Lipid Disorders

While many people were committing to their New Year’s resolutions to lose weight, in January 2020 Cosmopolitan UK magazine released covers portraying 11 women of different shapes and sizes, with the headline, “This is healthy!” Each version of the cover features one or more of the 11 women wearing athletic gear and makeup, some of whom are caught mid-action – boxing, doing yoga, or simply rejoicing in being who they are. Seeing these, I was reminded of a patient I cared for as an intern.

Janet Spears (not her real name) was thin. Standing barely 5 feet 3 inches, she weighed 110 pounds. For those out there who think of size in terms of body mass index (BMI), it was about 20 kg/m², solidly in the “normal” category. At the age of 62, despite this healthy BMI, she had so much plaque in her arteries that she needed surgery to improve blood flow to her foot.

Admittedly, whenever I had read about people with high cholesterol, type 2 diabetes, or atherosclerosis, I pictured bigger people. But when I met Ms. Spears, I realized that one’s health cannot necessarily be inferred from physical appearance.

As a bariatric surgeon board certified in obesity medicine, I’ve probably spent more time thinking and learning about obesity than most people – and yet I still didn’t know what to make of the Cosmopolitan covers.

I saw the reaction on Twitter before I saw the magazines themselves, and I quickly observed a number of people decrying the covers, suggesting that they promote obesity:

Multiple people suggested that this was inappropriate, especially in the context of the COVID-19 pandemic and the fact that people with obesity are at risk for worse outcomes, compared with those without obesity. (As an aside, these comments suggest that people did not read the associated article, which is about fitness and body image more than it is about obesity.)
 

Does size reflect health?

Putting the pandemic aside for a moment, the question the magazine covers raise is whether physical appearance reflects health. That’s what got me thinking about Ms. Spears, who, though appearing healthy, was sick enough that she needed to have major surgery. This whole conversation hinges, of course, on one’s definition of health.

A common knee-jerk response, especially from physicians, would be to say that obesity is by definition unhealthy. Some researchers have suggested though that a segment of people with obesity fall into a category called metabolically healthy obesity, which is typically characterized by a limited set of data such as cholesterol, blood sugar, and blood pressure. Indeed, some people with obesity have normal values in those categories.

Being metabolically healthy, however, does not preclude other medical problems associated with obesity, including joint pain, cancer, and mood disorders, among other issues. So even those who have metabolically healthy obesity are not necessarily immune to the many other obesity-related conditions.
 

What about body positivity?

As I delved further into the conversation about these covers, I saw people embracing the idea of promoting different-sized bodies. With almost two thirds of the U.S. population having overweight or obesity, one might argue that it’s high time magazine covers and the media reflect the reality in our hometowns. Unrealistic images in the media are associated with negative self-image and disordered eating, so perhaps embracing the shapes of real people may help us all have healthier attitudes toward our bodies.

That said, this idea can be taken too far. The Health at Every Size movement, which some might consider to be the ultimate body-positivity movement, espouses the idea that size and health are completely unrelated. That crosses a line between what we know to be true – that, at a population level, higher weight is associated with more medical problems – and fake news.

Another idea to consider is fitness, as opposed to health. Fitness can be defined multiple ways, but if we consider it to be measured exercise capacity, those who are more fit have a longer life expectancy than those with lower fitness levels at a given BMI. While some feel that the Cosmopolitan covers promote obesity and are therefore irresponsible, it’s at least as likely that highlighting people with obesity being active may inspire others with obesity to do the same.

Now let’s bring the pandemic back into the picture. As much as we all wish that it was over, with uncontrolled spread in every state and record numbers of people dying, COVID-19 is still very much a part of our reality. Having obesity increases the risk of having a severe case of COVID-19 if infected. Patients with obesity are also more likely than those without obesity to be hospitalized, require intensive care, and die with COVID-19.
 

Guiding the conversation

Pandemic or not, the truth is that obesity is related to multiple medical problems. That does not mean that every person with obesity has medical problems. The musician Lizzo, for example, is someone with obesity who considers herself to be healthy. She posts images and videos of working out and shares her personal fitness routine with her millions of fans. As a physician, I worry about the medical conditions – metabolic or otherwise – that someone like her may develop. But I love how she embraces who she is while striving to be healthier.

Most of the critical comments I have seen about the Cosmopolitan covers have, at best, bordered on fat shaming; others are solidly in that category. And the vitriol aimed at the larger models is despicable. It seems that conversations about obesity often vacillate from one extreme (fat shaming) to the other (extreme body positivity).

Although it may not sell magazines, I would love to see more nuanced, fact-based discussions, both in the media and in our clinics. We can start by acknowledging the fact that people of different sizes can be healthy. The truth is that we can’t tell very much about a person’s health from their outward appearance, and we should probably stop trying to make such inferences.

Assessment of health is most accurately judged by each person with their medical team, not by observers who use media images as part of their own propaganda machine, pushing one extreme view or another. As physicians, we have the opportunity and the responsibility to support our patients in the pursuit of health, without shame or judgment. Maybe that’s a New Year’s resolution worth committing to.

Arghavan Salles, MD, PhD, is a bariatric surgeon.

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

While many people were committing to their New Year’s resolutions to lose weight, in January 2020 Cosmopolitan UK magazine released covers portraying 11 women of different shapes and sizes, with the headline, “This is healthy!” Each version of the cover features one or more of the 11 women wearing athletic gear and makeup, some of whom are caught mid-action – boxing, doing yoga, or simply rejoicing in being who they are. Seeing these, I was reminded of a patient I cared for as an intern.

Janet Spears (not her real name) was thin. Standing barely 5 feet 3 inches, she weighed 110 pounds. For those out there who think of size in terms of body mass index (BMI), it was about 20 kg/m², solidly in the “normal” category. At the age of 62, despite this healthy BMI, she had so much plaque in her arteries that she needed surgery to improve blood flow to her foot.

Admittedly, whenever I had read about people with high cholesterol, type 2 diabetes, or atherosclerosis, I pictured bigger people. But when I met Ms. Spears, I realized that one’s health cannot necessarily be inferred from physical appearance.

As a bariatric surgeon board certified in obesity medicine, I’ve probably spent more time thinking and learning about obesity than most people – and yet I still didn’t know what to make of the Cosmopolitan covers.

I saw the reaction on Twitter before I saw the magazines themselves, and I quickly observed a number of people decrying the covers, suggesting that they promote obesity:

Multiple people suggested that this was inappropriate, especially in the context of the COVID-19 pandemic and the fact that people with obesity are at risk for worse outcomes, compared with those without obesity. (As an aside, these comments suggest that people did not read the associated article, which is about fitness and body image more than it is about obesity.)
 

Does size reflect health?

Putting the pandemic aside for a moment, the question the magazine covers raise is whether physical appearance reflects health. That’s what got me thinking about Ms. Spears, who, though appearing healthy, was sick enough that she needed to have major surgery. This whole conversation hinges, of course, on one’s definition of health.

A common knee-jerk response, especially from physicians, would be to say that obesity is by definition unhealthy. Some researchers have suggested though that a segment of people with obesity fall into a category called metabolically healthy obesity, which is typically characterized by a limited set of data such as cholesterol, blood sugar, and blood pressure. Indeed, some people with obesity have normal values in those categories.

Being metabolically healthy, however, does not preclude other medical problems associated with obesity, including joint pain, cancer, and mood disorders, among other issues. So even those who have metabolically healthy obesity are not necessarily immune to the many other obesity-related conditions.
 

What about body positivity?

As I delved further into the conversation about these covers, I saw people embracing the idea of promoting different-sized bodies. With almost two thirds of the U.S. population having overweight or obesity, one might argue that it’s high time magazine covers and the media reflect the reality in our hometowns. Unrealistic images in the media are associated with negative self-image and disordered eating, so perhaps embracing the shapes of real people may help us all have healthier attitudes toward our bodies.

That said, this idea can be taken too far. The Health at Every Size movement, which some might consider to be the ultimate body-positivity movement, espouses the idea that size and health are completely unrelated. That crosses a line between what we know to be true – that, at a population level, higher weight is associated with more medical problems – and fake news.

Another idea to consider is fitness, as opposed to health. Fitness can be defined multiple ways, but if we consider it to be measured exercise capacity, those who are more fit have a longer life expectancy than those with lower fitness levels at a given BMI. While some feel that the Cosmopolitan covers promote obesity and are therefore irresponsible, it’s at least as likely that highlighting people with obesity being active may inspire others with obesity to do the same.

Now let’s bring the pandemic back into the picture. As much as we all wish that it was over, with uncontrolled spread in every state and record numbers of people dying, COVID-19 is still very much a part of our reality. Having obesity increases the risk of having a severe case of COVID-19 if infected. Patients with obesity are also more likely than those without obesity to be hospitalized, require intensive care, and die with COVID-19.
 

Guiding the conversation

Pandemic or not, the truth is that obesity is related to multiple medical problems. That does not mean that every person with obesity has medical problems. The musician Lizzo, for example, is someone with obesity who considers herself to be healthy. She posts images and videos of working out and shares her personal fitness routine with her millions of fans. As a physician, I worry about the medical conditions – metabolic or otherwise – that someone like her may develop. But I love how she embraces who she is while striving to be healthier.

Most of the critical comments I have seen about the Cosmopolitan covers have, at best, bordered on fat shaming; others are solidly in that category. And the vitriol aimed at the larger models is despicable. It seems that conversations about obesity often vacillate from one extreme (fat shaming) to the other (extreme body positivity).

Although it may not sell magazines, I would love to see more nuanced, fact-based discussions, both in the media and in our clinics. We can start by acknowledging the fact that people of different sizes can be healthy. The truth is that we can’t tell very much about a person’s health from their outward appearance, and we should probably stop trying to make such inferences.

Assessment of health is most accurately judged by each person with their medical team, not by observers who use media images as part of their own propaganda machine, pushing one extreme view or another. As physicians, we have the opportunity and the responsibility to support our patients in the pursuit of health, without shame or judgment. Maybe that’s a New Year’s resolution worth committing to.

Arghavan Salles, MD, PhD, is a bariatric surgeon.

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

While many people were committing to their New Year’s resolutions to lose weight, in January 2020 Cosmopolitan UK magazine released covers portraying 11 women of different shapes and sizes, with the headline, “This is healthy!” Each version of the cover features one or more of the 11 women wearing athletic gear and makeup, some of whom are caught mid-action – boxing, doing yoga, or simply rejoicing in being who they are. Seeing these, I was reminded of a patient I cared for as an intern.

Janet Spears (not her real name) was thin. Standing barely 5 feet 3 inches, she weighed 110 pounds. For those out there who think of size in terms of body mass index (BMI), it was about 20 kg/m², solidly in the “normal” category. At the age of 62, despite this healthy BMI, she had so much plaque in her arteries that she needed surgery to improve blood flow to her foot.

Admittedly, whenever I had read about people with high cholesterol, type 2 diabetes, or atherosclerosis, I pictured bigger people. But when I met Ms. Spears, I realized that one’s health cannot necessarily be inferred from physical appearance.

As a bariatric surgeon board certified in obesity medicine, I’ve probably spent more time thinking and learning about obesity than most people – and yet I still didn’t know what to make of the Cosmopolitan covers.

I saw the reaction on Twitter before I saw the magazines themselves, and I quickly observed a number of people decrying the covers, suggesting that they promote obesity:

Multiple people suggested that this was inappropriate, especially in the context of the COVID-19 pandemic and the fact that people with obesity are at risk for worse outcomes, compared with those without obesity. (As an aside, these comments suggest that people did not read the associated article, which is about fitness and body image more than it is about obesity.)
 

Does size reflect health?

Putting the pandemic aside for a moment, the question the magazine covers raise is whether physical appearance reflects health. That’s what got me thinking about Ms. Spears, who, though appearing healthy, was sick enough that she needed to have major surgery. This whole conversation hinges, of course, on one’s definition of health.

A common knee-jerk response, especially from physicians, would be to say that obesity is by definition unhealthy. Some researchers have suggested though that a segment of people with obesity fall into a category called metabolically healthy obesity, which is typically characterized by a limited set of data such as cholesterol, blood sugar, and blood pressure. Indeed, some people with obesity have normal values in those categories.

Being metabolically healthy, however, does not preclude other medical problems associated with obesity, including joint pain, cancer, and mood disorders, among other issues. So even those who have metabolically healthy obesity are not necessarily immune to the many other obesity-related conditions.
 

What about body positivity?

As I delved further into the conversation about these covers, I saw people embracing the idea of promoting different-sized bodies. With almost two thirds of the U.S. population having overweight or obesity, one might argue that it’s high time magazine covers and the media reflect the reality in our hometowns. Unrealistic images in the media are associated with negative self-image and disordered eating, so perhaps embracing the shapes of real people may help us all have healthier attitudes toward our bodies.

That said, this idea can be taken too far. The Health at Every Size movement, which some might consider to be the ultimate body-positivity movement, espouses the idea that size and health are completely unrelated. That crosses a line between what we know to be true – that, at a population level, higher weight is associated with more medical problems – and fake news.

Another idea to consider is fitness, as opposed to health. Fitness can be defined multiple ways, but if we consider it to be measured exercise capacity, those who are more fit have a longer life expectancy than those with lower fitness levels at a given BMI. While some feel that the Cosmopolitan covers promote obesity and are therefore irresponsible, it’s at least as likely that highlighting people with obesity being active may inspire others with obesity to do the same.

Now let’s bring the pandemic back into the picture. As much as we all wish that it was over, with uncontrolled spread in every state and record numbers of people dying, COVID-19 is still very much a part of our reality. Having obesity increases the risk of having a severe case of COVID-19 if infected. Patients with obesity are also more likely than those without obesity to be hospitalized, require intensive care, and die with COVID-19.
 

Guiding the conversation

Pandemic or not, the truth is that obesity is related to multiple medical problems. That does not mean that every person with obesity has medical problems. The musician Lizzo, for example, is someone with obesity who considers herself to be healthy. She posts images and videos of working out and shares her personal fitness routine with her millions of fans. As a physician, I worry about the medical conditions – metabolic or otherwise – that someone like her may develop. But I love how she embraces who she is while striving to be healthier.

Most of the critical comments I have seen about the Cosmopolitan covers have, at best, bordered on fat shaming; others are solidly in that category. And the vitriol aimed at the larger models is despicable. It seems that conversations about obesity often vacillate from one extreme (fat shaming) to the other (extreme body positivity).

Although it may not sell magazines, I would love to see more nuanced, fact-based discussions, both in the media and in our clinics. We can start by acknowledging the fact that people of different sizes can be healthy. The truth is that we can’t tell very much about a person’s health from their outward appearance, and we should probably stop trying to make such inferences.

Assessment of health is most accurately judged by each person with their medical team, not by observers who use media images as part of their own propaganda machine, pushing one extreme view or another. As physicians, we have the opportunity and the responsibility to support our patients in the pursuit of health, without shame or judgment. Maybe that’s a New Year’s resolution worth committing to.

Arghavan Salles, MD, PhD, is a bariatric surgeon.

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

In a phase 2 randomized clinical trial of adults with type 2 diabetes and obesity, investigational drug bimagrumab (BYM338, Novartis) – a monoclonal antibody that blocks activin type II receptors and stimulates skeletal muscle growth – led to big reductions in total body fat mass and A1c and significant increases in lean mass compared with placebo.

The efficacy and safety findings “suggest that blockade of the activin receptor with bimagrumab could provide a novel pharmacologic approach for managing patients with type 2 diabetes with excess adiposity,” Steven B. Heymsfield, MD, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, and colleagues reported in their study, published online Jan. 13 in JAMA Network Open. 

Preliminary findings from the study of 75 patients treated for 48 weeks – in which neither group ate less despite intensive nutrition advice – were presented at Obesity Week in 2019.

As reported then, Lee M. Kaplan, MD, PhD, noted that the 6.5% weight loss in the bimagrumab group was similar to that seen with antiobesity medications that suppress appetite.

“What it suggests,” he said in an interview, “is that there may be a completely new mechanism at play here,” because patients receiving bimagrumab weren’t eating less but were losing the same amount of weight as reported for weight-loss drugs that work by decreasing appetite.

“Is this going to be the kind of complementary drug with a different mechanism that’s going to augment the effects of other drugs?” wondered Dr. Kaplan, director of the Obesity, Metabolism & Nutrition Institute at Massachusetts General Hospital, Boston, who has previously served as a scientific consultant to Novartis.

Asked about future plans for bimagrumab, a Novartis spokesperson said in an interview, “We are currently reviewing the program strategy and considering next steps.”
 

Four FDA-approved weight-loss drugs now approved

The Food and Drug Administration approval for lorcaserin (Belviq, Belviq XR, Eisai) for weight loss was rescinded on Feb. 13, 2020, when a postmarketing trial revealed an increased occurrence of cancer, leaving four drugs approved for weight loss in the United States, plus several drugs in development, Dr. Heymsfield and colleagues wrote.

The current phase 2 trial was designed to determine the safety and efficacy of bimagrumab – which had originally been studied to see if it would increase lean muscle mass in people with sarcopenia – on total body fat mass and glycemic control in patients with type 2 diabetes and overweight or obesity.

Researchers enrolled 75 adults at eight sites in the United States and one in Wales, United Kingdom, from 2017 to 2019.

On average, patients were 60 years old with an A1c of 7.8% and a body mass index of 32.9 kg/m²; they weighed 93.6 kg and had a fat mass of 35 kg.

Patients received an intravenous infusion of bimagrumab (10 mg/kg up to 1,200 mg in 5% dextrose solution) or placebo (5% dextrose solution) every 4 weeks for 48 weeks. They met with a registered dietitian at each monthly study visit and had a virtual check-in between visits.

Participants were advised to follow a diet that would cut 500 calories a day and encouraged to follow the American Diabetes Association walking program.

Body fat mass was measured by dual-energy x-ray absorptiometry (DEXA).

There were more women in the bimagrumab group than in the placebo group (62% vs. 32%), but baseline BMI, total body fat mass, and A1c were similar in both groups.
 

Same caloric intake, less fat tissue, more muscle, smaller waist

At 48 weeks in the bimagrumab vs. placebo group, there was on average (all P < .001):

• A loss of 20.5% vs. 0.5% (−7.5 vs. −0.2 kg) of total body fat mass.
• A loss of 6.5% vs. 0.8% (−5.9 vs. −0.8 kg) of body weight.  
• A gain of 3.6% vs. a loss of 0.8% (1.7 vs. −0.4 kg) of lean mass.

Similarly, the relatively large between-group differences in total body fat mass and body weight at 48 weeks with bimagrumab were accompanied by favorable differences in BMI (−2.19 vs. −0.28 kg/m²; P < .001) and waist circumference (−9.0 vs. 0.5 cm; P < .001), the investigators pointed out.

Moreover, the reduction of abdominal visceral adipose tissue and waist circumference with bimagrumab “was nearly twice that observed in a recently published study of patients with type 2 diabetes treated with an intensive lifestyle program and the glucagon-like peptide 1 (GLP-1) agonist liraglutide,” they noted.

This highlights “the importance of moving away from body weight as a primary efficacy marker of drugs to more metabolically relevant endpoints.”

Also, A1c decreased by 0.76% in the bimagrumab group and increased by 0.04% in the placebo group (P = .005).

Serious adverse events occurred in three patients (8%) in the bimagrumab group (elevated lipase, epigastric pain, pancreatitis, pneumonia) and three patients (8%) in the placebo group (cellulitis, acute coronary syndrome, acute myocardial infarction, worsening gastroparesis, thermal burn).  

Adverse events were reported by 31 of 37 patients in the bimagrumab group, most often mild diarrhea (41%) and muscle spasms (41%), and 31 of 38 patients in the placebo group, most often headache (13%) and upper respiratory tract infection (13%).

The study was funded by Novartis. Dr. Heymsfield has reported receiving personal fees from Tanita and Medifast outside the submitted work. Disclosures for the other authors are listed in the article. Dr. Kaplan has reported previously serving as a scientific consultant to Novartis.

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

In a phase 2 randomized clinical trial of adults with type 2 diabetes and obesity, investigational drug bimagrumab (BYM338, Novartis) – a monoclonal antibody that blocks activin type II receptors and stimulates skeletal muscle growth – led to big reductions in total body fat mass and A1c and significant increases in lean mass compared with placebo.

The efficacy and safety findings “suggest that blockade of the activin receptor with bimagrumab could provide a novel pharmacologic approach for managing patients with type 2 diabetes with excess adiposity,” Steven B. Heymsfield, MD, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, and colleagues reported in their study, published online Jan. 13 in JAMA Network Open. 

Preliminary findings from the study of 75 patients treated for 48 weeks – in which neither group ate less despite intensive nutrition advice – were presented at Obesity Week in 2019.

As reported then, Lee M. Kaplan, MD, PhD, noted that the 6.5% weight loss in the bimagrumab group was similar to that seen with antiobesity medications that suppress appetite.

“What it suggests,” he said in an interview, “is that there may be a completely new mechanism at play here,” because patients receiving bimagrumab weren’t eating less but were losing the same amount of weight as reported for weight-loss drugs that work by decreasing appetite.

“Is this going to be the kind of complementary drug with a different mechanism that’s going to augment the effects of other drugs?” wondered Dr. Kaplan, director of the Obesity, Metabolism & Nutrition Institute at Massachusetts General Hospital, Boston, who has previously served as a scientific consultant to Novartis.

Asked about future plans for bimagrumab, a Novartis spokesperson said in an interview, “We are currently reviewing the program strategy and considering next steps.”
 

Four FDA-approved weight-loss drugs now approved

The Food and Drug Administration approval for lorcaserin (Belviq, Belviq XR, Eisai) for weight loss was rescinded on Feb. 13, 2020, when a postmarketing trial revealed an increased occurrence of cancer, leaving four drugs approved for weight loss in the United States, plus several drugs in development, Dr. Heymsfield and colleagues wrote.

The current phase 2 trial was designed to determine the safety and efficacy of bimagrumab – which had originally been studied to see if it would increase lean muscle mass in people with sarcopenia – on total body fat mass and glycemic control in patients with type 2 diabetes and overweight or obesity.

Researchers enrolled 75 adults at eight sites in the United States and one in Wales, United Kingdom, from 2017 to 2019.

On average, patients were 60 years old with an A1c of 7.8% and a body mass index of 32.9 kg/m²; they weighed 93.6 kg and had a fat mass of 35 kg.

Patients received an intravenous infusion of bimagrumab (10 mg/kg up to 1,200 mg in 5% dextrose solution) or placebo (5% dextrose solution) every 4 weeks for 48 weeks. They met with a registered dietitian at each monthly study visit and had a virtual check-in between visits.

Participants were advised to follow a diet that would cut 500 calories a day and encouraged to follow the American Diabetes Association walking program.

Body fat mass was measured by dual-energy x-ray absorptiometry (DEXA).

There were more women in the bimagrumab group than in the placebo group (62% vs. 32%), but baseline BMI, total body fat mass, and A1c were similar in both groups.
 

Same caloric intake, less fat tissue, more muscle, smaller waist

At 48 weeks in the bimagrumab vs. placebo group, there was on average (all P < .001):

• A loss of 20.5% vs. 0.5% (−7.5 vs. −0.2 kg) of total body fat mass.
• A loss of 6.5% vs. 0.8% (−5.9 vs. −0.8 kg) of body weight.  
• A gain of 3.6% vs. a loss of 0.8% (1.7 vs. −0.4 kg) of lean mass.

Similarly, the relatively large between-group differences in total body fat mass and body weight at 48 weeks with bimagrumab were accompanied by favorable differences in BMI (−2.19 vs. −0.28 kg/m²; P < .001) and waist circumference (−9.0 vs. 0.5 cm; P < .001), the investigators pointed out.

Moreover, the reduction of abdominal visceral adipose tissue and waist circumference with bimagrumab “was nearly twice that observed in a recently published study of patients with type 2 diabetes treated with an intensive lifestyle program and the glucagon-like peptide 1 (GLP-1) agonist liraglutide,” they noted.

This highlights “the importance of moving away from body weight as a primary efficacy marker of drugs to more metabolically relevant endpoints.”

Also, A1c decreased by 0.76% in the bimagrumab group and increased by 0.04% in the placebo group (P = .005).

