question of whether COVID shots are safe with IVF has been answered and the results of the latest study add proof to counter misinformation around the issue.

“The COVID-19 vaccine does not affect fertility,” she said. “I don’t know how many more [studies] we need.”

The harm is in not getting vaccinated, she said. Pregnancy significantly increases a woman’s chance of getting severe COVID, the need for hospitalization, mechanical ventilation, and risk of death.

“I personally have never had a hospitalized patient who’s been vaccinated,” Dr. Cross said. “The worst thing for the fetus is to have a critically ill mother.”

Dr. Cross, whose high-risk patients include those seeking counseling before IVF, added: “I would counsel all of them that they should absolutely get vaccinated prior to pregnancy, when they’re pregnant, whenever it is, as soon as they possibly can.”

The study authors and Dr. Cross report no relevant financial relationships.

Getting a COVID-19 mRNA vaccine did not affect pregnancy rates for women trying to conceive with in vitro fertilization or ovarian response to treatment, findings of a new study indicate.

The study was led by Sarit Avraham, MD, with the IVF unit, department of obstetrics and gynecology, Shamir Medical Center in Tzrifi, Israel. The findings were published online in Fertility and Sterility in a preproof version.

“Women should be vaccinated for COVID-19 prior to attempting to conceive via IVF treatments, given the higher risk of severe illness in pregnant women,” the authors wrote.

Doubts arose from “the theoretical concept of the supposed similarity between the SARS-CoV-2 spike protein and the syncytin protein that is speculated to take part in the fertilization process and the formation of the placenta,” the authors wrote.

Some then assumed that the COVID vaccine might kick off an immune response that could affect implantation and pregnancy. But this study and others before it found otherwise.

Researchers included 200 vaccinated women trying to conceive with IVF treatments in the retrospective study, and compared them with 200 unvaccinated patients of similar age (average age in both groups, 36 years) who were not previously infected with COVID-19. All the women were undergoing IVF from January to April 2021 and all the vaccinated women completed two doses of the BNT162b2 (Pfizer/BioNTech) vaccine at least 2 weeks before ovarian stimulation.

Researchers compared the average number of oocytes retrieved and clinical pregnancy rates between the two groups.
 

No difference between groups

Two hundred patients underwent oocyte retrieval 14-68 days after receiving a COVID shot; there was no significant difference by vaccination status in the number retrieved per cycle (10.63 in the vaccinated group vs. 10.72 in the unvaccinated group; P = .93).

There was also no difference in the clinical pregnancy rates after fresh embryo transfers. The rate among 128 vaccinated patients was 32.8% versus 33.1% in the 133 unvaccinated patients (P = .96), with 42 and 44 clinical pregnancies, respectively.

A total of 113 patients (66 in the study group and 47 in the controls) underwent freeze-all cycles to preserve fertility and fertilization rates were similar between vaccinated and unvaccinated (55.43% vaccinated vs. 54.29% unvaccinated; P = .73). The average number of cryopreserved embryos was 3.59 (vaccinated) versus 3.28 (unvaccinated) (P = .80).

In a subanalysis of outcomes by age, researchers found vaccination status had no effect on number of oocytes or pregnancy rates in the 39-and-older group. That’s important because it shows the vaccine did not affect outcomes even in a population with reduced ovarian reserves, the authors wrote.

The authors noted one of the study’s limitations is that it didn’t include information about vaccination or past infection status of the male partners.
 

Question should be put to rest

Sarah Cross, MD, a maternal-fetal medicine specialist at the University of Minnesota, Minneapolis, said the study is the biggest she’s seen that concludes COVID vaccinations are safe and highly encouraged for women before trying to conceive, but other smaller studies have come to the same conclusion.

She pointed to research including a study from 2021 with similar findings that concluded: “Physicians and public health personnel can counsel women of reproductive age that neither previous illness with COVID-19 nor antibodies produced from vaccination to COVID-19 will cause sterility.”

She said she thinks the question of whether COVID shots are safe with IVF has been answered and the results of the latest study add proof to counter misinformation around the issue.

“The COVID-19 vaccine does not affect fertility,” she said. “I don’t know how many more [studies] we need.”

The harm is in not getting vaccinated, she said. Pregnancy significantly increases a woman’s chance of getting severe COVID, the need for hospitalization, mechanical ventilation, and risk of death.