Serious adverse events occurred in three patients (8%) in the bimagrumab group (elevated lipase, epigastric pain, pancreatitis, pneumonia) and three patients (8%) in the placebo group (cellulitis, acute coronary syndrome, acute myocardial infarction, worsening gastroparesis, thermal burn).  

Adverse events were reported by 31 of 37 patients in the bimagrumab group, most often mild diarrhea (41%) and muscle spasms (41%), and 31 of 38 patients in the placebo group, most often headache (13%) and upper respiratory tract infection (13%).

The study was funded by Novartis. Dr. Heymsfield has reported receiving personal fees from Tanita and Medifast outside the submitted work. Disclosures for the other authors are listed in the article. Dr. Kaplan has reported previously serving as a scientific consultant to Novartis.

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

In a phase 2 randomized clinical trial of adults with type 2 diabetes and obesity, investigational drug bimagrumab (BYM338, Novartis) – a monoclonal antibody that blocks activin type II receptors and stimulates skeletal muscle growth – led to big reductions in total body fat mass and A1c and significant increases in lean mass compared with placebo.

The efficacy and safety findings “suggest that blockade of the activin receptor with bimagrumab could provide a novel pharmacologic approach for managing patients with type 2 diabetes with excess adiposity,” Steven B. Heymsfield, MD, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, and colleagues reported in their study, published online Jan. 13 in JAMA Network Open. 

Preliminary findings from the study of 75 patients treated for 48 weeks – in which neither group ate less despite intensive nutrition advice – were presented at Obesity Week in 2019.

As reported then, Lee M. Kaplan, MD, PhD, noted that the 6.5% weight loss in the bimagrumab group was similar to that seen with antiobesity medications that suppress appetite.

“What it suggests,” he said in an interview, “is that there may be a completely new mechanism at play here,” because patients receiving bimagrumab weren’t eating less but were losing the same amount of weight as reported for weight-loss drugs that work by decreasing appetite.

“Is this going to be the kind of complementary drug with a different mechanism that’s going to augment the effects of other drugs?” wondered Dr. Kaplan, director of the Obesity, Metabolism & Nutrition Institute at Massachusetts General Hospital, Boston, who has previously served as a scientific consultant to Novartis.

Asked about future plans for bimagrumab, a Novartis spokesperson said in an interview, “We are currently reviewing the program strategy and considering next steps.”
 

Four FDA-approved weight-loss drugs now approved

The Food and Drug Administration approval for lorcaserin (Belviq, Belviq XR, Eisai) for weight loss was rescinded on Feb. 13, 2020, when a postmarketing trial revealed an increased occurrence of cancer, leaving four drugs approved for weight loss in the United States, plus several drugs in development, Dr. Heymsfield and colleagues wrote.

The current phase 2 trial was designed to determine the safety and efficacy of bimagrumab – which had originally been studied to see if it would increase lean muscle mass in people with sarcopenia – on total body fat mass and glycemic control in patients with type 2 diabetes and overweight or obesity.

Researchers enrolled 75 adults at eight sites in the United States and one in Wales, United Kingdom, from 2017 to 2019.

On average, patients were 60 years old with an A1c of 7.8% and a body mass index of 32.9 kg/m²; they weighed 93.6 kg and had a fat mass of 35 kg.

Patients received an intravenous infusion of bimagrumab (10 mg/kg up to 1,200 mg in 5% dextrose solution) or placebo (5% dextrose solution) every 4 weeks for 48 weeks. They met with a registered dietitian at each monthly study visit and had a virtual check-in between visits.

Participants were advised to follow a diet that would cut 500 calories a day and encouraged to follow the American Diabetes Association walking program.

Body fat mass was measured by dual-energy x-ray absorptiometry (DEXA).

There were more women in the bimagrumab group than in the placebo group (62% vs. 32%), but baseline BMI, total body fat mass, and A1c were similar in both groups.
 

Same caloric intake, less fat tissue, more muscle, smaller waist

At 48 weeks in the bimagrumab vs. placebo group, there was on average (all P < .001):

• A loss of 20.5% vs. 0.5% (−7.5 vs. −0.2 kg) of total body fat mass.
• A loss of 6.5% vs. 0.8% (−5.9 vs. −0.8 kg) of body weight.  
• A gain of 3.6% vs. a loss of 0.8% (1.7 vs. −0.4 kg) of lean mass.

Similarly, the relatively large between-group differences in total body fat mass and body weight at 48 weeks with bimagrumab were accompanied by favorable differences in BMI (−2.19 vs. −0.28 kg/m²; P < .001) and waist circumference (−9.0 vs. 0.5 cm; P < .001), the investigators pointed out.

Moreover, the reduction of abdominal visceral adipose tissue and waist circumference with bimagrumab “was nearly twice that observed in a recently published study of patients with type 2 diabetes treated with an intensive lifestyle program and the glucagon-like peptide 1 (GLP-1) agonist liraglutide,” they noted.

This highlights “the importance of moving away from body weight as a primary efficacy marker of drugs to more metabolically relevant endpoints.”

Also, A1c decreased by 0.76% in the bimagrumab group and increased by 0.04% in the placebo group (P = .005).

Serious adverse events occurred in three patients (8%) in the bimagrumab group (elevated lipase, epigastric pain, pancreatitis, pneumonia) and three patients (8%) in the placebo group (cellulitis, acute coronary syndrome, acute myocardial infarction, worsening gastroparesis, thermal burn).  

Adverse events were reported by 31 of 37 patients in the bimagrumab group, most often mild diarrhea (41%) and muscle spasms (41%), and 31 of 38 patients in the placebo group, most often headache (13%) and upper respiratory tract infection (13%).

The study was funded by Novartis. Dr. Heymsfield has reported receiving personal fees from Tanita and Medifast outside the submitted work. Disclosures for the other authors are listed in the article. Dr. Kaplan has reported previously serving as a scientific consultant to Novartis.

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

Mounting evidence of strikingly high prevalence rates of fatty liver disease, advanced fibrosis, and cirrhosis among patients with type 2 diabetes has led to calls for heightened awareness and screening to identify these patients and target treatments to reduce their risk for irreversible liver damage.

Courtesy Dr. Christos S. Mantzoros

Among these calls is a pending statement from the Endocrine Society, the American Association of Clinical Endocrinologists, the American Gastroenterology Association, and other groups on what the growing appreciation of highly prevalent liver disease in patients with type 2 diabetes (T2D) means for assessing and managing patients. Publication of the statement is expected by spring 2021, said Christos S. Mantzoros, MD, DSc, PhD, chief of endocrinology for the Veterans Affairs Boston Healthcare System and a representative from the Endocrine Society to the statement-writing panel.

This upcoming “Call to Action” from these groups argues for a “need to collaborate across disciplines, and work together on establishing clinical guidelines, and creating new diagnostics and therapeutics,” said Dr. Mantzoros in an interview.

“Over time, it is becoming clearer that management of NAFLD [nonalcoholic fatty liver disease]/NASH [nonalcoholic steatohepatitis] requires a multidisciplinary panel of doctors ranging from primary care practitioners, to endocrinologists, and hepatologists. Given that the nature of the disease crosses scientific discipline boundaries, and that the number of patients is so large (it is estimated that about one in four U.S. adults have NAFLD), not all patients can be treated at the limited number of hepatology centers.

“However, not all stakeholders have fully realized this fact, and no effort had been undertaken so far by any professional society to develop a coordinated approach and clinical care pathway for NAFLD/NASH. The ‘Call to Action’ meeting can be considered as a starting point for such an important effort,” said Dr. Mantzoros, who is also a professor of medicine at Harvard Medical School and director of the human nutrition unit at Beth Israel Deaconess Medical Center, both in Boston.
 

Dramatic prevalence rates in patients with T2D

Results from two independent epidemiology reports, published in December 2020, documented steatosis (the fatty liver of NAFLD) in 70%-74% of unselected U.S. patients with T2D, advanced liver fibrosis accompanying this disease in 6%-15%, and previously unrecognized cirrhosis in 3%-8%.

One of these reports analyzed 825 patients with T2D included in the National Health and Nutritional Examination Survey of 2017-2018 run by the Centers for Disease Control and Prevention. All these patients, selected to be representative of the overall U.S. adult population with T2D, underwent transient elastography to identify steatosis and fibrosis, the first U.S. National Health Survey to run this type of population-based survey. The results showed an overall steatosis prevalence of 74% with grade 3 steatosis in 58%, advanced liver fibrosis in 15%, and cirrhosis in 8%, reported the team of Italian researchers who analyzed the data .

The second study focused on a single-center series of 561 patients with T2D who also underwent screening by transient elastography during 2018-2020 and had no history of NAFLD or other liver disease, or alcohol abuse. The imaging results showed a NAFLD prevalence of 70%, with 54% of the entire group diagnosed with severe steatosis, severe fibrosis in 6%, and cirrhosis in 3%. Among the 54% of patients with severe steatosis, 30% also had severe liver fibrosis. About 70% of the 561 patients assessed came from either the family medicine or general internal medicine clinics of the University of Florida, Gainesville, with the remaining 30% enrolled from the center’s endocrinology/diabetes outpatient clinic.

Neither report documented a NASH prevalence, which cannot receive definitive diagnosis by imaging alone. “This is the first study of its kind in the U.S. to establish the magnitude of [liver] disease burden in random patients with T2D seeking regular outpatient care,” wrote the University of Florida research team, led by Kenneth Cusi, MD, professor and chief of the university’s division of endocrinology, diabetes, and metabolism. Their finding that patients with T2D and previously unknown to have NAFLD had a 15% prevalence of moderate or advanced liver fibrosis “should trigger a call to action by all clinicians taking care of patients with T2D. Patient and physician awareness of the hepatic and extrahepatic complications of NASH, and reversing current diagnosis and treatment inertia will be the only way to avert the looming epidemic of cirrhosis in patients with diabetes.”

“Endocrinologists don’t ‘see’ NAFLD and NASH” in their patients with T2D “ because they don’t think about it,” Dr. Mantzoros declared.

Doug Brunk/Frontline Medical News

“Why is NASH underdiagnosed and undertreated? Because many physicians aren’t aware of it,” agreed Dr. Cusi during a talk in December 2020 at the 18th World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease (WCIRDC). “You never find what you don’t look for.”

“Endocrinologists should do the tests for NASH [in patients with T2D], but we’re all guilty of not doing it enough,” Tracey McLaughlin, MD, an endocrinologist and professor of medicine at Stanford (Calif.) University, commented during the WCIRDC.

These prevalence numbers demand that clinicians suspect liver disease “in any patient with diabetes, especially patients with obesity who are older and have components of metabolic syndrome,” said Dr. Mantzoros. “We need to screen, refer the most advanced cases, and treat the early- and mid-stage cases.”
 

How to find NASH

Both the American Diabetes Association and the European Association for the Study of Diabetes call for routine screening of patients with T2D, starting with a check of liver enzymes, such as ALT, but no clear consensus exists for the specifics of screening beyond that. Dr. Mantzoros, Dr. Cusi, and other experts agree that the scheme for assessing liver disease in patients with T2D starts with regular monitoring of elevations in liver enzymes including ALT. Next is noninvasive ultrasound assessment of the extent of liver fibrosis inferred from the organ’s stiffness using transient elastography. Another frequently cited initial screening tool is the Fibrosis-4 (FIB-4) score, which incorporates a patient’s age, platelet count, and levels of ALT and a second liver enzyme, AST.

“There is more consensus about FIB-4 and then elastography, but some people use tests other than FIB-4. Unfortunately there is no perfect diagnostic test today. A top priority is to define the best diagnostic test,” said Dr. Mantzoros, who is leading an effort to try to refine screening using artificial intelligence.

“FIB-4 is simple, easy, and well validated,” commented Dr. Cusi during the WCIRDC last December. “FIB-4 and elastography should get you pretty close” to identifying patients with T2D and significant liver disease.

But in a recent editorial, Dr. Cusi agreed on the need for “more reliable tests for the diagnosis of NASH and advanced fibrosis in patients with T2D. Significant work is being done in the field to validate novel and more sophisticated fibrosis biomarkers. Future studies will help us enter a new era of precision medicine where biomarkers will identify and target therapy to those with more active disease at risk for cirrhosis,” he wrote.

“The ultimate goal is to diagnose fibrosis at an early stage to prevent people from developing cirrhosis,” Dr. Cusi said in a recent written statement. “We’re trying to identify these problems before they’re unfixable. Once someone has cirrhosis, there isn’t a whole lot you can do.”
 

Pioglitazone remains the best-documented treatment

Perhaps some of the inertia in diagnosing NAFLD, NASH, and liver fibrosis in patients with T2D is dissatisfaction with current treatment options, although several proven options exist, notably weight loss and diet, and thiazolidinedione (TZD) pioglitazone. But weight loss and diet pose issues for patient compliance and durability of the intervention, and many clinicians consider pioglitazone flawed by its potential adverse effects.

“When we don’t have an established treatment for something, we tend to not measure it or go after it. That’s been true of liver disease” in patients with T2D, said Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of the Metabolic Institute of America in Tarzana, Calif., during the WCIRDC.

Treatment with pioglitazone has resolved NASH in about a third of patients compared with placebo, prevented fibrosis progression, and cut cardiovascular disease events, noted Dr. Cusi during the WCIRDC.

“Pioglitazone is used in only 8% of patients with T2D, or less, but we need to use it more often because of its proven efficacy in patients with T2D and NASH” said Dr. Mantzoros. “The problem is that pioglitazone has side effects, including weight gain and fluid retention, that makes it less attractive unless one thinks about the diagnosis of NASH.”

Others highlight that the adverse effects of pioglitazone have been either misunderstood, or can be effectively minimized with careful dosing.

“The data with the TZDs are much stronger than the data from anything else. TZDs have gotten a bad name because they also work in the kidney and enhance fluid reabsorption. We use modest dosages of pioglitazone, 15 mg or 30 mg a day, to avoid excess fluid retention,” Ralph A. DeFronzo, MD, chief of the diabetes division and professor of medicine at the University of Texas Health Science Center, San Antonio, said during the WCIRDC. “The best drug for NASH is pioglitazone. No other drug beats it” based on current data, Dr. DeFronzo asserted.

Other strategies include the potential to pair pioglitazone with other interventions that can blunt a weight-gain effect. One intriguing combination would combine pioglitazone with a GLP-1 receptor agonist, a drug class that can produce significant weight loss. Results from a phase 2 study showed promise for semaglutide (Rybelsus) in treating patients with NASH.
 

Getting the name right

Another factor that may be keeping NAFLD and NASH from achieving a higher profile for patients with T2D are those names, which focus on what the diseases are not – nonalcoholic – rather than what they are.

A series of recent publications in both the endocrinology and hepatology literature have called for renaming these disorders either “metabolic (dysfunction)–associated fatty liver disease (MALFD)”, or “dysmetabolism-associated fatty liver disease (DALFD)”.

“The names NAFLD and NASH indicate absence of alcohol as a cause, but the disease is also characterized by the absence of other causes, such as autoimmune disorders or hepatitis. The names were coined when we did not know much about these diseases. We now know that it is dysmetabolism that causes these conditions, and so we need to adopt a new, more accurate name,” explained Dr. Mantzoros, who has published support for a name change.

While many agree, some have raised concerns as to whether a name change now is premature. A group of hepatologists recently published a rebuttal to an immediate name change , saying that, “although we are in agreement that metabolic fatty liver disease may more accurately and positively reflect the relevant risk factors better than the age-old term nonalcoholic fatty liver disease, the term still leaves a great deal of ambiguity. A name change will be appropriate when informed by a new understanding of the molecular basis of the disease entity, insights that fundamentally change risk stratification, or other important aspects of the disease. We may be on the cusp of this, but we are not there yet.”

Dr. Mantzoros agreed, but for somewhat different reasons.

“We need to be careful and deliberate, because there is a significant body of knowledge and a lot of data from clinical trials collected using the old definitions. We need to find an appropriate time frame for a [name] transition. We need to find a nice and robust way to productively bridge the old to the new,” he said. “We also need new diagnostic criteria, and new therapies. A new name and definition will facilitate progress.”

Dr. Mantzoros been a shareholder of and consultant to Coherus and Pangea, he has been a consultant to AstraZeneca, Eisai, Genfit, Intercept, Novo Nordisk, P.E.S., and Regeneron, and has received travel support from the Metabolic Institute of America and the California Walnut Commission. Dr. Cusi has been a consultant to and has received research funding from numerous drug companies. Dr. McLaughlin is a consultant to January AI. Dr. Handelsman has been a consultant to numerous drug companies. Dr. DeFronzo received research grants from AstraZeneca, Janssen, and Merck; he has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk; and he has been a speaker on behalf of AstraZeneca and Novo Nordisk.

[email protected]

Mounting evidence of strikingly high prevalence rates of fatty liver disease, advanced fibrosis, and cirrhosis among patients with type 2 diabetes has led to calls for heightened awareness and screening to identify these patients and target treatments to reduce their risk for irreversible liver damage.

Courtesy Dr. Christos S. Mantzoros

Among these calls is a pending statement from the Endocrine Society, the American Association of Clinical Endocrinologists, the American Gastroenterology Association, and other groups on what the growing appreciation of highly prevalent liver disease in patients with type 2 diabetes (T2D) means for assessing and managing patients. Publication of the statement is expected by spring 2021, said Christos S. Mantzoros, MD, DSc, PhD, chief of endocrinology for the Veterans Affairs Boston Healthcare System and a representative from the Endocrine Society to the statement-writing panel.

This upcoming “Call to Action” from these groups argues for a “need to collaborate across disciplines, and work together on establishing clinical guidelines, and creating new diagnostics and therapeutics,” said Dr. Mantzoros in an interview.

“Over time, it is becoming clearer that management of NAFLD [nonalcoholic fatty liver disease]/NASH [nonalcoholic steatohepatitis] requires a multidisciplinary panel of doctors ranging from primary care practitioners, to endocrinologists, and hepatologists. Given that the nature of the disease crosses scientific discipline boundaries, and that the number of patients is so large (it is estimated that about one in four U.S. adults have NAFLD), not all patients can be treated at the limited number of hepatology centers.

“However, not all stakeholders have fully realized this fact, and no effort had been undertaken so far by any professional society to develop a coordinated approach and clinical care pathway for NAFLD/NASH. The ‘Call to Action’ meeting can be considered as a starting point for such an important effort,” said Dr. Mantzoros, who is also a professor of medicine at Harvard Medical School and director of the human nutrition unit at Beth Israel Deaconess Medical Center, both in Boston.
 

Dramatic prevalence rates in patients with T2D

Results from two independent epidemiology reports, published in December 2020, documented steatosis (the fatty liver of NAFLD) in 70%-74% of unselected U.S. patients with T2D, advanced liver fibrosis accompanying this disease in 6%-15%, and previously unrecognized cirrhosis in 3%-8%.

One of these reports analyzed 825 patients with T2D included in the National Health and Nutritional Examination Survey of 2017-2018 run by the Centers for Disease Control and Prevention. All these patients, selected to be representative of the overall U.S. adult population with T2D, underwent transient elastography to identify steatosis and fibrosis, the first U.S. National Health Survey to run this type of population-based survey. The results showed an overall steatosis prevalence of 74% with grade 3 steatosis in 58%, advanced liver fibrosis in 15%, and cirrhosis in 8%, reported the team of Italian researchers who analyzed the data .

The second study focused on a single-center series of 561 patients with T2D who also underwent screening by transient elastography during 2018-2020 and had no history of NAFLD or other liver disease, or alcohol abuse. The imaging results showed a NAFLD prevalence of 70%, with 54% of the entire group diagnosed with severe steatosis, severe fibrosis in 6%, and cirrhosis in 3%. Among the 54% of patients with severe steatosis, 30% also had severe liver fibrosis. About 70% of the 561 patients assessed came from either the family medicine or general internal medicine clinics of the University of Florida, Gainesville, with the remaining 30% enrolled from the center’s endocrinology/diabetes outpatient clinic.

Neither report documented a NASH prevalence, which cannot receive definitive diagnosis by imaging alone. “This is the first study of its kind in the U.S. to establish the magnitude of [liver] disease burden in random patients with T2D seeking regular outpatient care,” wrote the University of Florida research team, led by Kenneth Cusi, MD, professor and chief of the university’s division of endocrinology, diabetes, and metabolism. Their finding that patients with T2D and previously unknown to have NAFLD had a 15% prevalence of moderate or advanced liver fibrosis “should trigger a call to action by all clinicians taking care of patients with T2D. Patient and physician awareness of the hepatic and extrahepatic complications of NASH, and reversing current diagnosis and treatment inertia will be the only way to avert the looming epidemic of cirrhosis in patients with diabetes.”

“Endocrinologists don’t ‘see’ NAFLD and NASH” in their patients with T2D “ because they don’t think about it,” Dr. Mantzoros declared.

Doug Brunk/Frontline Medical News

“Why is NASH underdiagnosed and undertreated? Because many physicians aren’t aware of it,” agreed Dr. Cusi during a talk in December 2020 at the 18th World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease (WCIRDC). “You never find what you don’t look for.”

“Endocrinologists should do the tests for NASH [in patients with T2D], but we’re all guilty of not doing it enough,” Tracey McLaughlin, MD, an endocrinologist and professor of medicine at Stanford (Calif.) University, commented during the WCIRDC.

These prevalence numbers demand that clinicians suspect liver disease “in any patient with diabetes, especially patients with obesity who are older and have components of metabolic syndrome,” said Dr. Mantzoros. “We need to screen, refer the most advanced cases, and treat the early- and mid-stage cases.”
 

How to find NASH

Both the American Diabetes Association and the European Association for the Study of Diabetes call for routine screening of patients with T2D, starting with a check of liver enzymes, such as ALT, but no clear consensus exists for the specifics of screening beyond that. Dr. Mantzoros, Dr. Cusi, and other experts agree that the scheme for assessing liver disease in patients with T2D starts with regular monitoring of elevations in liver enzymes including ALT. Next is noninvasive ultrasound assessment of the extent of liver fibrosis inferred from the organ’s stiffness using transient elastography. Another frequently cited initial screening tool is the Fibrosis-4 (FIB-4) score, which incorporates a patient’s age, platelet count, and levels of ALT and a second liver enzyme, AST.

“There is more consensus about FIB-4 and then elastography, but some people use tests other than FIB-4. Unfortunately there is no perfect diagnostic test today. A top priority is to define the best diagnostic test,” said Dr. Mantzoros, who is leading an effort to try to refine screening using artificial intelligence.

“FIB-4 is simple, easy, and well validated,” commented Dr. Cusi during the WCIRDC last December. “FIB-4 and elastography should get you pretty close” to identifying patients with T2D and significant liver disease.

But in a recent editorial, Dr. Cusi agreed on the need for “more reliable tests for the diagnosis of NASH and advanced fibrosis in patients with T2D. Significant work is being done in the field to validate novel and more sophisticated fibrosis biomarkers. Future studies will help us enter a new era of precision medicine where biomarkers will identify and target therapy to those with more active disease at risk for cirrhosis,” he wrote.

“The ultimate goal is to diagnose fibrosis at an early stage to prevent people from developing cirrhosis,” Dr. Cusi said in a recent written statement. “We’re trying to identify these problems before they’re unfixable. Once someone has cirrhosis, there isn’t a whole lot you can do.”
 

Pioglitazone remains the best-documented treatment

Perhaps some of the inertia in diagnosing NAFLD, NASH, and liver fibrosis in patients with T2D is dissatisfaction with current treatment options, although several proven options exist, notably weight loss and diet, and thiazolidinedione (TZD) pioglitazone. But weight loss and diet pose issues for patient compliance and durability of the intervention, and many clinicians consider pioglitazone flawed by its potential adverse effects.

“When we don’t have an established treatment for something, we tend to not measure it or go after it. That’s been true of liver disease” in patients with T2D, said Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of the Metabolic Institute of America in Tarzana, Calif., during the WCIRDC.

Treatment with pioglitazone has resolved NASH in about a third of patients compared with placebo, prevented fibrosis progression, and cut cardiovascular disease events, noted Dr. Cusi during the WCIRDC.

“Pioglitazone is used in only 8% of patients with T2D, or less, but we need to use it more often because of its proven efficacy in patients with T2D and NASH” said Dr. Mantzoros. “The problem is that pioglitazone has side effects, including weight gain and fluid retention, that makes it less attractive unless one thinks about the diagnosis of NASH.”

Others highlight that the adverse effects of pioglitazone have been either misunderstood, or can be effectively minimized with careful dosing.

“The data with the TZDs are much stronger than the data from anything else. TZDs have gotten a bad name because they also work in the kidney and enhance fluid reabsorption. We use modest dosages of pioglitazone, 15 mg or 30 mg a day, to avoid excess fluid retention,” Ralph A. DeFronzo, MD, chief of the diabetes division and professor of medicine at the University of Texas Health Science Center, San Antonio, said during the WCIRDC. “The best drug for NASH is pioglitazone. No other drug beats it” based on current data, Dr. DeFronzo asserted.

Other strategies include the potential to pair pioglitazone with other interventions that can blunt a weight-gain effect. One intriguing combination would combine pioglitazone with a GLP-1 receptor agonist, a drug class that can produce significant weight loss. Results from a phase 2 study showed promise for semaglutide (Rybelsus) in treating patients with NASH.
 

Getting the name right

Another factor that may be keeping NAFLD and NASH from achieving a higher profile for patients with T2D are those names, which focus on what the diseases are not – nonalcoholic – rather than what they are.

A series of recent publications in both the endocrinology and hepatology literature have called for renaming these disorders either “metabolic (dysfunction)–associated fatty liver disease (MALFD)”, or “dysmetabolism-associated fatty liver disease (DALFD)”.

“The names NAFLD and NASH indicate absence of alcohol as a cause, but the disease is also characterized by the absence of other causes, such as autoimmune disorders or hepatitis. The names were coined when we did not know much about these diseases. We now know that it is dysmetabolism that causes these conditions, and so we need to adopt a new, more accurate name,” explained Dr. Mantzoros, who has published support for a name change.

While many agree, some have raised concerns as to whether a name change now is premature. A group of hepatologists recently published a rebuttal to an immediate name change , saying that, “although we are in agreement that metabolic fatty liver disease may more accurately and positively reflect the relevant risk factors better than the age-old term nonalcoholic fatty liver disease, the term still leaves a great deal of ambiguity. A name change will be appropriate when informed by a new understanding of the molecular basis of the disease entity, insights that fundamentally change risk stratification, or other important aspects of the disease. We may be on the cusp of this, but we are not there yet.”

Dr. Mantzoros agreed, but for somewhat different reasons.

“We need to be careful and deliberate, because there is a significant body of knowledge and a lot of data from clinical trials collected using the old definitions. We need to find an appropriate time frame for a [name] transition. We need to find a nice and robust way to productively bridge the old to the new,” he said. “We also need new diagnostic criteria, and new therapies. A new name and definition will facilitate progress.”

Dr. Mantzoros been a shareholder of and consultant to Coherus and Pangea, he has been a consultant to AstraZeneca, Eisai, Genfit, Intercept, Novo Nordisk, P.E.S., and Regeneron, and has received travel support from the Metabolic Institute of America and the California Walnut Commission. Dr. Cusi has been a consultant to and has received research funding from numerous drug companies. Dr. McLaughlin is a consultant to January AI. Dr. Handelsman has been a consultant to numerous drug companies. Dr. DeFronzo received research grants from AstraZeneca, Janssen, and Merck; he has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk; and he has been a speaker on behalf of AstraZeneca and Novo Nordisk.

[email protected]

Mounting evidence of strikingly high prevalence rates of fatty liver disease, advanced fibrosis, and cirrhosis among patients with type 2 diabetes has led to calls for heightened awareness and screening to identify these patients and target treatments to reduce their risk for irreversible liver damage.

Courtesy Dr. Christos S. Mantzoros

Among these calls is a pending statement from the Endocrine Society, the American Association of Clinical Endocrinologists, the American Gastroenterology Association, and other groups on what the growing appreciation of highly prevalent liver disease in patients with type 2 diabetes (T2D) means for assessing and managing patients. Publication of the statement is expected by spring 2021, said Christos S. Mantzoros, MD, DSc, PhD, chief of endocrinology for the Veterans Affairs Boston Healthcare System and a representative from the Endocrine Society to the statement-writing panel.

This upcoming “Call to Action” from these groups argues for a “need to collaborate across disciplines, and work together on establishing clinical guidelines, and creating new diagnostics and therapeutics,” said Dr. Mantzoros in an interview.

“Over time, it is becoming clearer that management of NAFLD [nonalcoholic fatty liver disease]/NASH [nonalcoholic steatohepatitis] requires a multidisciplinary panel of doctors ranging from primary care practitioners, to endocrinologists, and hepatologists. Given that the nature of the disease crosses scientific discipline boundaries, and that the number of patients is so large (it is estimated that about one in four U.S. adults have NAFLD), not all patients can be treated at the limited number of hepatology centers.

“However, not all stakeholders have fully realized this fact, and no effort had been undertaken so far by any professional society to develop a coordinated approach and clinical care pathway for NAFLD/NASH. The ‘Call to Action’ meeting can be considered as a starting point for such an important effort,” said Dr. Mantzoros, who is also a professor of medicine at Harvard Medical School and director of the human nutrition unit at Beth Israel Deaconess Medical Center, both in Boston.
 

Dramatic prevalence rates in patients with T2D

Results from two independent epidemiology reports, published in December 2020, documented steatosis (the fatty liver of NAFLD) in 70%-74% of unselected U.S. patients with T2D, advanced liver fibrosis accompanying this disease in 6%-15%, and previously unrecognized cirrhosis in 3%-8%.

One of these reports analyzed 825 patients with T2D included in the National Health and Nutritional Examination Survey of 2017-2018 run by the Centers for Disease Control and Prevention. All these patients, selected to be representative of the overall U.S. adult population with T2D, underwent transient elastography to identify steatosis and fibrosis, the first U.S. National Health Survey to run this type of population-based survey. The results showed an overall steatosis prevalence of 74% with grade 3 steatosis in 58%, advanced liver fibrosis in 15%, and cirrhosis in 8%, reported the team of Italian researchers who analyzed the data .

The second study focused on a single-center series of 561 patients with T2D who also underwent screening by transient elastography during 2018-2020 and had no history of NAFLD or other liver disease, or alcohol abuse. The imaging results showed a NAFLD prevalence of 70%, with 54% of the entire group diagnosed with severe steatosis, severe fibrosis in 6%, and cirrhosis in 3%. Among the 54% of patients with severe steatosis, 30% also had severe liver fibrosis. About 70% of the 561 patients assessed came from either the family medicine or general internal medicine clinics of the University of Florida, Gainesville, with the remaining 30% enrolled from the center’s endocrinology/diabetes outpatient clinic.

Neither report documented a NASH prevalence, which cannot receive definitive diagnosis by imaging alone. “This is the first study of its kind in the U.S. to establish the magnitude of [liver] disease burden in random patients with T2D seeking regular outpatient care,” wrote the University of Florida research team, led by Kenneth Cusi, MD, professor and chief of the university’s division of endocrinology, diabetes, and metabolism. Their finding that patients with T2D and previously unknown to have NAFLD had a 15% prevalence of moderate or advanced liver fibrosis “should trigger a call to action by all clinicians taking care of patients with T2D. Patient and physician awareness of the hepatic and extrahepatic complications of NASH, and reversing current diagnosis and treatment inertia will be the only way to avert the looming epidemic of cirrhosis in patients with diabetes.”

“Endocrinologists don’t ‘see’ NAFLD and NASH” in their patients with T2D “ because they don’t think about it,” Dr. Mantzoros declared.

Doug Brunk/Frontline Medical News

“Why is NASH underdiagnosed and undertreated? Because many physicians aren’t aware of it,” agreed Dr. Cusi during a talk in December 2020 at the 18th World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease (WCIRDC). “You never find what you don’t look for.”

“Endocrinologists should do the tests for NASH [in patients with T2D], but we’re all guilty of not doing it enough,” Tracey McLaughlin, MD, an endocrinologist and professor of medicine at Stanford (Calif.) University, commented during the WCIRDC.

These prevalence numbers demand that clinicians suspect liver disease “in any patient with diabetes, especially patients with obesity who are older and have components of metabolic syndrome,” said Dr. Mantzoros. “We need to screen, refer the most advanced cases, and treat the early- and mid-stage cases.”
 

How to find NASH

Both the American Diabetes Association and the European Association for the Study of Diabetes call for routine screening of patients with T2D, starting with a check of liver enzymes, such as ALT, but no clear consensus exists for the specifics of screening beyond that. Dr. Mantzoros, Dr. Cusi, and other experts agree that the scheme for assessing liver disease in patients with T2D starts with regular monitoring of elevations in liver enzymes including ALT. Next is noninvasive ultrasound assessment of the extent of liver fibrosis inferred from the organ’s stiffness using transient elastography. Another frequently cited initial screening tool is the Fibrosis-4 (FIB-4) score, which incorporates a patient’s age, platelet count, and levels of ALT and a second liver enzyme, AST.

“There is more consensus about FIB-4 and then elastography, but some people use tests other than FIB-4. Unfortunately there is no perfect diagnostic test today. A top priority is to define the best diagnostic test,” said Dr. Mantzoros, who is leading an effort to try to refine screening using artificial intelligence.

“FIB-4 is simple, easy, and well validated,” commented Dr. Cusi during the WCIRDC last December. “FIB-4 and elastography should get you pretty close” to identifying patients with T2D and significant liver disease.

But in a recent editorial, Dr. Cusi agreed on the need for “more reliable tests for the diagnosis of NASH and advanced fibrosis in patients with T2D. Significant work is being done in the field to validate novel and more sophisticated fibrosis biomarkers. Future studies will help us enter a new era of precision medicine where biomarkers will identify and target therapy to those with more active disease at risk for cirrhosis,” he wrote.

“The ultimate goal is to diagnose fibrosis at an early stage to prevent people from developing cirrhosis,” Dr. Cusi said in a recent written statement. “We’re trying to identify these problems before they’re unfixable. Once someone has cirrhosis, there isn’t a whole lot you can do.”
 

Pioglitazone remains the best-documented treatment

Perhaps some of the inertia in diagnosing NAFLD, NASH, and liver fibrosis in patients with T2D is dissatisfaction with current treatment options, although several proven options exist, notably weight loss and diet, and thiazolidinedione (TZD) pioglitazone. But weight loss and diet pose issues for patient compliance and durability of the intervention, and many clinicians consider pioglitazone flawed by its potential adverse effects.

“When we don’t have an established treatment for something, we tend to not measure it or go after it. That’s been true of liver disease” in patients with T2D, said Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of the Metabolic Institute of America in Tarzana, Calif., during the WCIRDC.

Treatment with pioglitazone has resolved NASH in about a third of patients compared with placebo, prevented fibrosis progression, and cut cardiovascular disease events, noted Dr. Cusi during the WCIRDC.

“Pioglitazone is used in only 8% of patients with T2D, or less, but we need to use it more often because of its proven efficacy in patients with T2D and NASH” said Dr. Mantzoros. “The problem is that pioglitazone has side effects, including weight gain and fluid retention, that makes it less attractive unless one thinks about the diagnosis of NASH.”

Others highlight that the adverse effects of pioglitazone have been either misunderstood, or can be effectively minimized with careful dosing.

“The data with the TZDs are much stronger than the data from anything else. TZDs have gotten a bad name because they also work in the kidney and enhance fluid reabsorption. We use modest dosages of pioglitazone, 15 mg or 30 mg a day, to avoid excess fluid retention,” Ralph A. DeFronzo, MD, chief of the diabetes division and professor of medicine at the University of Texas Health Science Center, San Antonio, said during the WCIRDC. “The best drug for NASH is pioglitazone. No other drug beats it” based on current data, Dr. DeFronzo asserted.

Other strategies include the potential to pair pioglitazone with other interventions that can blunt a weight-gain effect. One intriguing combination would combine pioglitazone with a GLP-1 receptor agonist, a drug class that can produce significant weight loss. Results from a phase 2 study showed promise for semaglutide (Rybelsus) in treating patients with NASH.
 

Getting the name right

Another factor that may be keeping NAFLD and NASH from achieving a higher profile for patients with T2D are those names, which focus on what the diseases are not – nonalcoholic – rather than what they are.

A series of recent publications in both the endocrinology and hepatology literature have called for renaming these disorders either “metabolic (dysfunction)–associated fatty liver disease (MALFD)”, or “dysmetabolism-associated fatty liver disease (DALFD)”.

“The names NAFLD and NASH indicate absence of alcohol as a cause, but the disease is also characterized by the absence of other causes, such as autoimmune disorders or hepatitis. The names were coined when we did not know much about these diseases. We now know that it is dysmetabolism that causes these conditions, and so we need to adopt a new, more accurate name,” explained Dr. Mantzoros, who has published support for a name change.

While many agree, some have raised concerns as to whether a name change now is premature. A group of hepatologists recently published a rebuttal to an immediate name change , saying that, “although we are in agreement that metabolic fatty liver disease may more accurately and positively reflect the relevant risk factors better than the age-old term nonalcoholic fatty liver disease, the term still leaves a great deal of ambiguity. A name change will be appropriate when informed by a new understanding of the molecular basis of the disease entity, insights that fundamentally change risk stratification, or other important aspects of the disease. We may be on the cusp of this, but we are not there yet.”

Dr. Mantzoros agreed, but for somewhat different reasons.

“We need to be careful and deliberate, because there is a significant body of knowledge and a lot of data from clinical trials collected using the old definitions. We need to find an appropriate time frame for a [name] transition. We need to find a nice and robust way to productively bridge the old to the new,” he said. “We also need new diagnostic criteria, and new therapies. A new name and definition will facilitate progress.”

Dr. Mantzoros been a shareholder of and consultant to Coherus and Pangea, he has been a consultant to AstraZeneca, Eisai, Genfit, Intercept, Novo Nordisk, P.E.S., and Regeneron, and has received travel support from the Metabolic Institute of America and the California Walnut Commission. Dr. Cusi has been a consultant to and has received research funding from numerous drug companies. Dr. McLaughlin is a consultant to January AI. Dr. Handelsman has been a consultant to numerous drug companies. Dr. DeFronzo received research grants from AstraZeneca, Janssen, and Merck; he has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk; and he has been a speaker on behalf of AstraZeneca and Novo Nordisk.

[email protected]

Cardiologist Ethan J. Weiss, MD, followed an intermittent-fasting diet for 7 years. He lost about 3.6 kg (8 lb) and began recommending the approach to friends and patients who wanted to lose weight.

“I liked the way the diet was so simple,” said Dr. Weiss, an associate professor at the Cardiovascular Research Institute, University of California, San Francisco. But he also felt “it was too good to be true because you can eat what you want as long as it’s within a narrow window.”

So when, last year, he conducted a randomized, controlled trial, TREAT, testing such an approach – eating during just 8 hours a day, fasting for the remaining 16 hours – versus an eating plan of three meals a day without restrictions, he was somewhat dismayed to find the group of people who fasted didn’t lose any more weight than the other group.

The approach used in this study is known as time-restricted eating. It involves designating periods of time within the day when people can consume whatever they want; they then “fast” at times outside those eating windows. Other methods include alternate-day fasting, or the well-known 5:2 diet. In the latter, people eat a “normal” amount of around 2,000 calories per day on 5 days of the week, but for the other 2 days, they restrict caloric intake to 500 calories per day.

Intermittent fasting is an umbrella term encompassing all of these different approaches.

Dr. Weiss’s work builds on more than a decade of research into this type of eating plan by scientists, including Krista Varady, PhD, professor of nutrition at the University of Illinois at Chicago, who presented an overview of her own studies last fall at the virtual annual meeting of the European Association for the Study of Diabetes.

Although much of the work has suggested that the shorter duration of eating period in this type of diet leads to lower calorie intake and weight loss while avoiding the need for the tedious calorie-counting of conventional diets, Dr. Weiss’s data – published last year – throws a spanner in the works and now complicates the evidence base.
 

A promise of simplicity: ‘All you have to do is watch the clock’

Dr. Varady said she, too, is intrigued by the simplicity of intermittent-fasting diets.

In 2018, Dr. Varady and colleagues tested the weight-loss efficacy of 12 weeks of time-restricted feeding in a pilot study of 23 people with obesity.

Participants were permitted an 8-hour eating window (10 a.m. to 6 p.m.) followed by water-only fasting of 16 hours (6 p.m. to 10 a.m.) the next day (sometimes referred to as the 16:8 diet). Researchers measured weight loss and fat mass, as well as metabolic parameters, and compared the active group with 23 matched-control participants who ate freely.

There were no restrictions on type or quantity of food consumed by the control group during the 8-hour period, but individuals in the time-restricted feeding group consumed around 350 calories less than the comparator group.

Dr. Varady thinks this is most likely because of the fact that people normally eat during a 14-hour window and time-restricted feeding cuts that down by 6 hours.

“One of the most beautiful things about time-restricted feeding is that it doesn’t require calorie monitoring,” she explained. “People get burnt out with having to constantly monitor calories. All you have to do is watch the clock.”

Adherence was quite high, she reported, although most people skipped 1 day, often a Saturday, likely because of social engagements.

Weight loss in the time-restricted feeding group was mild to moderate. After 3 months, mean body weight decreased by 2.6%, or approximately 3 kg (7-8 lb), relative to those who ate freely, but this was a significant difference (P  < .05).

But the researchers observed little change in metabolic disease risk factors between the groups.

In the time-restricted feeding group, systolic blood pressure dropped from 128 mm Hg to 121 mm Hg over the 12-week period, which was significant relative to the control group (P  <  .05) but there were no significant changes in fasting glucose, fasting lipids, fasting insulin, or insulin resistance relative to the comparator group.

In contrast to Dr. Varady’s findings, Dr. Weiss’s randomized TREAT trial, which used a similar 16:8 period of time-restricted versus unrestricted eating in 116 individuals with overweight or obesity, did not find greater weight loss in the group restricted to eating within the 8-hour window.

As previously reported by this news organization, those who fasted for 16 hours of each day (n = 59) did lose some weight, compared with the control group (n = 57) over 12 weeks, but the difference in weight loss between the groups was not significant (−0.26 kg; P = .63).

And there were no significant differences in any of the secondary outcomes of fat mass, fasting insulin, fasting glucose, hemoglobin A1c levels, estimated energy intake, total energy expenditure, and resting energy expenditure between the time-restricted eating and regular feeding groups.

“I don’t claim time-restricted eating is dead,” Dr. Weiss said, “but the hope that you can eat for a limited time each day and solve metabolic disease is not there.”

Does the length of the eating window matter?

Following her pilot study of an 8-hour eating window, Dr. Varady conducted further research with 4- or 6-hour eating windows to see if even shorter periods would precipitate greater weight loss, ideally a clinically significant loss of 5% of body weight.

She ran a 2-month randomized, controlled study in people with obesity, published in 2020, which was the first to examine both a 4-hour (3 p.m. to 7 p.m.; n = 19) or 6-hour (1 p.m to 7 p.m.; n = 20) eating window versus a diet without any food restrictions as a control (n = 19) (Cell Metab. 2020;32:366-78.e3).

Dr. Varady explained that they decided to shift the eating window to later in the day for this trial (in contrast to the earlier 8-hour study) to allow people to eat dinner at a sociable time, and thereby hopefully reduce dropouts from the study. 

“Unlike with alternate-day fasting, most people find time-restricted feeding easy to incorporate into their lifestyles,” she remarked.

Both the 4- and 6-hour eating window groups experienced a mean 3.2% body weight loss, compared with controls, and this correlated with a 550-calorie reduction in their daily consumption, compared with their baseline calorie intake.

In terms of other outcomes – and in contrast to the 8-hour window study which showed very little changed other than a minor decrease in blood pressure – researchers saw some changes in metabolic risk factors with the 4- and 6-hour eating windows, Dr. Varady reported.

Compared with the control group, fasting insulin decreased in both time-restricted feeding groups by a mean of 15% (P < .05). Insulin resistance also decreased by 25% in the 4-hour group and by 15% in the 6-hour group, compared with the control group. Fasting glucose did not change in either group, however.

The researchers did not observe any effect on blood pressure or plasma lipids in the 4- or 6-hour eating window groups, compared with controls. However, measures of oxidative stress and inflammation decreased in both groups versus controls by approximately 35% (P < .05).

“These findings suggest that this form of severe time-restricted feeding is achievable and can help adults with obesity lose weight, without having to count calories,” Dr. Varady and colleagues conclude.
 

Is intermittent fasting better for weight loss than calorie restriction?

Ultimately, if weight loss is the primary goal, many want to know how time-restricted feeding compares with conventional daily calorie restriction.

Back in 2017, Dr. Varady published a year-long randomized, controlled study that compared alternate-day fasting with a calorie-restriction diet and a conventional/usual diet among 100 participants with obesity who were otherwise healthy.  

Participants on the alternate-day fasting plan (n = 34) consumed 500 calories on fasting days for the first 6 months for weight loss (approximately 25% of energy needs) followed by 125% of energy needs on alternating “feast days”. For an additional 6 months, they ate 1,000 calories on fasting days – aimed at weight maintenance.

Those following the calorie-restriction diet (n = 35) reduced energy intake by 25% (approximately 500 kcal) for the first 6 months for weight loss, followed by enough calories sufficient for weight maintenance (so no further loss nor gain).

However, the study showed alternate-day fasting did not produce better weight loss than conventional calorie counting.

“Over the first 6 months [during the weight-loss period] both groups lost an average of 6% body weight. After 12 months it crept back to 5% weight loss,” reported Dr. Varady.

“Realistically, if the study continued for 2 or 3 years, they probably would have regained much of their weight,” she admitted.

Dr. Varady suspects it might be better for the alternate-day fasting participants to continue eating only 500 calories on their fast day during the weight-loss maintenance period rather than increasing calorie intake during this phase.

Heart rate and blood pressure did not change in either group, while triglycerides decreased in the alternate-day fasting group, and LDL cholesterol decreased in the calorie-restriction group.

Glucose level decreased in the calorie-restriction group but not the alternate-day fasting group, and insulin and HOMA-IR were unaffected in both groups, reported Dr. Varady, noting that these findings were in healthy people with obesity.

In people with obesity and insulin resistance – evaluated as a subgroup in a separate study by Dr. Varady of alternate-day fasting versus daily calorie restriction published in 2019 – she noted that when insulin levels and HOMA-IR were measured, there was a greater reduction in both variables in the fasting group, compared with the calorie-restriction group.

“For people at risk of diabetes, maybe fasting produces more potent effects on glycemic control?” she ventured.
 

Who fares best with which fasting diets?

Summing up, Dr. Varady provided some practical pointers regarding who she feels is best suited to intermittent fasting and who should avoid it.

Those who binge eat, shift-workers, and frequent snackers do not do well with fasting, she said.

The first 10 days of intermittent fasting are rough, she pointed out, with the most common complaint being headaches.

“Eventually, people do feel an energy boost on fast days, and they say they concentrate better and have lots of energy. People won’t feel lethargic. Also, eating protein on fast days has been shown to keep hunger at bay.”

She cautiously concluded that weight loss with “alternate-day fasting” is quicker than some other methods, at 4.5-7 kg (10-15 lb) in 3 months, but is harder to follow and requires some calorie counting.

“In comparison, with time-restricted feeding, for which there have been very few ... studies to date, weight loss is slower at 2-4.5 kg (5-10 lb) in 3 months, but it is easier to follow and tolerable because you don’t need to count calories.”

Dr. Weiss has reported no relevant financial relationships. Dr. Varady has reported receiving author fees from Hachette for her book, “Every Other Day Diet.” (New York: Hachette, 2013)

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

Cardiologist Ethan J. Weiss, MD, followed an intermittent-fasting diet for 7 years. He lost about 3.6 kg (8 lb) and began recommending the approach to friends and patients who wanted to lose weight.

“I liked the way the diet was so simple,” said Dr. Weiss, an associate professor at the Cardiovascular Research Institute, University of California, San Francisco. But he also felt “it was too good to be true because you can eat what you want as long as it’s within a narrow window.”