“I personally have never had a hospitalized patient who’s been vaccinated,” Dr. Cross said. “The worst thing for the fetus is to have a critically ill mother.”

Dr. Cross, whose high-risk patients include those seeking counseling before IVF, added: “I would counsel all of them that they should absolutely get vaccinated prior to pregnancy, when they’re pregnant, whenever it is, as soon as they possibly can.”

The study authors and Dr. Cross report no relevant financial relationships.

Getting a COVID-19 mRNA vaccine did not affect pregnancy rates for women trying to conceive with in vitro fertilization or ovarian response to treatment, findings of a new study indicate.

The study was led by Sarit Avraham, MD, with the IVF unit, department of obstetrics and gynecology, Shamir Medical Center in Tzrifi, Israel. The findings were published online in Fertility and Sterility in a preproof version.

“Women should be vaccinated for COVID-19 prior to attempting to conceive via IVF treatments, given the higher risk of severe illness in pregnant women,” the authors wrote.

Doubts arose from “the theoretical concept of the supposed similarity between the SARS-CoV-2 spike protein and the syncytin protein that is speculated to take part in the fertilization process and the formation of the placenta,” the authors wrote.

Some then assumed that the COVID vaccine might kick off an immune response that could affect implantation and pregnancy. But this study and others before it found otherwise.

Researchers included 200 vaccinated women trying to conceive with IVF treatments in the retrospective study, and compared them with 200 unvaccinated patients of similar age (average age in both groups, 36 years) who were not previously infected with COVID-19. All the women were undergoing IVF from January to April 2021 and all the vaccinated women completed two doses of the BNT162b2 (Pfizer/BioNTech) vaccine at least 2 weeks before ovarian stimulation.

Researchers compared the average number of oocytes retrieved and clinical pregnancy rates between the two groups.
 

No difference between groups

Two hundred patients underwent oocyte retrieval 14-68 days after receiving a COVID shot; there was no significant difference by vaccination status in the number retrieved per cycle (10.63 in the vaccinated group vs. 10.72 in the unvaccinated group; P = .93).

There was also no difference in the clinical pregnancy rates after fresh embryo transfers. The rate among 128 vaccinated patients was 32.8% versus 33.1% in the 133 unvaccinated patients (P = .96), with 42 and 44 clinical pregnancies, respectively.

A total of 113 patients (66 in the study group and 47 in the controls) underwent freeze-all cycles to preserve fertility and fertilization rates were similar between vaccinated and unvaccinated (55.43% vaccinated vs. 54.29% unvaccinated; P = .73). The average number of cryopreserved embryos was 3.59 (vaccinated) versus 3.28 (unvaccinated) (P = .80).

In a subanalysis of outcomes by age, researchers found vaccination status had no effect on number of oocytes or pregnancy rates in the 39-and-older group. That’s important because it shows the vaccine did not affect outcomes even in a population with reduced ovarian reserves, the authors wrote.

The authors noted one of the study’s limitations is that it didn’t include information about vaccination or past infection status of the male partners.
 

Question should be put to rest

Sarah Cross, MD, a maternal-fetal medicine specialist at the University of Minnesota, Minneapolis, said the study is the biggest she’s seen that concludes COVID vaccinations are safe and highly encouraged for women before trying to conceive, but other smaller studies have come to the same conclusion.

She pointed to research including a study from 2021 with similar findings that concluded: “Physicians and public health personnel can counsel women of reproductive age that neither previous illness with COVID-19 nor antibodies produced from vaccination to COVID-19 will cause sterility.”

She said she thinks the question of whether COVID shots are safe with IVF has been answered and the results of the latest study add proof to counter misinformation around the issue.

“The COVID-19 vaccine does not affect fertility,” she said. “I don’t know how many more [studies] we need.”

The harm is in not getting vaccinated, she said. Pregnancy significantly increases a woman’s chance of getting severe COVID, the need for hospitalization, mechanical ventilation, and risk of death.

“I personally have never had a hospitalized patient who’s been vaccinated,” Dr. Cross said. “The worst thing for the fetus is to have a critically ill mother.”

Dr. Cross, whose high-risk patients include those seeking counseling before IVF, added: “I would counsel all of them that they should absolutely get vaccinated prior to pregnancy, when they’re pregnant, whenever it is, as soon as they possibly can.”

The study authors and Dr. Cross report no relevant financial relationships.