So when, last year, he conducted a randomized, controlled trial, TREAT, testing such an approach – eating during just 8 hours a day, fasting for the remaining 16 hours – versus an eating plan of three meals a day without restrictions, he was somewhat dismayed to find the group of people who fasted didn’t lose any more weight than the other group.

The approach used in this study is known as time-restricted eating. It involves designating periods of time within the day when people can consume whatever they want; they then “fast” at times outside those eating windows. Other methods include alternate-day fasting, or the well-known 5:2 diet. In the latter, people eat a “normal” amount of around 2,000 calories per day on 5 days of the week, but for the other 2 days, they restrict caloric intake to 500 calories per day.

Intermittent fasting is an umbrella term encompassing all of these different approaches.

Dr. Weiss’s work builds on more than a decade of research into this type of eating plan by scientists, including Krista Varady, PhD, professor of nutrition at the University of Illinois at Chicago, who presented an overview of her own studies last fall at the virtual annual meeting of the European Association for the Study of Diabetes.

Although much of the work has suggested that the shorter duration of eating period in this type of diet leads to lower calorie intake and weight loss while avoiding the need for the tedious calorie-counting of conventional diets, Dr. Weiss’s data – published last year – throws a spanner in the works and now complicates the evidence base.
 

A promise of simplicity: ‘All you have to do is watch the clock’

Dr. Varady said she, too, is intrigued by the simplicity of intermittent-fasting diets.

In 2018, Dr. Varady and colleagues tested the weight-loss efficacy of 12 weeks of time-restricted feeding in a pilot study of 23 people with obesity.

Participants were permitted an 8-hour eating window (10 a.m. to 6 p.m.) followed by water-only fasting of 16 hours (6 p.m. to 10 a.m.) the next day (sometimes referred to as the 16:8 diet). Researchers measured weight loss and fat mass, as well as metabolic parameters, and compared the active group with 23 matched-control participants who ate freely.

There were no restrictions on type or quantity of food consumed by the control group during the 8-hour period, but individuals in the time-restricted feeding group consumed around 350 calories less than the comparator group.

Dr. Varady thinks this is most likely because of the fact that people normally eat during a 14-hour window and time-restricted feeding cuts that down by 6 hours.

“One of the most beautiful things about time-restricted feeding is that it doesn’t require calorie monitoring,” she explained. “People get burnt out with having to constantly monitor calories. All you have to do is watch the clock.”

Adherence was quite high, she reported, although most people skipped 1 day, often a Saturday, likely because of social engagements.

Weight loss in the time-restricted feeding group was mild to moderate. After 3 months, mean body weight decreased by 2.6%, or approximately 3 kg (7-8 lb), relative to those who ate freely, but this was a significant difference (P  < .05).

But the researchers observed little change in metabolic disease risk factors between the groups.

In the time-restricted feeding group, systolic blood pressure dropped from 128 mm Hg to 121 mm Hg over the 12-week period, which was significant relative to the control group (P  <  .05) but there were no significant changes in fasting glucose, fasting lipids, fasting insulin, or insulin resistance relative to the comparator group.

In contrast to Dr. Varady’s findings, Dr. Weiss’s randomized TREAT trial, which used a similar 16:8 period of time-restricted versus unrestricted eating in 116 individuals with overweight or obesity, did not find greater weight loss in the group restricted to eating within the 8-hour window.

As previously reported by this news organization, those who fasted for 16 hours of each day (n = 59) did lose some weight, compared with the control group (n = 57) over 12 weeks, but the difference in weight loss between the groups was not significant (−0.26 kg; P = .63).

And there were no significant differences in any of the secondary outcomes of fat mass, fasting insulin, fasting glucose, hemoglobin A1c levels, estimated energy intake, total energy expenditure, and resting energy expenditure between the time-restricted eating and regular feeding groups.

“I don’t claim time-restricted eating is dead,” Dr. Weiss said, “but the hope that you can eat for a limited time each day and solve metabolic disease is not there.”

Does the length of the eating window matter?

Following her pilot study of an 8-hour eating window, Dr. Varady conducted further research with 4- or 6-hour eating windows to see if even shorter periods would precipitate greater weight loss, ideally a clinically significant loss of 5% of body weight.

She ran a 2-month randomized, controlled study in people with obesity, published in 2020, which was the first to examine both a 4-hour (3 p.m. to 7 p.m.; n = 19) or 6-hour (1 p.m to 7 p.m.; n = 20) eating window versus a diet without any food restrictions as a control (n = 19) (Cell Metab. 2020;32:366-78.e3).

Dr. Varady explained that they decided to shift the eating window to later in the day for this trial (in contrast to the earlier 8-hour study) to allow people to eat dinner at a sociable time, and thereby hopefully reduce dropouts from the study. 

“Unlike with alternate-day fasting, most people find time-restricted feeding easy to incorporate into their lifestyles,” she remarked.

Both the 4- and 6-hour eating window groups experienced a mean 3.2% body weight loss, compared with controls, and this correlated with a 550-calorie reduction in their daily consumption, compared with their baseline calorie intake.

In terms of other outcomes – and in contrast to the 8-hour window study which showed very little changed other than a minor decrease in blood pressure – researchers saw some changes in metabolic risk factors with the 4- and 6-hour eating windows, Dr. Varady reported.

Compared with the control group, fasting insulin decreased in both time-restricted feeding groups by a mean of 15% (P < .05). Insulin resistance also decreased by 25% in the 4-hour group and by 15% in the 6-hour group, compared with the control group. Fasting glucose did not change in either group, however.

The researchers did not observe any effect on blood pressure or plasma lipids in the 4- or 6-hour eating window groups, compared with controls. However, measures of oxidative stress and inflammation decreased in both groups versus controls by approximately 35% (P < .05).

“These findings suggest that this form of severe time-restricted feeding is achievable and can help adults with obesity lose weight, without having to count calories,” Dr. Varady and colleagues conclude.
 

Is intermittent fasting better for weight loss than calorie restriction?

Ultimately, if weight loss is the primary goal, many want to know how time-restricted feeding compares with conventional daily calorie restriction.

Back in 2017, Dr. Varady published a year-long randomized, controlled study that compared alternate-day fasting with a calorie-restriction diet and a conventional/usual diet among 100 participants with obesity who were otherwise healthy.  

Participants on the alternate-day fasting plan (n = 34) consumed 500 calories on fasting days for the first 6 months for weight loss (approximately 25% of energy needs) followed by 125% of energy needs on alternating “feast days”. For an additional 6 months, they ate 1,000 calories on fasting days – aimed at weight maintenance.

Those following the calorie-restriction diet (n = 35) reduced energy intake by 25% (approximately 500 kcal) for the first 6 months for weight loss, followed by enough calories sufficient for weight maintenance (so no further loss nor gain).

However, the study showed alternate-day fasting did not produce better weight loss than conventional calorie counting.

“Over the first 6 months [during the weight-loss period] both groups lost an average of 6% body weight. After 12 months it crept back to 5% weight loss,” reported Dr. Varady.

“Realistically, if the study continued for 2 or 3 years, they probably would have regained much of their weight,” she admitted.

Dr. Varady suspects it might be better for the alternate-day fasting participants to continue eating only 500 calories on their fast day during the weight-loss maintenance period rather than increasing calorie intake during this phase.

Heart rate and blood pressure did not change in either group, while triglycerides decreased in the alternate-day fasting group, and LDL cholesterol decreased in the calorie-restriction group.

Glucose level decreased in the calorie-restriction group but not the alternate-day fasting group, and insulin and HOMA-IR were unaffected in both groups, reported Dr. Varady, noting that these findings were in healthy people with obesity.

In people with obesity and insulin resistance – evaluated as a subgroup in a separate study by Dr. Varady of alternate-day fasting versus daily calorie restriction published in 2019 – she noted that when insulin levels and HOMA-IR were measured, there was a greater reduction in both variables in the fasting group, compared with the calorie-restriction group.

“For people at risk of diabetes, maybe fasting produces more potent effects on glycemic control?” she ventured.
 

Who fares best with which fasting diets?

Summing up, Dr. Varady provided some practical pointers regarding who she feels is best suited to intermittent fasting and who should avoid it.

Those who binge eat, shift-workers, and frequent snackers do not do well with fasting, she said.

The first 10 days of intermittent fasting are rough, she pointed out, with the most common complaint being headaches.

“Eventually, people do feel an energy boost on fast days, and they say they concentrate better and have lots of energy. People won’t feel lethargic. Also, eating protein on fast days has been shown to keep hunger at bay.”

She cautiously concluded that weight loss with “alternate-day fasting” is quicker than some other methods, at 4.5-7 kg (10-15 lb) in 3 months, but is harder to follow and requires some calorie counting.

“In comparison, with time-restricted feeding, for which there have been very few ... studies to date, weight loss is slower at 2-4.5 kg (5-10 lb) in 3 months, but it is easier to follow and tolerable because you don’t need to count calories.”

Dr. Weiss has reported no relevant financial relationships. Dr. Varady has reported receiving author fees from Hachette for her book, “Every Other Day Diet.” (New York: Hachette, 2013)

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

Cardiologist Ethan J. Weiss, MD, followed an intermittent-fasting diet for 7 years. He lost about 3.6 kg (8 lb) and began recommending the approach to friends and patients who wanted to lose weight.

“I liked the way the diet was so simple,” said Dr. Weiss, an associate professor at the Cardiovascular Research Institute, University of California, San Francisco. But he also felt “it was too good to be true because you can eat what you want as long as it’s within a narrow window.”

So when, last year, he conducted a randomized, controlled trial, TREAT, testing such an approach – eating during just 8 hours a day, fasting for the remaining 16 hours – versus an eating plan of three meals a day without restrictions, he was somewhat dismayed to find the group of people who fasted didn’t lose any more weight than the other group.

The approach used in this study is known as time-restricted eating. It involves designating periods of time within the day when people can consume whatever they want; they then “fast” at times outside those eating windows. Other methods include alternate-day fasting, or the well-known 5:2 diet. In the latter, people eat a “normal” amount of around 2,000 calories per day on 5 days of the week, but for the other 2 days, they restrict caloric intake to 500 calories per day.

Intermittent fasting is an umbrella term encompassing all of these different approaches.

Dr. Weiss’s work builds on more than a decade of research into this type of eating plan by scientists, including Krista Varady, PhD, professor of nutrition at the University of Illinois at Chicago, who presented an overview of her own studies last fall at the virtual annual meeting of the European Association for the Study of Diabetes.

Although much of the work has suggested that the shorter duration of eating period in this type of diet leads to lower calorie intake and weight loss while avoiding the need for the tedious calorie-counting of conventional diets, Dr. Weiss’s data – published last year – throws a spanner in the works and now complicates the evidence base.
 

A promise of simplicity: ‘All you have to do is watch the clock’

Dr. Varady said she, too, is intrigued by the simplicity of intermittent-fasting diets.

In 2018, Dr. Varady and colleagues tested the weight-loss efficacy of 12 weeks of time-restricted feeding in a pilot study of 23 people with obesity.

Participants were permitted an 8-hour eating window (10 a.m. to 6 p.m.) followed by water-only fasting of 16 hours (6 p.m. to 10 a.m.) the next day (sometimes referred to as the 16:8 diet). Researchers measured weight loss and fat mass, as well as metabolic parameters, and compared the active group with 23 matched-control participants who ate freely.

There were no restrictions on type or quantity of food consumed by the control group during the 8-hour period, but individuals in the time-restricted feeding group consumed around 350 calories less than the comparator group.

Dr. Varady thinks this is most likely because of the fact that people normally eat during a 14-hour window and time-restricted feeding cuts that down by 6 hours.

“One of the most beautiful things about time-restricted feeding is that it doesn’t require calorie monitoring,” she explained. “People get burnt out with having to constantly monitor calories. All you have to do is watch the clock.”

Adherence was quite high, she reported, although most people skipped 1 day, often a Saturday, likely because of social engagements.

Weight loss in the time-restricted feeding group was mild to moderate. After 3 months, mean body weight decreased by 2.6%, or approximately 3 kg (7-8 lb), relative to those who ate freely, but this was a significant difference (P  < .05).

But the researchers observed little change in metabolic disease risk factors between the groups.

In the time-restricted feeding group, systolic blood pressure dropped from 128 mm Hg to 121 mm Hg over the 12-week period, which was significant relative to the control group (P  <  .05) but there were no significant changes in fasting glucose, fasting lipids, fasting insulin, or insulin resistance relative to the comparator group.

In contrast to Dr. Varady’s findings, Dr. Weiss’s randomized TREAT trial, which used a similar 16:8 period of time-restricted versus unrestricted eating in 116 individuals with overweight or obesity, did not find greater weight loss in the group restricted to eating within the 8-hour window.

As previously reported by this news organization, those who fasted for 16 hours of each day (n = 59) did lose some weight, compared with the control group (n = 57) over 12 weeks, but the difference in weight loss between the groups was not significant (−0.26 kg; P = .63).

And there were no significant differences in any of the secondary outcomes of fat mass, fasting insulin, fasting glucose, hemoglobin A1c levels, estimated energy intake, total energy expenditure, and resting energy expenditure between the time-restricted eating and regular feeding groups.

“I don’t claim time-restricted eating is dead,” Dr. Weiss said, “but the hope that you can eat for a limited time each day and solve metabolic disease is not there.”

Does the length of the eating window matter?

Following her pilot study of an 8-hour eating window, Dr. Varady conducted further research with 4- or 6-hour eating windows to see if even shorter periods would precipitate greater weight loss, ideally a clinically significant loss of 5% of body weight.

She ran a 2-month randomized, controlled study in people with obesity, published in 2020, which was the first to examine both a 4-hour (3 p.m. to 7 p.m.; n = 19) or 6-hour (1 p.m to 7 p.m.; n = 20) eating window versus a diet without any food restrictions as a control (n = 19) (Cell Metab. 2020;32:366-78.e3).

Dr. Varady explained that they decided to shift the eating window to later in the day for this trial (in contrast to the earlier 8-hour study) to allow people to eat dinner at a sociable time, and thereby hopefully reduce dropouts from the study. 

“Unlike with alternate-day fasting, most people find time-restricted feeding easy to incorporate into their lifestyles,” she remarked.

Both the 4- and 6-hour eating window groups experienced a mean 3.2% body weight loss, compared with controls, and this correlated with a 550-calorie reduction in their daily consumption, compared with their baseline calorie intake.

In terms of other outcomes – and in contrast to the 8-hour window study which showed very little changed other than a minor decrease in blood pressure – researchers saw some changes in metabolic risk factors with the 4- and 6-hour eating windows, Dr. Varady reported.

Compared with the control group, fasting insulin decreased in both time-restricted feeding groups by a mean of 15% (P < .05). Insulin resistance also decreased by 25% in the 4-hour group and by 15% in the 6-hour group, compared with the control group. Fasting glucose did not change in either group, however.

The researchers did not observe any effect on blood pressure or plasma lipids in the 4- or 6-hour eating window groups, compared with controls. However, measures of oxidative stress and inflammation decreased in both groups versus controls by approximately 35% (P < .05).

“These findings suggest that this form of severe time-restricted feeding is achievable and can help adults with obesity lose weight, without having to count calories,” Dr. Varady and colleagues conclude.
 

Is intermittent fasting better for weight loss than calorie restriction?

Ultimately, if weight loss is the primary goal, many want to know how time-restricted feeding compares with conventional daily calorie restriction.

Back in 2017, Dr. Varady published a year-long randomized, controlled study that compared alternate-day fasting with a calorie-restriction diet and a conventional/usual diet among 100 participants with obesity who were otherwise healthy.  

Participants on the alternate-day fasting plan (n = 34) consumed 500 calories on fasting days for the first 6 months for weight loss (approximately 25% of energy needs) followed by 125% of energy needs on alternating “feast days”. For an additional 6 months, they ate 1,000 calories on fasting days – aimed at weight maintenance.

Those following the calorie-restriction diet (n = 35) reduced energy intake by 25% (approximately 500 kcal) for the first 6 months for weight loss, followed by enough calories sufficient for weight maintenance (so no further loss nor gain).

However, the study showed alternate-day fasting did not produce better weight loss than conventional calorie counting.

“Over the first 6 months [during the weight-loss period] both groups lost an average of 6% body weight. After 12 months it crept back to 5% weight loss,” reported Dr. Varady.

“Realistically, if the study continued for 2 or 3 years, they probably would have regained much of their weight,” she admitted.

Dr. Varady suspects it might be better for the alternate-day fasting participants to continue eating only 500 calories on their fast day during the weight-loss maintenance period rather than increasing calorie intake during this phase.

Heart rate and blood pressure did not change in either group, while triglycerides decreased in the alternate-day fasting group, and LDL cholesterol decreased in the calorie-restriction group.

Glucose level decreased in the calorie-restriction group but not the alternate-day fasting group, and insulin and HOMA-IR were unaffected in both groups, reported Dr. Varady, noting that these findings were in healthy people with obesity.

In people with obesity and insulin resistance – evaluated as a subgroup in a separate study by Dr. Varady of alternate-day fasting versus daily calorie restriction published in 2019 – she noted that when insulin levels and HOMA-IR were measured, there was a greater reduction in both variables in the fasting group, compared with the calorie-restriction group.

“For people at risk of diabetes, maybe fasting produces more potent effects on glycemic control?” she ventured.
 

Who fares best with which fasting diets?

Summing up, Dr. Varady provided some practical pointers regarding who she feels is best suited to intermittent fasting and who should avoid it.

Those who binge eat, shift-workers, and frequent snackers do not do well with fasting, she said.

The first 10 days of intermittent fasting are rough, she pointed out, with the most common complaint being headaches.

“Eventually, people do feel an energy boost on fast days, and they say they concentrate better and have lots of energy. People won’t feel lethargic. Also, eating protein on fast days has been shown to keep hunger at bay.”

She cautiously concluded that weight loss with “alternate-day fasting” is quicker than some other methods, at 4.5-7 kg (10-15 lb) in 3 months, but is harder to follow and requires some calorie counting.

“In comparison, with time-restricted feeding, for which there have been very few ... studies to date, weight loss is slower at 2-4.5 kg (5-10 lb) in 3 months, but it is easier to follow and tolerable because you don’t need to count calories.”

Dr. Weiss has reported no relevant financial relationships. Dr. Varady has reported receiving author fees from Hachette for her book, “Every Other Day Diet.” (New York: Hachette, 2013)

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

People who have brown fat detected on imaging seem to be at reduced risk of cardiac and metabolic conditions, ranging from type 2 diabetes to hypertension and coronary artery disease, with a notably strong effect in people with obesity, according to a new study of more than 52,000 individuals who had PET/CT scans as part of cancer evaluation.

Although this has been studied for decades in newborns and animals, only in the past decade have scientists appreciated that some adults have brown fat, typically around the neck and shoulders.

The new study, by far the largest of its kind in humans, appears to confirm the health benefits of brown fat suggested by previous studies, Tobias Becher, MD, and colleagues from The Rockefeller University, New York, wrote in their article published online Jan. 4 in Nature Medicine.

“Our study indicates an important contribution of brown adipose tissue to cardiometabolic health and suggests ... [it] has therapeutic potential in humans,” they stated.

But Caroline M. Apovian, MD, Center for Weight Management and Wellness, Brigham and Women’s Hospital, Boston, is more cautious in her interpretation of the findings.

“It’s nice to see that what we believe about this is correct, and it’s great to see that with obesity and more brown fat there is reduced diabetes and hypertension, but it’s only an association,” she said in an interview.

“This is a good study, but I don’t think we have an understanding of exactly why some people have more brown fat than others, how white fat becomes brown fat, the role of therapeutics, or if it’s important to try to create more brown fat.

“We don’t know if it’s a matter of exercise or something like living in a colder environment, so we need to find out whether or not brown fat is, for instance, a genetic issue, and if it is, if there is a way to increase it in humans,” she added.

And the fact that the study included patients with or being screened for cancer is one of the most important limitations of the study, Dr. Apovian noted.
 

Brown fat detected in 10% of participants

Contrary to white fat, which stores energy, brown fat is thermogenic, activated by cold conditions, and instead burns energy. And although animal studies have shown a link between brown fat and improvements in glucose and lipid homeostasis, the effects of brown fat in humans are not well understood.

Dr. Becher and colleagues explained that large-scale studies of brown fat have been practically impossible because the tissue only shows up on medical imaging and it would be unethical to expose people to radiation just to study brown fat.  

But they realized that, across the street from their lab, many thousands of people visit Memorial Sloan Kettering Cancer Center each year to undergo PET/CT scans for cancer evaluation.

Because radiologists routinely take note when brown adipose tissue is detected to prevent its misinterpretation as a tumor, the information was readily available with the scan data.

“We realized this could be a valuable resource to get us started with looking at brown fat at a population scale,” Dr. Becher said in a press statement from The Rockefeller University.

So they reviewed 134,529 PET/CT scans from 52,487 individuals attending Memorial Sloan Kettering between June 2009 and March 2018 for indications ranging from cancer diagnosis to treatment or surveillance.

Participants were classified by the presence or absence of brown adipose tissue and researchers were able to use electronic health records to comprehensively examine associations between brown fat and rates of disease.

Overall, brown adipose tissue was identified in 5,070 (9.7%) of patients, with higher rates of brown fat among women than men (13.8% vs. 4.9%; P < .0001) and reduced rates with advancing age (P < .0001), as has been observed in previous studies.

The researchers noted, however, that this rate of around 10% of people having brown fat is likely an underestimate because the patients had been instructed to avoid cold exposure, exercise, and caffeine – all of which are thought to increase brown adipose tissue – prior to having their scans.
 

Does brown fat mitigate some harms of obesity?

Among those with brown fat, the rate of type 2 diabetes was 4.6% compared with 9.5% in those with no detected brown fat (P < .0001), and in a multivariate analysis, the odds ratio (OR) for type 2 diabetes in the presence of brown fat was 0.44.

The occurrence of coronary artery disease was significantly lower in those with brown fat (OR, 0.68; P = .0002), as was cerebrovascular disease (OR, 0.77; P = .0317), heart failure (OR, 0.62; P = .0043), and hypertension (OR, 0.85; P = .0014).

Brown fat also was associated with notable improvements in glucose, triglycerides, and HDL-C levels (all P < .0001), while no differences were seen in measures of LDL-Cs or total cholesterol.

Leukocyte and platelet counts were significantly decreased in individuals with brown fat (both P < .0001).

The findings “suggest potential roles for brown adipose beyond regulation of lipid and glucose metabolism,” the authors wrote.

Most notably, the effects were more pronounced in people with obesity. For example, the prevalence of type 2 diabetes in those with obesity and brown fat was less than half the rate in those with obesity without brown fat (7.5% vs. 20.3%; P < .0001).

This could indicate that brown adipose tissue “might play a role in mitigating the deleterious effects of obesity,” the researchers stated.

“Future research should aim to improve our understanding of brown adipose tissue regulation in humans and to develop mechanisms to safely modulate [its activity],” they concluded.

The study received funding from the American Diabetes Association, the Sinsheimer Foundation, and the National Center for Advancing Translational Sciences of the U.S. Department of Health & Human Services. The authors and Dr. Apovian have reported no relevant financial relationships.

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

People who have brown fat detected on imaging seem to be at reduced risk of cardiac and metabolic conditions, ranging from type 2 diabetes to hypertension and coronary artery disease, with a notably strong effect in people with obesity, according to a new study of more than 52,000 individuals who had PET/CT scans as part of cancer evaluation.

Although this has been studied for decades in newborns and animals, only in the past decade have scientists appreciated that some adults have brown fat, typically around the neck and shoulders.

The new study, by far the largest of its kind in humans, appears to confirm the health benefits of brown fat suggested by previous studies, Tobias Becher, MD, and colleagues from The Rockefeller University, New York, wrote in their article published online Jan. 4 in Nature Medicine.

“Our study indicates an important contribution of brown adipose tissue to cardiometabolic health and suggests ... [it] has therapeutic potential in humans,” they stated.

But Caroline M. Apovian, MD, Center for Weight Management and Wellness, Brigham and Women’s Hospital, Boston, is more cautious in her interpretation of the findings.

“It’s nice to see that what we believe about this is correct, and it’s great to see that with obesity and more brown fat there is reduced diabetes and hypertension, but it’s only an association,” she said in an interview.

“This is a good study, but I don’t think we have an understanding of exactly why some people have more brown fat than others, how white fat becomes brown fat, the role of therapeutics, or if it’s important to try to create more brown fat.

“We don’t know if it’s a matter of exercise or something like living in a colder environment, so we need to find out whether or not brown fat is, for instance, a genetic issue, and if it is, if there is a way to increase it in humans,” she added.

And the fact that the study included patients with or being screened for cancer is one of the most important limitations of the study, Dr. Apovian noted.
 

Brown fat detected in 10% of participants

Contrary to white fat, which stores energy, brown fat is thermogenic, activated by cold conditions, and instead burns energy. And although animal studies have shown a link between brown fat and improvements in glucose and lipid homeostasis, the effects of brown fat in humans are not well understood.

Dr. Becher and colleagues explained that large-scale studies of brown fat have been practically impossible because the tissue only shows up on medical imaging and it would be unethical to expose people to radiation just to study brown fat.  

But they realized that, across the street from their lab, many thousands of people visit Memorial Sloan Kettering Cancer Center each year to undergo PET/CT scans for cancer evaluation.

Because radiologists routinely take note when brown adipose tissue is detected to prevent its misinterpretation as a tumor, the information was readily available with the scan data.

“We realized this could be a valuable resource to get us started with looking at brown fat at a population scale,” Dr. Becher said in a press statement from The Rockefeller University.

So they reviewed 134,529 PET/CT scans from 52,487 individuals attending Memorial Sloan Kettering between June 2009 and March 2018 for indications ranging from cancer diagnosis to treatment or surveillance.

Participants were classified by the presence or absence of brown adipose tissue and researchers were able to use electronic health records to comprehensively examine associations between brown fat and rates of disease.

Overall, brown adipose tissue was identified in 5,070 (9.7%) of patients, with higher rates of brown fat among women than men (13.8% vs. 4.9%; P < .0001) and reduced rates with advancing age (P < .0001), as has been observed in previous studies.

The researchers noted, however, that this rate of around 10% of people having brown fat is likely an underestimate because the patients had been instructed to avoid cold exposure, exercise, and caffeine – all of which are thought to increase brown adipose tissue – prior to having their scans.
 

Does brown fat mitigate some harms of obesity?

Among those with brown fat, the rate of type 2 diabetes was 4.6% compared with 9.5% in those with no detected brown fat (P < .0001), and in a multivariate analysis, the odds ratio (OR) for type 2 diabetes in the presence of brown fat was 0.44.

The occurrence of coronary artery disease was significantly lower in those with brown fat (OR, 0.68; P = .0002), as was cerebrovascular disease (OR, 0.77; P = .0317), heart failure (OR, 0.62; P = .0043), and hypertension (OR, 0.85; P = .0014).

Brown fat also was associated with notable improvements in glucose, triglycerides, and HDL-C levels (all P < .0001), while no differences were seen in measures of LDL-Cs or total cholesterol.

Leukocyte and platelet counts were significantly decreased in individuals with brown fat (both P < .0001).

The findings “suggest potential roles for brown adipose beyond regulation of lipid and glucose metabolism,” the authors wrote.

Most notably, the effects were more pronounced in people with obesity. For example, the prevalence of type 2 diabetes in those with obesity and brown fat was less than half the rate in those with obesity without brown fat (7.5% vs. 20.3%; P < .0001).

This could indicate that brown adipose tissue “might play a role in mitigating the deleterious effects of obesity,” the researchers stated.

“Future research should aim to improve our understanding of brown adipose tissue regulation in humans and to develop mechanisms to safely modulate [its activity],” they concluded.

The study received funding from the American Diabetes Association, the Sinsheimer Foundation, and the National Center for Advancing Translational Sciences of the U.S. Department of Health & Human Services. The authors and Dr. Apovian have reported no relevant financial relationships.

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

People who have brown fat detected on imaging seem to be at reduced risk of cardiac and metabolic conditions, ranging from type 2 diabetes to hypertension and coronary artery disease, with a notably strong effect in people with obesity, according to a new study of more than 52,000 individuals who had PET/CT scans as part of cancer evaluation.

Although this has been studied for decades in newborns and animals, only in the past decade have scientists appreciated that some adults have brown fat, typically around the neck and shoulders.

The new study, by far the largest of its kind in humans, appears to confirm the health benefits of brown fat suggested by previous studies, Tobias Becher, MD, and colleagues from The Rockefeller University, New York, wrote in their article published online Jan. 4 in Nature Medicine.

“Our study indicates an important contribution of brown adipose tissue to cardiometabolic health and suggests ... [it] has therapeutic potential in humans,” they stated.

But Caroline M. Apovian, MD, Center for Weight Management and Wellness, Brigham and Women’s Hospital, Boston, is more cautious in her interpretation of the findings.

“It’s nice to see that what we believe about this is correct, and it’s great to see that with obesity and more brown fat there is reduced diabetes and hypertension, but it’s only an association,” she said in an interview.

“This is a good study, but I don’t think we have an understanding of exactly why some people have more brown fat than others, how white fat becomes brown fat, the role of therapeutics, or if it’s important to try to create more brown fat.

“We don’t know if it’s a matter of exercise or something like living in a colder environment, so we need to find out whether or not brown fat is, for instance, a genetic issue, and if it is, if there is a way to increase it in humans,” she added.

And the fact that the study included patients with or being screened for cancer is one of the most important limitations of the study, Dr. Apovian noted.
 

Brown fat detected in 10% of participants

Contrary to white fat, which stores energy, brown fat is thermogenic, activated by cold conditions, and instead burns energy. And although animal studies have shown a link between brown fat and improvements in glucose and lipid homeostasis, the effects of brown fat in humans are not well understood.

Dr. Becher and colleagues explained that large-scale studies of brown fat have been practically impossible because the tissue only shows up on medical imaging and it would be unethical to expose people to radiation just to study brown fat.  

But they realized that, across the street from their lab, many thousands of people visit Memorial Sloan Kettering Cancer Center each year to undergo PET/CT scans for cancer evaluation.

Because radiologists routinely take note when brown adipose tissue is detected to prevent its misinterpretation as a tumor, the information was readily available with the scan data.

“We realized this could be a valuable resource to get us started with looking at brown fat at a population scale,” Dr. Becher said in a press statement from The Rockefeller University.

So they reviewed 134,529 PET/CT scans from 52,487 individuals attending Memorial Sloan Kettering between June 2009 and March 2018 for indications ranging from cancer diagnosis to treatment or surveillance.

Participants were classified by the presence or absence of brown adipose tissue and researchers were able to use electronic health records to comprehensively examine associations between brown fat and rates of disease.

Overall, brown adipose tissue was identified in 5,070 (9.7%) of patients, with higher rates of brown fat among women than men (13.8% vs. 4.9%; P < .0001) and reduced rates with advancing age (P < .0001), as has been observed in previous studies.

The researchers noted, however, that this rate of around 10% of people having brown fat is likely an underestimate because the patients had been instructed to avoid cold exposure, exercise, and caffeine – all of which are thought to increase brown adipose tissue – prior to having their scans.
 

Does brown fat mitigate some harms of obesity?

Among those with brown fat, the rate of type 2 diabetes was 4.6% compared with 9.5% in those with no detected brown fat (P < .0001), and in a multivariate analysis, the odds ratio (OR) for type 2 diabetes in the presence of brown fat was 0.44.

The occurrence of coronary artery disease was significantly lower in those with brown fat (OR, 0.68; P = .0002), as was cerebrovascular disease (OR, 0.77; P = .0317), heart failure (OR, 0.62; P = .0043), and hypertension (OR, 0.85; P = .0014).

Brown fat also was associated with notable improvements in glucose, triglycerides, and HDL-C levels (all P < .0001), while no differences were seen in measures of LDL-Cs or total cholesterol.

Leukocyte and platelet counts were significantly decreased in individuals with brown fat (both P < .0001).

The findings “suggest potential roles for brown adipose beyond regulation of lipid and glucose metabolism,” the authors wrote.

Most notably, the effects were more pronounced in people with obesity. For example, the prevalence of type 2 diabetes in those with obesity and brown fat was less than half the rate in those with obesity without brown fat (7.5% vs. 20.3%; P < .0001).

This could indicate that brown adipose tissue “might play a role in mitigating the deleterious effects of obesity,” the researchers stated.

“Future research should aim to improve our understanding of brown adipose tissue regulation in humans and to develop mechanisms to safely modulate [its activity],” they concluded.

The study received funding from the American Diabetes Association, the Sinsheimer Foundation, and the National Center for Advancing Translational Sciences of the U.S. Department of Health & Human Services. The authors and Dr. Apovian have reported no relevant financial relationships.

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

Yet another study has linked the consumption of ultraprocessed, or “junk,” foods to bad health outcomes.

In a longitudinal analysis of more than 22,000 men and women from southern Italy, those who consumed the most ultraprocessed food (UPF) had the highest risk for cardiovascular disease (CVD) and all-cause mortality, likely mediated through a diet high in sugar, researchers said.

High consumption of UPF in this Mediterranean cohort was associated with a 58% increased risk for CVD mortality and 52% higher risk of dying from ischemic heart disease (IHD) and cerebrovascular causes, independently of known risk factors for CVD, even among individuals who otherwise adhered to the Mediterranean diet.

The findings “should serve as an incentive for limiting consumption of UPF and encouraging natural or minimally processed foods, as several national nutritional policies recommend,” Marialaura Bonaccio, PhD, department of epidemiology and prevention, IRCCS Neuromed, Pozzilli, Italy, and colleagues wrote. The results were published online Dec. 18 in the American Journal of Clinical Nutrition.

Earlier this year, as reported by this news organization, researchers found mounting evidence that the obesity epidemic and the increase in incidence of related chronic conditions corresponded with an increase in the intake of UPF.

A study that was conducted in a European cohort found that adults whose diet included more UPF and beverages, such as ice cream, soda, and hamburgers, were more likely to develop CVD or die sooner than others who had a more wholesome diet.

As reported previously by this news organization, among adults in France who had a 10% higher intake of UPF and beverages, the rate of CVD, coronary heart disease, and cerebrovascular disease was 11% to 13% higher over a period of about 5 years.

Similarly, university graduates in Spain who consumed more than four servings of UPF and beverages a day were 62% more likely to die of any cause over about a decade than those who consumed less than two servings per day.
 

Where’s the food?

There is very little actual food in UPF. “The NOVA classification provides 4 main classes of food and beverages, the last of which is represented by the ultraprocessed food group. This comprises products (e.g., snacks, drinks, and ready meals, ‘created mostly or entirely from substances extracted from foods or derived from food constituents with little, if any intact food, which often contain flavors, colors, and other additives that imitate or intensify the sensory qualities of foods or culinary preparations made from foods,’ ” Dr. Bonaccio and colleagues wrote.

Such foods are very convenient, tasty, inexpensive, and have a long shelf life. They are highly competitive with foods that are naturally ready to consume and freshly prepared dishes and meals, the authors add.

The researchers conducted a longitudinal analysis on 22,475 men and women (mean age, 55 years; range, 43-67 years) who were recruited from the Moli-sani Study, a population-based cohort of men and women aged 35 years and older in the Molise region of southern Italy, between 2005 and 2010. Participants were followed for 8.2 years.

Food intake was assessed with the Food Frequency Questionnaire; UPF was defined using the NOVA classification according to degree of processing.

UPF intakes were categorized as quartiles of the ratio of UPF to total food consumed.

Overall, study participants reported a median of 10% (interquartile range, 6.6%-14.6%) of dietary intake as UPF and a total of 181.5 g/d of UPF intake.

The foods that contributed most to total UPF consumed were processed meat, which accounted for 19.8% of UPF intake; pizza (16.8%); and cakes and pies (13.4%).

High consumers of UPF, defined as those for whom UPF constituted more than 14.6% of their total diet, were more likely to be women, to be younger, and to have a higher educational level. They also reported fewer risk factors and fewer baseline chronic diseases and health conditions than persons who consumed UPF less frequently.

In addition, high consumption of UPF was associated with lower adherence to the Mediterranean diet; higher intake of fat, sugar, dietary cholesterol, and sodium; and lower intake of fiber.

During a median follow-up of 8.2 years, 1,216 all-cause deaths occurred. Of these, 439 were attributed to CVD, 255 to IHD/cerebrovascular disease, 477 to cancer, and 300 to other causes.
 

The more UPF, the higher the risk for CVD, death

The researchers found a direct linear dose-response relation between a 5% increase in the proportion of UPF in the diet and risk for all-cause and CVD mortality.

Individuals who reported the highest intake of UPF (fourth quartile, 14.6% of total food) as opposed to the lowest (first quartile, UPF <6.6%) experienced increased risks for CVD mortality (hazard ratio, 1.58; 95% CI, 1.23-2.03), death from IHD/cerebrovascular disease (HR, 1.52, 95% CI, 1.10-2.09), and all-cause mortality (HR, 1.26; 95% CI, 1.09-1.46).

High sugar content accounted for 36.3% of the relation of UPF with IHD/cerebrovascular mortality. Other nutritional factors, such as saturated fats, were unlikely to play a role, the researchers wrote.

Biomarkers of renal function accounted for 20.1% of the association of UPF with all-cause mortality and 12.0% for that of UPF with CVD mortality.

Subgroup analyses indicated that the magnitude of the association between UPF and all-cause mortality risk was greater among high-risk individuals, such as those with a history of CVD or diabetes. UPF was also likely to be more strongly associated with CVD mortality among those high-risk groups.

The interesting finding that the association between UPF and CVD mortality was greater among individuals with good adherence to the Mediterranean diet, which is known to have health benefits, could be explained by the fact that people who may benefit from a Mediterranean diet are more susceptible to losing health advantages when they also include “detrimental dietary behavior,” whereas those who consume a poor-quality diet are less likely to be harmed by an additional unhealthy behavior such as eating UPF regularly, wrote Dr. Bonaccio and colleagues.

“This is an interesting study confirming that consumption of highly processed foods such as pizza, processed meats, and soda are associated with greater risks of cardiovascular disease,” Walter Willett, MD, professor of epidemiology and nutrition, Harvard School of Public Health, Boston, said in an interview.

“These higher risks appear to be mediated in part by high intakes of saturated fat and sugar, but lower intakes of health-promoting aspects of diet also likely contribute to the findings,” Dr. Willett said.

“Some processing of food can be useful for preservation and control of infectious agents, but in general, a diet emphasizing minimally processed fruits and vegetables, whole grains, nuts, legumes, and plant sources of fat will be best for long-term well-being,” he said.

The study was supported in part by the Italian Ministry of Health and the HYPERCAN Study Italian Association for Cancer Research. Dr. Bonaccio and Dr. Willett reported no relevant financial relationships.

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

Yet another study has linked the consumption of ultraprocessed, or “junk,” foods to bad health outcomes.

In a longitudinal analysis of more than 22,000 men and women from southern Italy, those who consumed the most ultraprocessed food (UPF) had the highest risk for cardiovascular disease (CVD) and all-cause mortality, likely mediated through a diet high in sugar, researchers said.

High consumption of UPF in this Mediterranean cohort was associated with a 58% increased risk for CVD mortality and 52% higher risk of dying from ischemic heart disease (IHD) and cerebrovascular causes, independently of known risk factors for CVD, even among individuals who otherwise adhered to the Mediterranean diet.

The findings “should serve as an incentive for limiting consumption of UPF and encouraging natural or minimally processed foods, as several national nutritional policies recommend,” Marialaura Bonaccio, PhD, department of epidemiology and prevention, IRCCS Neuromed, Pozzilli, Italy, and colleagues wrote. The results were published online Dec. 18 in the American Journal of Clinical Nutrition.

Earlier this year, as reported by this news organization, researchers found mounting evidence that the obesity epidemic and the increase in incidence of related chronic conditions corresponded with an increase in the intake of UPF.

A study that was conducted in a European cohort found that adults whose diet included more UPF and beverages, such as ice cream, soda, and hamburgers, were more likely to develop CVD or die sooner than others who had a more wholesome diet.

As reported previously by this news organization, among adults in France who had a 10% higher intake of UPF and beverages, the rate of CVD, coronary heart disease, and cerebrovascular disease was 11% to 13% higher over a period of about 5 years.

Similarly, university graduates in Spain who consumed more than four servings of UPF and beverages a day were 62% more likely to die of any cause over about a decade than those who consumed less than two servings per day.
 

Where’s the food?

There is very little actual food in UPF. “The NOVA classification provides 4 main classes of food and beverages, the last of which is represented by the ultraprocessed food group. This comprises products (e.g., snacks, drinks, and ready meals, ‘created mostly or entirely from substances extracted from foods or derived from food constituents with little, if any intact food, which often contain flavors, colors, and other additives that imitate or intensify the sensory qualities of foods or culinary preparations made from foods,’ ” Dr. Bonaccio and colleagues wrote.

Such foods are very convenient, tasty, inexpensive, and have a long shelf life. They are highly competitive with foods that are naturally ready to consume and freshly prepared dishes and meals, the authors add.

The researchers conducted a longitudinal analysis on 22,475 men and women (mean age, 55 years; range, 43-67 years) who were recruited from the Moli-sani Study, a population-based cohort of men and women aged 35 years and older in the Molise region of southern Italy, between 2005 and 2010. Participants were followed for 8.2 years.

Food intake was assessed with the Food Frequency Questionnaire; UPF was defined using the NOVA classification according to degree of processing.

UPF intakes were categorized as quartiles of the ratio of UPF to total food consumed.

Overall, study participants reported a median of 10% (interquartile range, 6.6%-14.6%) of dietary intake as UPF and a total of 181.5 g/d of UPF intake.

The foods that contributed most to total UPF consumed were processed meat, which accounted for 19.8% of UPF intake; pizza (16.8%); and cakes and pies (13.4%).

High consumers of UPF, defined as those for whom UPF constituted more than 14.6% of their total diet, were more likely to be women, to be younger, and to have a higher educational level. They also reported fewer risk factors and fewer baseline chronic diseases and health conditions than persons who consumed UPF less frequently.

In addition, high consumption of UPF was associated with lower adherence to the Mediterranean diet; higher intake of fat, sugar, dietary cholesterol, and sodium; and lower intake of fiber.

During a median follow-up of 8.2 years, 1,216 all-cause deaths occurred. Of these, 439 were attributed to CVD, 255 to IHD/cerebrovascular disease, 477 to cancer, and 300 to other causes.
 

The more UPF, the higher the risk for CVD, death

The researchers found a direct linear dose-response relation between a 5% increase in the proportion of UPF in the diet and risk for all-cause and CVD mortality.

Individuals who reported the highest intake of UPF (fourth quartile, 14.6% of total food) as opposed to the lowest (first quartile, UPF <6.6%) experienced increased risks for CVD mortality (hazard ratio, 1.58; 95% CI, 1.23-2.03), death from IHD/cerebrovascular disease (HR, 1.52, 95% CI, 1.10-2.09), and all-cause mortality (HR, 1.26; 95% CI, 1.09-1.46).

High sugar content accounted for 36.3% of the relation of UPF with IHD/cerebrovascular mortality. Other nutritional factors, such as saturated fats, were unlikely to play a role, the researchers wrote.

Biomarkers of renal function accounted for 20.1% of the association of UPF with all-cause mortality and 12.0% for that of UPF with CVD mortality.

Subgroup analyses indicated that the magnitude of the association between UPF and all-cause mortality risk was greater among high-risk individuals, such as those with a history of CVD or diabetes. UPF was also likely to be more strongly associated with CVD mortality among those high-risk groups.

The interesting finding that the association between UPF and CVD mortality was greater among individuals with good adherence to the Mediterranean diet, which is known to have health benefits, could be explained by the fact that people who may benefit from a Mediterranean diet are more susceptible to losing health advantages when they also include “detrimental dietary behavior,” whereas those who consume a poor-quality diet are less likely to be harmed by an additional unhealthy behavior such as eating UPF regularly, wrote Dr. Bonaccio and colleagues.

“This is an interesting study confirming that consumption of highly processed foods such as pizza, processed meats, and soda are associated with greater risks of cardiovascular disease,” Walter Willett, MD, professor of epidemiology and nutrition, Harvard School of Public Health, Boston, said in an interview.

“These higher risks appear to be mediated in part by high intakes of saturated fat and sugar, but lower intakes of health-promoting aspects of diet also likely contribute to the findings,” Dr. Willett said.

“Some processing of food can be useful for preservation and control of infectious agents, but in general, a diet emphasizing minimally processed fruits and vegetables, whole grains, nuts, legumes, and plant sources of fat will be best for long-term well-being,” he said.

The study was supported in part by the Italian Ministry of Health and the HYPERCAN Study Italian Association for Cancer Research. Dr. Bonaccio and Dr. Willett reported no relevant financial relationships.

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

Yet another study has linked the consumption of ultraprocessed, or “junk,” foods to bad health outcomes.

In a longitudinal analysis of more than 22,000 men and women from southern Italy, those who consumed the most ultraprocessed food (UPF) had the highest risk for cardiovascular disease (CVD) and all-cause mortality, likely mediated through a diet high in sugar, researchers said.

High consumption of UPF in this Mediterranean cohort was associated with a 58% increased risk for CVD mortality and 52% higher risk of dying from ischemic heart disease (IHD) and cerebrovascular causes, independently of known risk factors for CVD, even among individuals who otherwise adhered to the Mediterranean diet.

The findings “should serve as an incentive for limiting consumption of UPF and encouraging natural or minimally processed foods, as several national nutritional policies recommend,” Marialaura Bonaccio, PhD, department of epidemiology and prevention, IRCCS Neuromed, Pozzilli, Italy, and colleagues wrote. The results were published online Dec. 18 in the American Journal of Clinical Nutrition.

Earlier this year, as reported by this news organization, researchers found mounting evidence that the obesity epidemic and the increase in incidence of related chronic conditions corresponded with an increase in the intake of UPF.

A study that was conducted in a European cohort found that adults whose diet included more UPF and beverages, such as ice cream, soda, and hamburgers, were more likely to develop CVD or die sooner than others who had a more wholesome diet.

As reported previously by this news organization, among adults in France who had a 10% higher intake of UPF and beverages, the rate of CVD, coronary heart disease, and cerebrovascular disease was 11% to 13% higher over a period of about 5 years.

Similarly, university graduates in Spain who consumed more than four servings of UPF and beverages a day were 62% more likely to die of any cause over about a decade than those who consumed less than two servings per day.
 

Where’s the food?

There is very little actual food in UPF. “The NOVA classification provides 4 main classes of food and beverages, the last of which is represented by the ultraprocessed food group. This comprises products (e.g., snacks, drinks, and ready meals, ‘created mostly or entirely from substances extracted from foods or derived from food constituents with little, if any intact food, which often contain flavors, colors, and other additives that imitate or intensify the sensory qualities of foods or culinary preparations made from foods,’ ” Dr. Bonaccio and colleagues wrote.

Such foods are very convenient, tasty, inexpensive, and have a long shelf life. They are highly competitive with foods that are naturally ready to consume and freshly prepared dishes and meals, the authors add.

The researchers conducted a longitudinal analysis on 22,475 men and women (mean age, 55 years; range, 43-67 years) who were recruited from the Moli-sani Study, a population-based cohort of men and women aged 35 years and older in the Molise region of southern Italy, between 2005 and 2010. Participants were followed for 8.2 years.

Food intake was assessed with the Food Frequency Questionnaire; UPF was defined using the NOVA classification according to degree of processing.

UPF intakes were categorized as quartiles of the ratio of UPF to total food consumed.

Overall, study participants reported a median of 10% (interquartile range, 6.6%-14.6%) of dietary intake as UPF and a total of 181.5 g/d of UPF intake.

The foods that contributed most to total UPF consumed were processed meat, which accounted for 19.8% of UPF intake; pizza (16.8%); and cakes and pies (13.4%).

High consumers of UPF, defined as those for whom UPF constituted more than 14.6% of their total diet, were more likely to be women, to be younger, and to have a higher educational level. They also reported fewer risk factors and fewer baseline chronic diseases and health conditions than persons who consumed UPF less frequently.

In addition, high consumption of UPF was associated with lower adherence to the Mediterranean diet; higher intake of fat, sugar, dietary cholesterol, and sodium; and lower intake of fiber.

During a median follow-up of 8.2 years, 1,216 all-cause deaths occurred. Of these, 439 were attributed to CVD, 255 to IHD/cerebrovascular disease, 477 to cancer, and 300 to other causes.
 

The more UPF, the higher the risk for CVD, death

The researchers found a direct linear dose-response relation between a 5% increase in the proportion of UPF in the diet and risk for all-cause and CVD mortality.

Individuals who reported the highest intake of UPF (fourth quartile, 14.6% of total food) as opposed to the lowest (first quartile, UPF <6.6%) experienced increased risks for CVD mortality (hazard ratio, 1.58; 95% CI, 1.23-2.03), death from IHD/cerebrovascular disease (HR, 1.52, 95% CI, 1.10-2.09), and all-cause mortality (HR, 1.26; 95% CI, 1.09-1.46).

High sugar content accounted for 36.3% of the relation of UPF with IHD/cerebrovascular mortality. Other nutritional factors, such as saturated fats, were unlikely to play a role, the researchers wrote.

Biomarkers of renal function accounted for 20.1% of the association of UPF with all-cause mortality and 12.0% for that of UPF with CVD mortality.

Subgroup analyses indicated that the magnitude of the association between UPF and all-cause mortality risk was greater among high-risk individuals, such as those with a history of CVD or diabetes. UPF was also likely to be more strongly associated with CVD mortality among those high-risk groups.

The interesting finding that the association between UPF and CVD mortality was greater among individuals with good adherence to the Mediterranean diet, which is known to have health benefits, could be explained by the fact that people who may benefit from a Mediterranean diet are more susceptible to losing health advantages when they also include “detrimental dietary behavior,” whereas those who consume a poor-quality diet are less likely to be harmed by an additional unhealthy behavior such as eating UPF regularly, wrote Dr. Bonaccio and colleagues.

“This is an interesting study confirming that consumption of highly processed foods such as pizza, processed meats, and soda are associated with greater risks of cardiovascular disease,” Walter Willett, MD, professor of epidemiology and nutrition, Harvard School of Public Health, Boston, said in an interview.

“These higher risks appear to be mediated in part by high intakes of saturated fat and sugar, but lower intakes of health-promoting aspects of diet also likely contribute to the findings,” Dr. Willett said.

“Some processing of food can be useful for preservation and control of infectious agents, but in general, a diet emphasizing minimally processed fruits and vegetables, whole grains, nuts, legumes, and plant sources of fat will be best for long-term well-being,” he said.

The study was supported in part by the Italian Ministry of Health and the HYPERCAN Study Italian Association for Cancer Research. Dr. Bonaccio and Dr. Willett reported no relevant financial relationships.

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

Exercise and a hypocaloric, Mediterranean-style diet remain first-line interventions that can benefit all patients with nonalcoholic fatty liver disease (NAFLD), according to a clinical practice update from the American Gastroenterological Association.

“[W]eight loss is associated with a reduction in liver fat, which provides a potential for reversal of disease progression,” wrote Zobair M. Younossi, MD, MPH, of Inova Fairfax Medical Campus in Falls Church, Va., with his associates. Lifestyle modifications remain “the cornerstone for management” because, even though NAFLD affects approximately 25% of individuals worldwide according to one meta-analytic assessment, interventions such as medications, bariatric endoscopy, and surgery are usually reserved for the subset of patients with severe obesity, comorbid diabetes, or nonalcoholic steatohepatitis (NASH) with at least stage 2 fibrosis, the experts wrote in Gastroenterology.

They note that clinically significant weight loss typically requires a hypocaloric diet of 1,200-1,500 kilocalories/day or a decrease of 500-1,000 kilocalories/day from baseline. A Mediterranean diet of fresh vegetables, fruits, legumes, minimally processed whole grains, fish, olive oil, nuts, and seeds is recommended because its antioxidant, anti-inflammatory effects may slow NAFLD progression. This diet minimizes or eliminates sweets, refined grains, and red and processed meats. Fructose from fruit is not associated with NAFLD, but patients should consume little or no commercially prepared fructose, which has been linked to visceral adiposity, insulin resistance, hepatic inflammation, and fibrosis progression. Other hypocaloric diets have not been studied enough to support their routine use in NAFLD treatment, according to the clinical practice update.

For patients with NASH, which is the more severe form of NAFLD and is associated with significant morbidity and mortality caused by complications from cirrhosis, hepatic decompensation, and hepatocellular carcinoma, weight loss also has a big impact: Losing at least 5% of total body weight can decrease hepatic steatosis, losing at least 7% can resolve NASH, and losing at least 10% can lessen or stabilize hepatic fibrosis, according to level 1 evidence cited by the update. Weight loss “can significantly impact all aspects of NAFLD histology including fibrosis, but a goal of 10% total body weight loss should be considered for patients with overweight or obese NAFLD,” the authors wrote. Fat loss also improves liver histology in patients with lean NAFLD (body mass index, 26 kg/m² in non-Asian patients or 24 in Asians), for whom a hypocaloric diet targeting a more modest 3%-5% total body weight loss is recommended.

Because aerobic exercise reduces hepatic fat levels independently of hypocaloric diet, patients with NAFLD should consider a weekly regimen of 150-300 minutes of moderate-intensity exercise or 75-150 minutes of vigorous activity. Resistance training can complement aerobic exercise “but [is] not a replacement,” the authors noted. In addition, patients with NAFLD should restrict alcohol consumption to reduce the risk for liver-related events, and those with advanced hepatic fibrosis should “avoid alcohol entirely.” These recommendations reflect the findings of a large prospective study in which the consumption of even low amounts of alcohol led to worse liver-related outcomes among patients with NAFLD.

Clinicians should screen for and “aggressively” manage common NAFLD comorbidities, including diabetes mellitus, hypertension, and obstructive sleep apnea, according to the clinical practice update. Patients with coexisting metabolic conditions should be risk-stratified for cardiovascular disease and treated based on guidelines from the American College of Cardiology and the American Heart Association.

It is believed that sarcopenia affects patients with NASH cirrhosis because their livers cannot effectively store, metabolize, or mobilize carbohydrates, which leads to a catabolic state in which protein and fat are used as energy sources, according to the update. To avoid exacerbations, these patients may need to optimize their protein intake – a minimum of 1.2-1.5 g/kg of body weight is recommended – from sources of branched-chain amino acids, such as chicken, fish, eggs, nuts, lentils, or soy. Patients with sarcopenic NAFLD also should consume small, frequent meals spaced no more than 4-6 hours apart. When possible, they should consult with a specialized nutritionist. Moderate-intensity exercise may also benefit patients experiencing sarcopenia.

The researchers disclosed ties to Gilead Sciences, Intercept, Bristol Myers Squibb, Novo Nordisk, and several other companies. The review was commissioned and approved by the AGA Institute’s Clinical Practice Updates Committee and the AGA Governing Board.

SOURCE: Younossi ZM et al. Gastroenterology. 2020 Dec 8. doi: 10.1053/j.gastro.2020.11.051.

This article was updated Feb. 10, 2021.

Exercise and a hypocaloric, Mediterranean-style diet remain first-line interventions that can benefit all patients with nonalcoholic fatty liver disease (NAFLD), according to a clinical practice update from the American Gastroenterological Association.

“[W]eight loss is associated with a reduction in liver fat, which provides a potential for reversal of disease progression,” wrote Zobair M. Younossi, MD, MPH, of Inova Fairfax Medical Campus in Falls Church, Va., with his associates. Lifestyle modifications remain “the cornerstone for management” because, even though NAFLD affects approximately 25% of individuals worldwide according to one meta-analytic assessment, interventions such as medications, bariatric endoscopy, and surgery are usually reserved for the subset of patients with severe obesity, comorbid diabetes, or nonalcoholic steatohepatitis (NASH) with at least stage 2 fibrosis, the experts wrote in Gastroenterology.

They note that clinically significant weight loss typically requires a hypocaloric diet of 1,200-1,500 kilocalories/day or a decrease of 500-1,000 kilocalories/day from baseline. A Mediterranean diet of fresh vegetables, fruits, legumes, minimally processed whole grains, fish, olive oil, nuts, and seeds is recommended because its antioxidant, anti-inflammatory effects may slow NAFLD progression. This diet minimizes or eliminates sweets, refined grains, and red and processed meats. Fructose from fruit is not associated with NAFLD, but patients should consume little or no commercially prepared fructose, which has been linked to visceral adiposity, insulin resistance, hepatic inflammation, and fibrosis progression. Other hypocaloric diets have not been studied enough to support their routine use in NAFLD treatment, according to the clinical practice update.

For patients with NASH, which is the more severe form of NAFLD and is associated with significant morbidity and mortality caused by complications from cirrhosis, hepatic decompensation, and hepatocellular carcinoma, weight loss also has a big impact: Losing at least 5% of total body weight can decrease hepatic steatosis, losing at least 7% can resolve NASH, and losing at least 10% can lessen or stabilize hepatic fibrosis, according to level 1 evidence cited by the update. Weight loss “can significantly impact all aspects of NAFLD histology including fibrosis, but a goal of 10% total body weight loss should be considered for patients with overweight or obese NAFLD,” the authors wrote. Fat loss also improves liver histology in patients with lean NAFLD (body mass index, 26 kg/m² in non-Asian patients or 24 in Asians), for whom a hypocaloric diet targeting a more modest 3%-5% total body weight loss is recommended.

Because aerobic exercise reduces hepatic fat levels independently of hypocaloric diet, patients with NAFLD should consider a weekly regimen of 150-300 minutes of moderate-intensity exercise or 75-150 minutes of vigorous activity. Resistance training can complement aerobic exercise “but [is] not a replacement,” the authors noted. In addition, patients with NAFLD should restrict alcohol consumption to reduce the risk for liver-related events, and those with advanced hepatic fibrosis should “avoid alcohol entirely.” These recommendations reflect the findings of a large prospective study in which the consumption of even low amounts of alcohol led to worse liver-related outcomes among patients with NAFLD.

Clinicians should screen for and “aggressively” manage common NAFLD comorbidities, including diabetes mellitus, hypertension, and obstructive sleep apnea, according to the clinical practice update. Patients with coexisting metabolic conditions should be risk-stratified for cardiovascular disease and treated based on guidelines from the American College of Cardiology and the American Heart Association.

It is believed that sarcopenia affects patients with NASH cirrhosis because their livers cannot effectively store, metabolize, or mobilize carbohydrates, which leads to a catabolic state in which protein and fat are used as energy sources, according to the update. To avoid exacerbations, these patients may need to optimize their protein intake – a minimum of 1.2-1.5 g/kg of body weight is recommended – from sources of branched-chain amino acids, such as chicken, fish, eggs, nuts, lentils, or soy. Patients with sarcopenic NAFLD also should consume small, frequent meals spaced no more than 4-6 hours apart. When possible, they should consult with a specialized nutritionist. Moderate-intensity exercise may also benefit patients experiencing sarcopenia.

The researchers disclosed ties to Gilead Sciences, Intercept, Bristol Myers Squibb, Novo Nordisk, and several other companies. The review was commissioned and approved by the AGA Institute’s Clinical Practice Updates Committee and the AGA Governing Board.

SOURCE: Younossi ZM et al. Gastroenterology. 2020 Dec 8. doi: 10.1053/j.gastro.2020.11.051.

This article was updated Feb. 10, 2021.

Exercise and a hypocaloric, Mediterranean-style diet remain first-line interventions that can benefit all patients with nonalcoholic fatty liver disease (NAFLD), according to a clinical practice update from the American Gastroenterological Association.

“[W]eight loss is associated with a reduction in liver fat, which provides a potential for reversal of disease progression,” wrote Zobair M. Younossi, MD, MPH, of Inova Fairfax Medical Campus in Falls Church, Va., with his associates. Lifestyle modifications remain “the cornerstone for management” because, even though NAFLD affects approximately 25% of individuals worldwide according to one meta-analytic assessment, interventions such as medications, bariatric endoscopy, and surgery are usually reserved for the subset of patients with severe obesity, comorbid diabetes, or nonalcoholic steatohepatitis (NASH) with at least stage 2 fibrosis, the experts wrote in Gastroenterology.

They note that clinically significant weight loss typically requires a hypocaloric diet of 1,200-1,500 kilocalories/day or a decrease of 500-1,000 kilocalories/day from baseline. A Mediterranean diet of fresh vegetables, fruits, legumes, minimally processed whole grains, fish, olive oil, nuts, and seeds is recommended because its antioxidant, anti-inflammatory effects may slow NAFLD progression. This diet minimizes or eliminates sweets, refined grains, and red and processed meats. Fructose from fruit is not associated with NAFLD, but patients should consume little or no commercially prepared fructose, which has been linked to visceral adiposity, insulin resistance, hepatic inflammation, and fibrosis progression. Other hypocaloric diets have not been studied enough to support their routine use in NAFLD treatment, according to the clinical practice update.

For patients with NASH, which is the more severe form of NAFLD and is associated with significant morbidity and mortality caused by complications from cirrhosis, hepatic decompensation, and hepatocellular carcinoma, weight loss also has a big impact: Losing at least 5% of total body weight can decrease hepatic steatosis, losing at least 7% can resolve NASH, and losing at least 10% can lessen or stabilize hepatic fibrosis, according to level 1 evidence cited by the update. Weight loss “can significantly impact all aspects of NAFLD histology including fibrosis, but a goal of 10% total body weight loss should be considered for patients with overweight or obese NAFLD,” the authors wrote. Fat loss also improves liver histology in patients with lean NAFLD (body mass index, 26 kg/m² in non-Asian patients or 24 in Asians), for whom a hypocaloric diet targeting a more modest 3%-5% total body weight loss is recommended.

Because aerobic exercise reduces hepatic fat levels independently of hypocaloric diet, patients with NAFLD should consider a weekly regimen of 150-300 minutes of moderate-intensity exercise or 75-150 minutes of vigorous activity. Resistance training can complement aerobic exercise “but [is] not a replacement,” the authors noted. In addition, patients with NAFLD should restrict alcohol consumption to reduce the risk for liver-related events, and those with advanced hepatic fibrosis should “avoid alcohol entirely.” These recommendations reflect the findings of a large prospective study in which the consumption of even low amounts of alcohol led to worse liver-related outcomes among patients with NAFLD.

Clinicians should screen for and “aggressively” manage common NAFLD comorbidities, including diabetes mellitus, hypertension, and obstructive sleep apnea, according to the clinical practice update. Patients with coexisting metabolic conditions should be risk-stratified for cardiovascular disease and treated based on guidelines from the American College of Cardiology and the American Heart Association.

It is believed that sarcopenia affects patients with NASH cirrhosis because their livers cannot effectively store, metabolize, or mobilize carbohydrates, which leads to a catabolic state in which protein and fat are used as energy sources, according to the update. To avoid exacerbations, these patients may need to optimize their protein intake – a minimum of 1.2-1.5 g/kg of body weight is recommended – from sources of branched-chain amino acids, such as chicken, fish, eggs, nuts, lentils, or soy. Patients with sarcopenic NAFLD also should consume small, frequent meals spaced no more than 4-6 hours apart. When possible, they should consult with a specialized nutritionist. Moderate-intensity exercise may also benefit patients experiencing sarcopenia.

The researchers disclosed ties to Gilead Sciences, Intercept, Bristol Myers Squibb, Novo Nordisk, and several other companies. The review was commissioned and approved by the AGA Institute’s Clinical Practice Updates Committee and the AGA Governing Board.

SOURCE: Younossi ZM et al. Gastroenterology. 2020 Dec 8. doi: 10.1053/j.gastro.2020.11.051.

This article was updated Feb. 10, 2021.

Oxidative stress may account for the “lipid paradox,” a higher incidence of heart disease burden found in nonobese rheumatoid arthritis (RA) patients with lower levels of low-density lipoprotein (LDL). George Karpouzas, MD, an investigator at the Lundquist Institute of Biomedical Innovation, St, Torrance, Calif., discussed this exploratory finding at the virtual annual meeting of the American College of Rheumatology.

A complex dynamic exists between traditional risk factors and cardiovascular (CV) events in RA patients, said Dr. Karpouzas, professor of medicine at the University of California, Los Angeles, and chief of the division of rheumatology, Harbor-UCLA Medical Center. “Lower lipid levels, specifically total cholesterol and to a lesser extent LDL, may be associated with higher risk,” he said. One recent study found that coronary artery calcium (CAC) scores were four times higher in RA patients with lower LDL concentrations (> 70 mg/dL) than those in control groups. “This was especially true in patients who were nonobese, non-Hispanic Whites and never smokers,” said Dr. Karpouzas. Other studies have reported this association between low LDL and increased CVD risk.

These paradoxes led to several questions: Does obesity modify the effect of LDL on cardiovascular disease (CVD) risk in RA and does it moderate the effect of LDL on coronary plaque burden and progression? Do LDL particle composition and oxidation variations underlie the paradoxical association of low LDL with higher coronary atherosclerosis burden in RA? To find answers, Dr. Karpouzas’ team in the Prospective Evaluation of Latent Coronary Atherosclerosis in Rheumatoid Arthritis (PROTECT-RA) trial studied a cohort of 150 established RA patients without symptoms or diagnosis of CV disease.

Dr. Karpouzas presented two oral abstracts that summarized this research during the ACR 2020 session, “RA, diagnosis, manifestations and outcomes: heart of the matter,” which was held virtually.
 

Higher plaque burden seen in nonobese patients

In one part of the study, patients underwent baseline cardiac coronary CT angiography (CTA) over 1 year (2010-2011). Investigators evaluated CAC scores, segment involvement scores (SIS), segment stenosis scores (SSS), and extensive and obstructive disease. Low LDL was defined as < 70 mg/dL, obesity as a waist to height ratio of > 0.58 squared.

Investigators in follow-up work (2017-2018) evaluated for plaque progression, prospectively recording all cardiovascular disease events such as cardiac death, myocardial infarction, unstable angina, stroke, and heart failure hospitalization. Multivariable models assessed the effects of LDL lower than 70 mg/dL, obesity, and their interaction, accounting for factors such as age, sex, statin use, diabetes and hypertension.
 

Four LDL obesity cohorts

Nonobese RA patients with low LDL exhibited the highest plaque burden. “Despite no differences in RA inflammation, patients in this group were more likely to exhibit high levels of LDL oxidation,” Dr. Karpouzas said in an interview. “Nonobese patients with low LDL more likely exhibited new coronary plaque formation as well as increased stenotic severity of prevalent plaque after adjustments for relevant covariates,” he added.

The study’s observational nature exposed it to biases and unmeasured confounding, Dr. Karpouzas emphasized. Because it took place in a single center, the results might not be generalizable to ethnically and racially diverse cohorts. Patients with calcifications, extensive or obstructive coronary plaque at baseline scan received more aggressive treatments, which could have slowed CVD event risk and plaque progression. Investigators cautioned that the results should be seen as “exploratory,” given that CVD event analysis wasn’t applied to the original study design.
 

The oxidation-LDL connection

Another arm of the study examined the oxidation association question. Investigators did a similar analysis of the same patients but also evaluated for cholesterol content, Lp(a) mass, OxLDL levels, IgG and IgM anti-OxLDL and apoB100 immune complexes and proinflammatory cytokines.

RA patients with LDL lower than 70 mg/dL had higher SSS and CAC scores and were more likely to have extensive or obstructive plaque. Statin-naive patients with lower LDL exhibited greater LDL oxidation than higher LDL groups. In addition, those with lower LDL had higher anti-OxLDL and apoB100 than patients with higher LDL.

“Oxidation makes the cholesterol more ‘sticky,’ allowing it to penetrate into the walls of the endothelium, and changes macrophages to foam cells. This malignant process is very powerful and can potentially increase atheroma burden,” study coauthor Matthew Budoff, MD, professor of medicine at UCLA and endowed chair of preventive cardiology at the Lundquist Institute, said in an interview.

Investigators also found an independent association between Lp(a) content and LDL oxidation. This association seemed strong in patients with lower LDL compared to higher LDL groups. In addition, “greater oxidation and immune recognition of oxLDL further associated with higher IL-6 elaboration which may in turn augment atherosclerosis burden in the low LDL group,” said Dr. Karpouzas.

The analysis did not explore alternate mechanisms such as increased cholesterol loading capacity, lower efflux capacity or increased hepatocyte uptake through LDL-R upregulation, a key limitation. Dr. Karpouzas also acknowledged that higher cumulative inflammatory burden incurred before evaluating low LDL patients at baseline may have led to greater coronary plaque burden.

Overall, the study shows that low LDL is not protective in this population, said Dr. Budoff. “Low LDL patients who have atherosclerosis should be treated with statins and other therapies to lower their CV risk.”
 

Larger studies to confirm associations

Attendees of the ACR 2020 session called for additional studies to confirm that LDL oxidation leads to increased coronary atherosclerotic burden in RA patients.

The study provides “mechanistic insight into this important problem for patients with RA,” noted Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine at Harvard Medical School and associate physician at Brigham and Women’s Hospital, Boston.

Some of the patients studied were on lipid-lowering drugs such as statins, though the statistical analysis adjusted for use of these medications, noted Dr. Sparks. “It is possible that excess systemic inflammation alone is responsible for changes in LDL oxidation that may ultimately lead to cardiovascular disease,” he offered.

Future mechanistic and interventional studies related specifically to LDL oxidation “should establish the importance of this pathway in the development of cardiovascular disease in patients with RA,” said Dr. Sparks.

Large studies of patients with different BMI and LDL values followed prospectively for CV events would be ideal, said Joel M. Kremer, MD, president of the Corrona Research Foundation and founder of Corrona, a biopharma data solutions firm. Investigators would need to follow patients for several years. And, such a venture might face some obstacles. “The practical impediments and cost would be substantial. Also, as LDL oxidation may be related to disease activity, there would be ethical and pragmatic issues associated with controlling disease activity in these patients. This would obscure these outcomes of interest,” said Dr. Kremer.

Dr. Karpouzas receives grant and research support from the American Heart Association and Pfizer-Aspire. Dr. Budoff receives grant support from General Electric.

[email protected]

SOURCE: Karpouzas G et al. ACR 2020. Abstract 0485 and Abstract 0486.

Oxidative stress may account for the “lipid paradox,” a higher incidence of heart disease burden found in nonobese rheumatoid arthritis (RA) patients with lower levels of low-density lipoprotein (LDL). George Karpouzas, MD, an investigator at the Lundquist Institute of Biomedical Innovation, St, Torrance, Calif., discussed this exploratory finding at the virtual annual meeting of the American College of Rheumatology.

A complex dynamic exists between traditional risk factors and cardiovascular (CV) events in RA patients, said Dr. Karpouzas, professor of medicine at the University of California, Los Angeles, and chief of the division of rheumatology, Harbor-UCLA Medical Center. “Lower lipid levels, specifically total cholesterol and to a lesser extent LDL, may be associated with higher risk,” he said. One recent study found that coronary artery calcium (CAC) scores were four times higher in RA patients with lower LDL concentrations (> 70 mg/dL) than those in control groups. “This was especially true in patients who were nonobese, non-Hispanic Whites and never smokers,” said Dr. Karpouzas. Other studies have reported this association between low LDL and increased CVD risk.

These paradoxes led to several questions: Does obesity modify the effect of LDL on cardiovascular disease (CVD) risk in RA and does it moderate the effect of LDL on coronary plaque burden and progression? Do LDL particle composition and oxidation variations underlie the paradoxical association of low LDL with higher coronary atherosclerosis burden in RA? To find answers, Dr. Karpouzas’ team in the Prospective Evaluation of Latent Coronary Atherosclerosis in Rheumatoid Arthritis (PROTECT-RA) trial studied a cohort of 150 established RA patients without symptoms or diagnosis of CV disease.

Dr. Karpouzas presented two oral abstracts that summarized this research during the ACR 2020 session, “RA, diagnosis, manifestations and outcomes: heart of the matter,” which was held virtually.
 

Higher plaque burden seen in nonobese patients

In one part of the study, patients underwent baseline cardiac coronary CT angiography (CTA) over 1 year (2010-2011). Investigators evaluated CAC scores, segment involvement scores (SIS), segment stenosis scores (SSS), and extensive and obstructive disease. Low LDL was defined as < 70 mg/dL, obesity as a waist to height ratio of > 0.58 squared.

Investigators in follow-up work (2017-2018) evaluated for plaque progression, prospectively recording all cardiovascular disease events such as cardiac death, myocardial infarction, unstable angina, stroke, and heart failure hospitalization. Multivariable models assessed the effects of LDL lower than 70 mg/dL, obesity, and their interaction, accounting for factors such as age, sex, statin use, diabetes and hypertension.
 

Four LDL obesity cohorts

Nonobese RA patients with low LDL exhibited the highest plaque burden. “Despite no differences in RA inflammation, patients in this group were more likely to exhibit high levels of LDL oxidation,” Dr. Karpouzas said in an interview. “Nonobese patients with low LDL more likely exhibited new coronary plaque formation as well as increased stenotic severity of prevalent plaque after adjustments for relevant covariates,” he added.

The study’s observational nature exposed it to biases and unmeasured confounding, Dr. Karpouzas emphasized. Because it took place in a single center, the results might not be generalizable to ethnically and racially diverse cohorts. Patients with calcifications, extensive or obstructive coronary plaque at baseline scan received more aggressive treatments, which could have slowed CVD event risk and plaque progression. Investigators cautioned that the results should be seen as “exploratory,” given that CVD event analysis wasn’t applied to the original study design.
 

The oxidation-LDL connection

Another arm of the study examined the oxidation association question. Investigators did a similar analysis of the same patients but also evaluated for cholesterol content, Lp(a) mass, OxLDL levels, IgG and IgM anti-OxLDL and apoB100 immune complexes and proinflammatory cytokines.

RA patients with LDL lower than 70 mg/dL had higher SSS and CAC scores and were more likely to have extensive or obstructive plaque. Statin-naive patients with lower LDL exhibited greater LDL oxidation than higher LDL groups. In addition, those with lower LDL had higher anti-OxLDL and apoB100 than patients with higher LDL.

“Oxidation makes the cholesterol more ‘sticky,’ allowing it to penetrate into the walls of the endothelium, and changes macrophages to foam cells. This malignant process is very powerful and can potentially increase atheroma burden,” study coauthor Matthew Budoff, MD, professor of medicine at UCLA and endowed chair of preventive cardiology at the Lundquist Institute, said in an interview.

Investigators also found an independent association between Lp(a) content and LDL oxidation. This association seemed strong in patients with lower LDL compared to higher LDL groups. In addition, “greater oxidation and immune recognition of oxLDL further associated with higher IL-6 elaboration which may in turn augment atherosclerosis burden in the low LDL group,” said Dr. Karpouzas.

The analysis did not explore alternate mechanisms such as increased cholesterol loading capacity, lower efflux capacity or increased hepatocyte uptake through LDL-R upregulation, a key limitation. Dr. Karpouzas also acknowledged that higher cumulative inflammatory burden incurred before evaluating low LDL patients at baseline may have led to greater coronary plaque burden.

Overall, the study shows that low LDL is not protective in this population, said Dr. Budoff. “Low LDL patients who have atherosclerosis should be treated with statins and other therapies to lower their CV risk.”
 

Larger studies to confirm associations

Attendees of the ACR 2020 session called for additional studies to confirm that LDL oxidation leads to increased coronary atherosclerotic burden in RA patients.

The study provides “mechanistic insight into this important problem for patients with RA,” noted Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine at Harvard Medical School and associate physician at Brigham and Women’s Hospital, Boston.

Some of the patients studied were on lipid-lowering drugs such as statins, though the statistical analysis adjusted for use of these medications, noted Dr. Sparks. “It is possible that excess systemic inflammation alone is responsible for changes in LDL oxidation that may ultimately lead to cardiovascular disease,” he offered.

Future mechanistic and interventional studies related specifically to LDL oxidation “should establish the importance of this pathway in the development of cardiovascular disease in patients with RA,” said Dr. Sparks.

Large studies of patients with different BMI and LDL values followed prospectively for CV events would be ideal, said Joel M. Kremer, MD, president of the Corrona Research Foundation and founder of Corrona, a biopharma data solutions firm. Investigators would need to follow patients for several years. And, such a venture might face some obstacles. “The practical impediments and cost would be substantial. Also, as LDL oxidation may be related to disease activity, there would be ethical and pragmatic issues associated with controlling disease activity in these patients. This would obscure these outcomes of interest,” said Dr. Kremer.

Dr. Karpouzas receives grant and research support from the American Heart Association and Pfizer-Aspire. Dr. Budoff receives grant support from General Electric.

[email protected]

SOURCE: Karpouzas G et al. ACR 2020. Abstract 0485 and Abstract 0486.

Oxidative stress may account for the “lipid paradox,” a higher incidence of heart disease burden found in nonobese rheumatoid arthritis (RA) patients with lower levels of low-density lipoprotein (LDL). George Karpouzas, MD, an investigator at the Lundquist Institute of Biomedical Innovation, St, Torrance, Calif., discussed this exploratory finding at the virtual annual meeting of the American College of Rheumatology.

A complex dynamic exists between traditional risk factors and cardiovascular (CV) events in RA patients, said Dr. Karpouzas, professor of medicine at the University of California, Los Angeles, and chief of the division of rheumatology, Harbor-UCLA Medical Center. “Lower lipid levels, specifically total cholesterol and to a lesser extent LDL, may be associated with higher risk,” he said. One recent study found that coronary artery calcium (CAC) scores were four times higher in RA patients with lower LDL concentrations (> 70 mg/dL) than those in control groups. “This was especially true in patients who were nonobese, non-Hispanic Whites and never smokers,” said Dr. Karpouzas. Other studies have reported this association between low LDL and increased CVD risk.

These paradoxes led to several questions: Does obesity modify the effect of LDL on cardiovascular disease (CVD) risk in RA and does it moderate the effect of LDL on coronary plaque burden and progression? Do LDL particle composition and oxidation variations underlie the paradoxical association of low LDL with higher coronary atherosclerosis burden in RA? To find answers, Dr. Karpouzas’ team in the Prospective Evaluation of Latent Coronary Atherosclerosis in Rheumatoid Arthritis (PROTECT-RA) trial studied a cohort of 150 established RA patients without symptoms or diagnosis of CV disease.

Dr. Karpouzas presented two oral abstracts that summarized this research during the ACR 2020 session, “RA, diagnosis, manifestations and outcomes: heart of the matter,” which was held virtually.
 

Higher plaque burden seen in nonobese patients

In one part of the study, patients underwent baseline cardiac coronary CT angiography (CTA) over 1 year (2010-2011). Investigators evaluated CAC scores, segment involvement scores (SIS), segment stenosis scores (SSS), and extensive and obstructive disease. Low LDL was defined as < 70 mg/dL, obesity as a waist to height ratio of > 0.58 squared.

Investigators in follow-up work (2017-2018) evaluated for plaque progression, prospectively recording all cardiovascular disease events such as cardiac death, myocardial infarction, unstable angina, stroke, and heart failure hospitalization. Multivariable models assessed the effects of LDL lower than 70 mg/dL, obesity, and their interaction, accounting for factors such as age, sex, statin use, diabetes and hypertension.
 

Four LDL obesity cohorts

Nonobese RA patients with low LDL exhibited the highest plaque burden. “Despite no differences in RA inflammation, patients in this group were more likely to exhibit high levels of LDL oxidation,” Dr. Karpouzas said in an interview. “Nonobese patients with low LDL more likely exhibited new coronary plaque formation as well as increased stenotic severity of prevalent plaque after adjustments for relevant covariates,” he added.

The study’s observational nature exposed it to biases and unmeasured confounding, Dr. Karpouzas emphasized. Because it took place in a single center, the results might not be generalizable to ethnically and racially diverse cohorts. Patients with calcifications, extensive or obstructive coronary plaque at baseline scan received more aggressive treatments, which could have slowed CVD event risk and plaque progression. Investigators cautioned that the results should be seen as “exploratory,” given that CVD event analysis wasn’t applied to the original study design.
 

The oxidation-LDL connection

Another arm of the study examined the oxidation association question. Investigators did a similar analysis of the same patients but also evaluated for cholesterol content, Lp(a) mass, OxLDL levels, IgG and IgM anti-OxLDL and apoB100 immune complexes and proinflammatory cytokines.

RA patients with LDL lower than 70 mg/dL had higher SSS and CAC scores and were more likely to have extensive or obstructive plaque. Statin-naive patients with lower LDL exhibited greater LDL oxidation than higher LDL groups. In addition, those with lower LDL had higher anti-OxLDL and apoB100 than patients with higher LDL.

“Oxidation makes the cholesterol more ‘sticky,’ allowing it to penetrate into the walls of the endothelium, and changes macrophages to foam cells. This malignant process is very powerful and can potentially increase atheroma burden,” study coauthor Matthew Budoff, MD, professor of medicine at UCLA and endowed chair of preventive cardiology at the Lundquist Institute, said in an interview.

Investigators also found an independent association between Lp(a) content and LDL oxidation. This association seemed strong in patients with lower LDL compared to higher LDL groups. In addition, “greater oxidation and immune recognition of oxLDL further associated with higher IL-6 elaboration which may in turn augment atherosclerosis burden in the low LDL group,” said Dr. Karpouzas.

The analysis did not explore alternate mechanisms such as increased cholesterol loading capacity, lower efflux capacity or increased hepatocyte uptake through LDL-R upregulation, a key limitation. Dr. Karpouzas also acknowledged that higher cumulative inflammatory burden incurred before evaluating low LDL patients at baseline may have led to greater coronary plaque burden.

Overall, the study shows that low LDL is not protective in this population, said Dr. Budoff. “Low LDL patients who have atherosclerosis should be treated with statins and other therapies to lower their CV risk.”
 

Larger studies to confirm associations

Attendees of the ACR 2020 session called for additional studies to confirm that LDL oxidation leads to increased coronary atherosclerotic burden in RA patients.

The study provides “mechanistic insight into this important problem for patients with RA,” noted Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine at Harvard Medical School and associate physician at Brigham and Women’s Hospital, Boston.

Some of the patients studied were on lipid-lowering drugs such as statins, though the statistical analysis adjusted for use of these medications, noted Dr. Sparks. “It is possible that excess systemic inflammation alone is responsible for changes in LDL oxidation that may ultimately lead to cardiovascular disease,” he offered.

Future mechanistic and interventional studies related specifically to LDL oxidation “should establish the importance of this pathway in the development of cardiovascular disease in patients with RA,” said Dr. Sparks.

Large studies of patients with different BMI and LDL values followed prospectively for CV events would be ideal, said Joel M. Kremer, MD, president of the Corrona Research Foundation and founder of Corrona, a biopharma data solutions firm. Investigators would need to follow patients for several years. And, such a venture might face some obstacles. “The practical impediments and cost would be substantial. Also, as LDL oxidation may be related to disease activity, there would be ethical and pragmatic issues associated with controlling disease activity in these patients. This would obscure these outcomes of interest,” said Dr. Kremer.

Dr. Karpouzas receives grant and research support from the American Heart Association and Pfizer-Aspire. Dr. Budoff receives grant support from General Electric.

[email protected]

SOURCE: Karpouzas G et al. ACR 2020. Abstract 0485 and Abstract 0486.

Two new studies suggest that LDL cholesterol (LDL-C) may be not the main driver of atherosclerotic cardiovascular disease (ASCVD).

The findings instead implicate remnant cholesterol (remnant-C) and very-low-density lipoprotein (VLDL) cholesterol in the development of cardiovascular disease (CVD) and MI.

The PREDIMED study, conducted in Spain, examined the association of triglycerides and remnant-C with major cardiovascular events (MACE) in older individuals with high CVD risk. It found that levels of triglycerides and remnant-C were associated with MACE independently of other risk factors, but there was no similar association with LDL-C.

“These findings lead [clinicians] to consider in the clinical management of dyslipidemias a greater control of the lipid profiles as a whole, including remnant-cholesterol and/or triglycerides,” Montserrat Fitó Colomer, MD, PhD, of the Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute, Barcelona, said in an interview.

In a separate analysis, the Copenhagen General Population Study, which focused on 25,000 individuals who were not taking lipid-lowering therapy, looked at the role of VLDL cholesterol and triglycerides in driving MI risk from apolipoprotein B (apoB)–containing lipoproteins.

Bruce Jancin/Frontline Medical News

“Elevated VLDL cholesterol explained a larger fraction of risk than did elevated LDL cholesterol, or elevated VLDL triglycerides,” Børge G. Nordestgaard, MD, DMSc, professor, University of Copenhagen, said in an interview.

Both studies were published online Nov. 30 in the Journal of the American College of Cardiology.

But in an editorial accompanying both reports, John Burnett, MD, PhD, from the University of Western Australia, Perth, and colleagues cautioned that it would be “premature to discard LDL-C based on PREDIMED.”

The findings are “insufficient to offset the mountain of literally hundreds of studies that uphold the value of LDL-C in prediction and intervention of ASCVD,” Dr. Burnett and coauthors wrote.

Similarly, the editorialists cautioned that, although the findings from the study by Dr. Nordestgaard and colleagues indicate that VLDL cholesterol is the “new kid in town for prediction, LDL cholesterol retains predictive power.” Clinical cardiologists should not “shelve LDL cholesterol and embrace VLDL and remnant cholesterol as the new oracles of ASCVD risk.” 

In a comment, Dr. Burnett said, “The take-home message for clinicians in both papers is that LDL-C is the main lipid measurement to guide clinical decisions; however, residual risk of atherosclerotic cardiovascular disease remains, even after LCL-C is treated.

“Assessment of residual ASCVD risk with nontraditional lipid biomarkers, including VLDL cholesterol and remnant cholesterol, as well as lipoprotein (a) and apoB, may improve prognostication and help guide preventive treatments,” he added.
 

“Affordable and inexpensive”

In their report, the PREDIMED study authors explained that atherogenic dyslipidemia is characterized by “an excess of serum triglycerides” contained in VLDL cholesterol, intermediate-density lipoproteins, and their remnants, all of which are called “triglyceride-rich lipoproteins (TRLs).”

TRLs and remnant-C “have the capacity to cross the arterial wall,” and may therefore play a causal role in atherosclerosis development, they wrote.

The main PREDIMED trial compared a low-fat diet with the Mediterranean diet for the primary prevention of CVD in high-risk participants. Those enrolled in the trial “had a high prevalence of diabetes, obesity, and metabolic syndrome, conditions that are associated with insulin resistance, hypertriglyceridemia, and atherogenic dyslipidemia,” the authors wrote. “Thus, this cohort of subjects at high cardiovascular risk was well suited to investigate the association of triglycerides and TRLs with cardiovascular outcomes.” 

The researchers investigated the role of triglycerides and remnant-C in incident CVD among these high-risk individuals, particularly those with chronic cardiometabolic disorders (prediabetes, type 2 diabetes, and poorly controlled diabetes), overweight and obesity, metabolic syndrome, and renal failure.

Their 6,901 participants (42.6% male, mean age 67 years, mean BMI 30.0 kg/m2) had a diagnosis of type 2 diabetes or at least three CVD risk factors including current smoking, hypertension, elevated LDL-C levels, low HDL cholesterol levels, elevated body mass index, or family history of premature coronary heart disease.

The primary study endpoint was a composite of adverse cardiovascular events (MACE): MI, stroke, or cardiovascular death. Participants were followed for a mean of 4.8 years, during which there was a total of 263 MACE events.

Multivariable-adjusted analyses showed that levels of triglycerides and remnant-C were both associated with MACE independent of other risk factors (hazard ratio, 1.04; 95% confidence interval, 1.02-1.06; and HR, 1.21; 95% CI, 1.10-1.33 per 10 mg/dl, respectively, both P < .001). Non–HDL cholesterol was also associated with MACE (HR, 1.05; 95% CI, 1.01-1.10 per 10 mg/dl, P = .026).

In particular, elevated remnant-C (≥30 mg/dL), compared with lower concentrations, flagged subjects at a higher risk of MACE, even if their LDL-C levels were at target (defined as ≤ 100 mg/dL).

Levels of LDL-C and HDL cholesterol were not associated with MACE.

“The indirect calculation of remnant-C is an affordable and inexpensive method, which could provide valuable data for clinical management,” Dr. Fitó Colomer said.

“The results of this study suggest that, in individuals at high cardiovascular risk with well-controlled LDL-C, triglycerides and mainly remnant-C should be considered as a treatment target,” she proposed.
 

New oracles?

Evidence has pointed to triglyceride-rich remnants or VLDL cholesterol as contributing to atherosclerotic CVD, together with LDL-C, but it is “unclear which fraction of risk is explained by, respectively, cholesterol and triglycerides in VLDL,” write the authors of the Copenhagen population study.

Dr. Nordestgaard said their study was motivated by an awareness that “in clinical practice, the focus for lipid-related risk is almost solely on reduction of LDL-C for prevention of ASCVD,” so the current focus needs to be reevaluated because patients with low LDL-C but elevated VLDL cholesterol and plasma triglycerides “may not be offered adequate preventive lipid-lowering therapy in order to prevent future MI and ASCVD.”

His group therefore tested the hypothesis that VLDL cholesterol and triglycerides may each explain part of the MI risk from apoB-containing lipoproteins.

They used measurements of plasma apoB and cholesterol and triglyceride content of VLDL cholesterol, intermediate-density-lipoprotein cholesterol, and LDL-C in the study participants (N = 25,480, median age 61 years, 53% female), who were required to be free of MI and not receiving lipid-lowering therapy at baseline.

During a median 11-year follow-up period, 1,816 participants experienced an MI. They tended to be older, compared with those who did not experience an MI, and also more likely to be male, to smoke, and to have higher systolic blood pressure.

Each 39-mg/dL increase in lipid level was found to be associated with higher MI risk.

The researchers looked at MI-associated risk of specific subfractions of apoB-containing lipoproteins. “VLDL cholesterol explained half of the MI risk from elevated apoB-containing lipoproteins, and [intermediate-density-lipoprotein] and LDL-C together accounted for only 29% of the risk,” Dr. Nordestgaard said.

“If LDL cholesterol is adequately reduced, clinicians need to evaluate possible elevated triglyceride-rich lipoproteins, either as elevated plasma triglycerides, remnant cholesterol, or elevated VLDL cholesterol; and, if elevated, consideration should also be given to reduction of triglyceride-rich lipoproteins,” he advised.

The Copenhagen General Population study was funded by the Danish Heart Foundation and the Novo Nordisk Foundation. Dr. Nordestgaard disclosed consulting for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin, Novartis, Novo Nordisk, and Silence Therapeutrics. PREDIMED was supported by grants from the Instituto de Salud Carlos III- FEDER, Fundació La Marató de TV3, and Agència de Gestió d’Ajuts Universitaris i de Recerca. Dr. Fitó Colomer disclosed no relevant financial relationships. Dr. Burnett disclosed no relevant financial relationships.

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

Two new studies suggest that LDL cholesterol (LDL-C) may be not the main driver of atherosclerotic cardiovascular disease (ASCVD).

The findings instead implicate remnant cholesterol (remnant-C) and very-low-density lipoprotein (VLDL) cholesterol in the development of cardiovascular disease (CVD) and MI.

The PREDIMED study, conducted in Spain, examined the association of triglycerides and remnant-C with major cardiovascular events (MACE) in older individuals with high CVD risk. It found that levels of triglycerides and remnant-C were associated with MACE independently of other risk factors, but there was no similar association with LDL-C.

“These findings lead [clinicians] to consider in the clinical management of dyslipidemias a greater control of the lipid profiles as a whole, including remnant-cholesterol and/or triglycerides,” Montserrat Fitó Colomer, MD, PhD, of the Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute, Barcelona, said in an interview.

In a separate analysis, the Copenhagen General Population Study, which focused on 25,000 individuals who were not taking lipid-lowering therapy, looked at the role of VLDL cholesterol and triglycerides in driving MI risk from apolipoprotein B (apoB)–containing lipoproteins.

Bruce Jancin/Frontline Medical News

“Elevated VLDL cholesterol explained a larger fraction of risk than did elevated LDL cholesterol, or elevated VLDL triglycerides,” Børge G. Nordestgaard, MD, DMSc, professor, University of Copenhagen, said in an interview.

Both studies were published online Nov. 30 in the Journal of the American College of Cardiology.

But in an editorial accompanying both reports, John Burnett, MD, PhD, from the University of Western Australia, Perth, and colleagues cautioned that it would be “premature to discard LDL-C based on PREDIMED.”

The findings are “insufficient to offset the mountain of literally hundreds of studies that uphold the value of LDL-C in prediction and intervention of ASCVD,” Dr. Burnett and coauthors wrote.

Similarly, the editorialists cautioned that, although the findings from the study by Dr. Nordestgaard and colleagues indicate that VLDL cholesterol is the “new kid in town for prediction, LDL cholesterol retains predictive power.” Clinical cardiologists should not “shelve LDL cholesterol and embrace VLDL and remnant cholesterol as the new oracles of ASCVD risk.” 

In a comment, Dr. Burnett said, “The take-home message for clinicians in both papers is that LDL-C is the main lipid measurement to guide clinical decisions; however, residual risk of atherosclerotic cardiovascular disease remains, even after LCL-C is treated.

“Assessment of residual ASCVD risk with nontraditional lipid biomarkers, including VLDL cholesterol and remnant cholesterol, as well as lipoprotein (a) and apoB, may improve prognostication and help guide preventive treatments,” he added.
 

“Affordable and inexpensive”

In their report, the PREDIMED study authors explained that atherogenic dyslipidemia is characterized by “an excess of serum triglycerides” contained in VLDL cholesterol, intermediate-density lipoproteins, and their remnants, all of which are called “triglyceride-rich lipoproteins (TRLs).”

TRLs and remnant-C “have the capacity to cross the arterial wall,” and may therefore play a causal role in atherosclerosis development, they wrote.

The main PREDIMED trial compared a low-fat diet with the Mediterranean diet for the primary prevention of CVD in high-risk participants. Those enrolled in the trial “had a high prevalence of diabetes, obesity, and metabolic syndrome, conditions that are associated with insulin resistance, hypertriglyceridemia, and atherogenic dyslipidemia,” the authors wrote. “Thus, this cohort of subjects at high cardiovascular risk was well suited to investigate the association of triglycerides and TRLs with cardiovascular outcomes.” 

The researchers investigated the role of triglycerides and remnant-C in incident CVD among these high-risk individuals, particularly those with chronic cardiometabolic disorders (prediabetes, type 2 diabetes, and poorly controlled diabetes), overweight and obesity, metabolic syndrome, and renal failure.

Their 6,901 participants (42.6% male, mean age 67 years, mean BMI 30.0 kg/m2) had a diagnosis of type 2 diabetes or at least three CVD risk factors including current smoking, hypertension, elevated LDL-C levels, low HDL cholesterol levels, elevated body mass index, or family history of premature coronary heart disease.

The primary study endpoint was a composite of adverse cardiovascular events (MACE): MI, stroke, or cardiovascular death. Participants were followed for a mean of 4.8 years, during which there was a total of 263 MACE events.

Multivariable-adjusted analyses showed that levels of triglycerides and remnant-C were both associated with MACE independent of other risk factors (hazard ratio, 1.04; 95% confidence interval, 1.02-1.06; and HR, 1.21; 95% CI, 1.10-1.33 per 10 mg/dl, respectively, both P < .001). Non–HDL cholesterol was also associated with MACE (HR, 1.05; 95% CI, 1.01-1.10 per 10 mg/dl, P = .026).

In particular, elevated remnant-C (≥30 mg/dL), compared with lower concentrations, flagged subjects at a higher risk of MACE, even if their LDL-C levels were at target (defined as ≤ 100 mg/dL).

Levels of LDL-C and HDL cholesterol were not associated with MACE.

“The indirect calculation of remnant-C is an affordable and inexpensive method, which could provide valuable data for clinical management,” Dr. Fitó Colomer said.

“The results of this study suggest that, in individuals at high cardiovascular risk with well-controlled LDL-C, triglycerides and mainly remnant-C should be considered as a treatment target,” she proposed.
 

New oracles?

Evidence has pointed to triglyceride-rich remnants or VLDL cholesterol as contributing to atherosclerotic CVD, together with LDL-C, but it is “unclear which fraction of risk is explained by, respectively, cholesterol and triglycerides in VLDL,” write the authors of the Copenhagen population study.

Dr. Nordestgaard said their study was motivated by an awareness that “in clinical practice, the focus for lipid-related risk is almost solely on reduction of LDL-C for prevention of ASCVD,” so the current focus needs to be reevaluated because patients with low LDL-C but elevated VLDL cholesterol and plasma triglycerides “may not be offered adequate preventive lipid-lowering therapy in order to prevent future MI and ASCVD.”

His group therefore tested the hypothesis that VLDL cholesterol and triglycerides may each explain part of the MI risk from apoB-containing lipoproteins.

They used measurements of plasma apoB and cholesterol and triglyceride content of VLDL cholesterol, intermediate-density-lipoprotein cholesterol, and LDL-C in the study participants (N = 25,480, median age 61 years, 53% female), who were required to be free of MI and not receiving lipid-lowering therapy at baseline.

During a median 11-year follow-up period, 1,816 participants experienced an MI. They tended to be older, compared with those who did not experience an MI, and also more likely to be male, to smoke, and to have higher systolic blood pressure.

Each 39-mg/dL increase in lipid level was found to be associated with higher MI risk.

The researchers looked at MI-associated risk of specific subfractions of apoB-containing lipoproteins. “VLDL cholesterol explained half of the MI risk from elevated apoB-containing lipoproteins, and [intermediate-density-lipoprotein] and LDL-C together accounted for only 29% of the risk,” Dr. Nordestgaard said.

“If LDL cholesterol is adequately reduced, clinicians need to evaluate possible elevated triglyceride-rich lipoproteins, either as elevated plasma triglycerides, remnant cholesterol, or elevated VLDL cholesterol; and, if elevated, consideration should also be given to reduction of triglyceride-rich lipoproteins,” he advised.

The Copenhagen General Population study was funded by the Danish Heart Foundation and the Novo Nordisk Foundation. Dr. Nordestgaard disclosed consulting for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin, Novartis, Novo Nordisk, and Silence Therapeutrics. PREDIMED was supported by grants from the Instituto de Salud Carlos III- FEDER, Fundació La Marató de TV3, and Agència de Gestió d’Ajuts Universitaris i de Recerca. Dr. Fitó Colomer disclosed no relevant financial relationships. Dr. Burnett disclosed no relevant financial relationships.

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

Two new studies suggest that LDL cholesterol (LDL-C) may be not the main driver of atherosclerotic cardiovascular disease (ASCVD).

The findings instead implicate remnant cholesterol (remnant-C) and very-low-density lipoprotein (VLDL) cholesterol in the development of cardiovascular disease (CVD) and MI.

The PREDIMED study, conducted in Spain, examined the association of triglycerides and remnant-C with major cardiovascular events (MACE) in older individuals with high CVD risk. It found that levels of triglycerides and remnant-C were associated with MACE independently of other risk factors, but there was no similar association with LDL-C.

“These findings lead [clinicians] to consider in the clinical management of dyslipidemias a greater control of the lipid profiles as a whole, including remnant-cholesterol and/or triglycerides,” Montserrat Fitó Colomer, MD, PhD, of the Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute, Barcelona, said in an interview.

In a separate analysis, the Copenhagen General Population Study, which focused on 25,000 individuals who were not taking lipid-lowering therapy, looked at the role of VLDL cholesterol and triglycerides in driving MI risk from apolipoprotein B (apoB)–containing lipoproteins.

Bruce Jancin/Frontline Medical News

“Elevated VLDL cholesterol explained a larger fraction of risk than did elevated LDL cholesterol, or elevated VLDL triglycerides,” Børge G. Nordestgaard, MD, DMSc, professor, University of Copenhagen, said in an interview.

Both studies were published online Nov. 30 in the Journal of the American College of Cardiology.

But in an editorial accompanying both reports, John Burnett, MD, PhD, from the University of Western Australia, Perth, and colleagues cautioned that it would be “premature to discard LDL-C based on PREDIMED.”

The findings are “insufficient to offset the mountain of literally hundreds of studies that uphold the value of LDL-C in prediction and intervention of ASCVD,” Dr. Burnett and coauthors wrote.

Similarly, the editorialists cautioned that, although the findings from the study by Dr. Nordestgaard and colleagues indicate that VLDL cholesterol is the “new kid in town for prediction, LDL cholesterol retains predictive power.” Clinical cardiologists should not “shelve LDL cholesterol and embrace VLDL and remnant cholesterol as the new oracles of ASCVD risk.” 

In a comment, Dr. Burnett said, “The take-home message for clinicians in both papers is that LDL-C is the main lipid measurement to guide clinical decisions; however, residual risk of atherosclerotic cardiovascular disease remains, even after LCL-C is treated.

“Assessment of residual ASCVD risk with nontraditional lipid biomarkers, including VLDL cholesterol and remnant cholesterol, as well as lipoprotein (a) and apoB, may improve prognostication and help guide preventive treatments,” he added.
 

“Affordable and inexpensive”

In their report, the PREDIMED study authors explained that atherogenic dyslipidemia is characterized by “an excess of serum triglycerides” contained in VLDL cholesterol, intermediate-density lipoproteins, and their remnants, all of which are called “triglyceride-rich lipoproteins (TRLs).”

TRLs and remnant-C “have the capacity to cross the arterial wall,” and may therefore play a causal role in atherosclerosis development, they wrote.

The main PREDIMED trial compared a low-fat diet with the Mediterranean diet for the primary prevention of CVD in high-risk participants. Those enrolled in the trial “had a high prevalence of diabetes, obesity, and metabolic syndrome, conditions that are associated with insulin resistance, hypertriglyceridemia, and atherogenic dyslipidemia,” the authors wrote. “Thus, this cohort of subjects at high cardiovascular risk was well suited to investigate the association of triglycerides and TRLs with cardiovascular outcomes.” 

The researchers investigated the role of triglycerides and remnant-C in incident CVD among these high-risk individuals, particularly those with chronic cardiometabolic disorders (prediabetes, type 2 diabetes, and poorly controlled diabetes), overweight and obesity, metabolic syndrome, and renal failure.

Their 6,901 participants (42.6% male, mean age 67 years, mean BMI 30.0 kg/m2) had a diagnosis of type 2 diabetes or at least three CVD risk factors including current smoking, hypertension, elevated LDL-C levels, low HDL cholesterol levels, elevated body mass index, or family history of premature coronary heart disease.

The primary study endpoint was a composite of adverse cardiovascular events (MACE): MI, stroke, or cardiovascular death. Participants were followed for a mean of 4.8 years, during which there was a total of 263 MACE events.

Multivariable-adjusted analyses showed that levels of triglycerides and remnant-C were both associated with MACE independent of other risk factors (hazard ratio, 1.04; 95% confidence interval, 1.02-1.06; and HR, 1.21; 95% CI, 1.10-1.33 per 10 mg/dl, respectively, both P < .001). Non–HDL cholesterol was also associated with MACE (HR, 1.05; 95% CI, 1.01-1.10 per 10 mg/dl, P = .026).

In particular, elevated remnant-C (≥30 mg/dL), compared with lower concentrations, flagged subjects at a higher risk of MACE, even if their LDL-C levels were at target (defined as ≤ 100 mg/dL).

Levels of LDL-C and HDL cholesterol were not associated with MACE.

“The indirect calculation of remnant-C is an affordable and inexpensive method, which could provide valuable data for clinical management,” Dr. Fitó Colomer said.

“The results of this study suggest that, in individuals at high cardiovascular risk with well-controlled LDL-C, triglycerides and mainly remnant-C should be considered as a treatment target,” she proposed.
 

New oracles?

Evidence has pointed to triglyceride-rich remnants or VLDL cholesterol as contributing to atherosclerotic CVD, together with LDL-C, but it is “unclear which fraction of risk is explained by, respectively, cholesterol and triglycerides in VLDL,” write the authors of the Copenhagen population study.

Dr. Nordestgaard said their study was motivated by an awareness that “in clinical practice, the focus for lipid-related risk is almost solely on reduction of LDL-C for prevention of ASCVD,” so the current focus needs to be reevaluated because patients with low LDL-C but elevated VLDL cholesterol and plasma triglycerides “may not be offered adequate preventive lipid-lowering therapy in order to prevent future MI and ASCVD.”

His group therefore tested the hypothesis that VLDL cholesterol and triglycerides may each explain part of the MI risk from apoB-containing lipoproteins.

They used measurements of plasma apoB and cholesterol and triglyceride content of VLDL cholesterol, intermediate-density-lipoprotein cholesterol, and LDL-C in the study participants (N = 25,480, median age 61 years, 53% female), who were required to be free of MI and not receiving lipid-lowering therapy at baseline.

During a median 11-year follow-up period, 1,816 participants experienced an MI. They tended to be older, compared with those who did not experience an MI, and also more likely to be male, to smoke, and to have higher systolic blood pressure.

Each 39-mg/dL increase in lipid level was found to be associated with higher MI risk.

The researchers looked at MI-associated risk of specific subfractions of apoB-containing lipoproteins. “VLDL cholesterol explained half of the MI risk from elevated apoB-containing lipoproteins, and [intermediate-density-lipoprotein] and LDL-C together accounted for only 29% of the risk,” Dr. Nordestgaard said.

“If LDL cholesterol is adequately reduced, clinicians need to evaluate possible elevated triglyceride-rich lipoproteins, either as elevated plasma triglycerides, remnant cholesterol, or elevated VLDL cholesterol; and, if elevated, consideration should also be given to reduction of triglyceride-rich lipoproteins,” he advised.

The Copenhagen General Population study was funded by the Danish Heart Foundation and the Novo Nordisk Foundation. Dr. Nordestgaard disclosed consulting for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin, Novartis, Novo Nordisk, and Silence Therapeutrics. PREDIMED was supported by grants from the Instituto de Salud Carlos III- FEDER, Fundació La Marató de TV3, and Agència de Gestió d’Ajuts Universitaris i de Recerca. Dr. Fitó Colomer disclosed no relevant financial relationships. Dr. Burnett disclosed no relevant financial relationships.

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

Peripheral neuropathy is common in U.S. adults and is associated with an increased risk of death, even in the absence of diabetes, researchers reported  in Annals of Internal Medicine.

©mheim3011/thinkstockphotos.com

The findings do not necessarily mean that doctors should implement broader screening for peripheral neuropathy at this time, however, the investigators said.

“Doctors don’t typically screen for peripheral neuropathy in persons without diabetes,” senior author Elizabeth Selvin, PhD, MPH, professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, Baltimore, said in an interview.

“Our study shows that peripheral neuropathy – as assessed by decreased sensation in the feet – is common, even in people without diabetes,” Dr. Selvin explained. “It is not yet clear whether we should be screening people without diabetes since we don’t have clear treatments, but our study does suggest that this condition is an underrecognized condition that is associated with poor outcomes.”

Patients with diabetes typically undergo annual foot examinations that include screening for peripheral neuropathy, but that’s not the case for most adults in the absence of diabetes.

“I don’t know if we can make the jump that we should be screening people without diabetes,” said first author Caitlin W. Hicks, MD, assistant professor of surgery, division of vascular surgery and endovascular therapy, Johns Hopkins University, Baltimore. “Right now, we do not exactly know what it means in the people without diabetes, and we definitely do not know how to treat it. So, screening for it will tell us that this person has this and is at higher risk of mortality than someone who doesn’t, but we do not know what to do with that information yet.”

Nevertheless, the study raises the question of whether physicians should pay more attention to peripheral neuropathy in people without diabetes, said Dr. Hicks, director of research at the university’s diabetic foot and wound service.
 

Heightened risk

To examine associations between peripheral neuropathy and all-cause and cardiovascular mortality in U.S. adults, Dr. Hicks and colleagues analyzed data from 7,116 adults aged 40 years or older who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004.

The study included participants who underwent monofilament testing for peripheral neuropathy. During testing, technicians used a standard 5.07 Semmes-Weinstein nylon monofilament to apply slight pressure to the bottom of each foot at three sites. If participants could not correctly identify where pressure was applied, the test was repeated. After participants gave two incorrect or undeterminable responses for a site, the site was defined as insensate. The researchers defined peripheral neuropathy as at least one insensate site on either foot.

The researchers determined deaths and causes of death using death certificate records from the National Death Index through 2015.

In all, 13.5% of the participants had peripheral neuropathy, including 27% of adults with diabetes and 11.6% of adults without diabetes. Those with peripheral neuropathy were older, were more likely to be male, and had lower levels of education, compared with participants without peripheral neuropathy. They also had higher body mass index, were more often former or current smokers, and had a higher prevalence of hypertension, hypercholesterolemia, and cardiovascular disease.

During a median follow-up of 13 years, 2,128 participants died, including 488 who died of cardiovascular causes.

The incidence rate of all-cause mortality per 1,000 person-years was 57.6 in adults with diabetes and peripheral neuropathy, 34.3 in adults with peripheral neuropathy but no diabetes, 27.1 in adults with diabetes but no peripheral neuropathy, and 13.0 in adults without diabetes or peripheral neuropathy.

Among participants with diabetes, the leading cause of death was cardiovascular disease (31% of deaths), whereas among participants without diabetes, the leading cause of death was malignant neoplasms (27% of deaths).

After adjustment for age, sex, race, or ethnicity, and risk factors such as cardiovascular disease, peripheral neuropathy was significantly associated with all-cause mortality (hazard ratio [HR], 1.49) and cardiovascular mortality (HR, 1.66) in participants with diabetes. In participants without diabetes, peripheral neuropathy was significantly associated with all-cause mortality (HR, 1.31), but its association with cardiovascular mortality was not statistically significant.

The association between peripheral neuropathy and all-cause mortality persisted in a sensitivity analysis that focused on adults with normoglycemia.
 

Related conditions

The study confirms findings from prior studies that examined the prevalence of loss of peripheral sensation in populations of older adults with and without diabetes, said Elsa S. Strotmeyer, PhD, MPH, associate professor of epidemiology at the University of Pittsburgh. “The clinical significance of the loss of peripheral sensation in older adults without diabetes is not fully appreciated,” she said.

A limitation of the study is that peripheral neuropathy was not a clinical diagnosis. “Monofilament testing at the foot is a quick clinical screen for decreased lower-extremity sensation that likely is a result of sensory peripheral nerve decline,” Dr. Strotmeyer said.

Another limitation is that death certificates are less accurate than medical records for determining cause of death.

“Past studies have indicated that peripheral nerve decline is related to common conditions in aging such as the metabolic syndrome and cardiovascular disease, cancer treatment, and physical function loss,” Dr. Strotmeyer said. “Therefore it is not surprising that is related to mortality as these conditions in aging are associated with increased mortality. Loss of peripheral sensation at the foot may also be related to fall injuries, and mortality from fall injuries has increased dramatically in older adults over the past several decades.”

Prior research has suggested that monofilament testing may play a role in screening for fall risk in older adults without diabetes, Dr. Strotmeyer added.

“For older adults both with and without diabetes, past studies have recommended monofilament testing be incorporated in geriatric screening for fall risk. Therefore, this article expands implications of clinical importance to understanding the pathology and consequences of loss of sensation at the foot in older patients,” she said.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute. Dr. Hicks, Dr. Selvin, and a coauthor, Kunihiro Matsushita, MD, PhD, disclosed NIH grants. In addition, Dr. Selvin disclosed personal fees from Novo Nordisk and grants from the Foundation for the National Institutes of Health outside the submitted work, and Dr. Matsushita disclosed grants and personal fees from Fukuda Denshi outside the submitted work. Dr. Strotmeyer receives funding from the National Institute on Aging and the National Institute of Arthritis and Musculoskeletal and Skin Diseases and is chair of the health sciences section of the Gerontological Society of America.

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

Peripheral neuropathy is common in U.S. adults and is associated with an increased risk of death, even in the absence of diabetes, researchers reported  in Annals of Internal Medicine.

©mheim3011/thinkstockphotos.com

The findings do not necessarily mean that doctors should implement broader screening for peripheral neuropathy at this time, however, the investigators said.

“Doctors don’t typically screen for peripheral neuropathy in persons without diabetes,” senior author Elizabeth Selvin, PhD, MPH, professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, Baltimore, said in an interview.

“Our study shows that peripheral neuropathy – as assessed by decreased sensation in the feet – is common, even in people without diabetes,” Dr. Selvin explained. “It is not yet clear whether we should be screening people without diabetes since we don’t have clear treatments, but our study does suggest that this condition is an underrecognized condition that is associated with poor outcomes.”

Patients with diabetes typically undergo annual foot examinations that include screening for peripheral neuropathy, but that’s not the case for most adults in the absence of diabetes.

“I don’t know if we can make the jump that we should be screening people without diabetes,” said first author Caitlin W. Hicks, MD, assistant professor of surgery, division of vascular surgery and endovascular therapy, Johns Hopkins University, Baltimore. “Right now, we do not exactly know what it means in the people without diabetes, and we definitely do not know how to treat it. So, screening for it will tell us that this person has this and is at higher risk of mortality than someone who doesn’t, but we do not know what to do with that information yet.”

Nevertheless, the study raises the question of whether physicians should pay more attention to peripheral neuropathy in people without diabetes, said Dr. Hicks, director of research at the university’s diabetic foot and wound service.
 

Heightened risk

To examine associations between peripheral neuropathy and all-cause and cardiovascular mortality in U.S. adults, Dr. Hicks and colleagues analyzed data from 7,116 adults aged 40 years or older who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004.

The study included participants who underwent monofilament testing for peripheral neuropathy. During testing, technicians used a standard 5.07 Semmes-Weinstein nylon monofilament to apply slight pressure to the bottom of each foot at three sites. If participants could not correctly identify where pressure was applied, the test was repeated. After participants gave two incorrect or undeterminable responses for a site, the site was defined as insensate. The researchers defined peripheral neuropathy as at least one insensate site on either foot.

The researchers determined deaths and causes of death using death certificate records from the National Death Index through 2015.

In all, 13.5% of the participants had peripheral neuropathy, including 27% of adults with diabetes and 11.6% of adults without diabetes. Those with peripheral neuropathy were older, were more likely to be male, and had lower levels of education, compared with participants without peripheral neuropathy. They also had higher body mass index, were more often former or current smokers, and had a higher prevalence of hypertension, hypercholesterolemia, and cardiovascular disease.

During a median follow-up of 13 years, 2,128 participants died, including 488 who died of cardiovascular causes.

The incidence rate of all-cause mortality per 1,000 person-years was 57.6 in adults with diabetes and peripheral neuropathy, 34.3 in adults with peripheral neuropathy but no diabetes, 27.1 in adults with diabetes but no peripheral neuropathy, and 13.0 in adults without diabetes or peripheral neuropathy.

Among participants with diabetes, the leading cause of death was cardiovascular disease (31% of deaths), whereas among participants without diabetes, the leading cause of death was malignant neoplasms (27% of deaths).

After adjustment for age, sex, race, or ethnicity, and risk factors such as cardiovascular disease, peripheral neuropathy was significantly associated with all-cause mortality (hazard ratio [HR], 1.49) and cardiovascular mortality (HR, 1.66) in participants with diabetes. In participants without diabetes, peripheral neuropathy was significantly associated with all-cause mortality (HR, 1.31), but its association with cardiovascular mortality was not statistically significant.

The association between peripheral neuropathy and all-cause mortality persisted in a sensitivity analysis that focused on adults with normoglycemia.
 

Related conditions

The study confirms findings from prior studies that examined the prevalence of loss of peripheral sensation in populations of older adults with and without diabetes, said Elsa S. Strotmeyer, PhD, MPH, associate professor of epidemiology at the University of Pittsburgh. “The clinical significance of the loss of peripheral sensation in older adults without diabetes is not fully appreciated,” she said.

A limitation of the study is that peripheral neuropathy was not a clinical diagnosis. “Monofilament testing at the foot is a quick clinical screen for decreased lower-extremity sensation that likely is a result of sensory peripheral nerve decline,” Dr. Strotmeyer said.

Another limitation is that death certificates are less accurate than medical records for determining cause of death.

“Past studies have indicated that peripheral nerve decline is related to common conditions in aging such as the metabolic syndrome and cardiovascular disease, cancer treatment, and physical function loss,” Dr. Strotmeyer said. “Therefore it is not surprising that is related to mortality as these conditions in aging are associated with increased mortality. Loss of peripheral sensation at the foot may also be related to fall injuries, and mortality from fall injuries has increased dramatically in older adults over the past several decades.”

Prior research has suggested that monofilament testing may play a role in screening for fall risk in older adults without diabetes, Dr. Strotmeyer added.

“For older adults both with and without diabetes, past studies have recommended monofilament testing be incorporated in geriatric screening for fall risk. Therefore, this article expands implications of clinical importance to understanding the pathology and consequences of loss of sensation at the foot in older patients,” she said.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute. Dr. Hicks, Dr. Selvin, and a coauthor, Kunihiro Matsushita, MD, PhD, disclosed NIH grants. In addition, Dr. Selvin disclosed personal fees from Novo Nordisk and grants from the Foundation for the National Institutes of Health outside the submitted work, and Dr. Matsushita disclosed grants and personal fees from Fukuda Denshi outside the submitted work. Dr. Strotmeyer receives funding from the National Institute on Aging and the National Institute of Arthritis and Musculoskeletal and Skin Diseases and is chair of the health sciences section of the Gerontological Society of America.

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

Peripheral neuropathy is common in U.S. adults and is associated with an increased risk of death, even in the absence of diabetes, researchers reported  in Annals of Internal Medicine.

©mheim3011/thinkstockphotos.com

The findings do not necessarily mean that doctors should implement broader screening for peripheral neuropathy at this time, however, the investigators said.

“Doctors don’t typically screen for peripheral neuropathy in persons without diabetes,” senior author Elizabeth Selvin, PhD, MPH, professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, Baltimore, said in an interview.

“Our study shows that peripheral neuropathy – as assessed by decreased sensation in the feet – is common, even in people without diabetes,” Dr. Selvin explained. “It is not yet clear whether we should be screening people without diabetes since we don’t have clear treatments, but our study does suggest that this condition is an underrecognized condition that is associated with poor outcomes.”

Patients with diabetes typically undergo annual foot examinations that include screening for peripheral neuropathy, but that’s not the case for most adults in the absence of diabetes.

“I don’t know if we can make the jump that we should be screening people without diabetes,” said first author Caitlin W. Hicks, MD, assistant professor of surgery, division of vascular surgery and endovascular therapy, Johns Hopkins University, Baltimore. “Right now, we do not exactly know what it means in the people without diabetes, and we definitely do not know how to treat it. So, screening for it will tell us that this person has this and is at higher risk of mortality than someone who doesn’t, but we do not know what to do with that information yet.”

Nevertheless, the study raises the question of whether physicians should pay more attention to peripheral neuropathy in people without diabetes, said Dr. Hicks, director of research at the university’s diabetic foot and wound service.
 

Heightened risk

To examine associations between peripheral neuropathy and all-cause and cardiovascular mortality in U.S. adults, Dr. Hicks and colleagues analyzed data from 7,116 adults aged 40 years or older who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004.

The study included participants who underwent monofilament testing for peripheral neuropathy. During testing, technicians used a standard 5.07 Semmes-Weinstein nylon monofilament to apply slight pressure to the bottom of each foot at three sites. If participants could not correctly identify where pressure was applied, the test was repeated. After participants gave two incorrect or undeterminable responses for a site, the site was defined as insensate. The researchers defined peripheral neuropathy as at least one insensate site on either foot.

The researchers determined deaths and causes of death using death certificate records from the National Death Index through 2015.

In all, 13.5% of the participants had peripheral neuropathy, including 27% of adults with diabetes and 11.6% of adults without diabetes. Those with peripheral neuropathy were older, were more likely to be male, and had lower levels of education, compared with participants without peripheral neuropathy. They also had higher body mass index, were more often former or current smokers, and had a higher prevalence of hypertension, hypercholesterolemia, and cardiovascular disease.

During a median follow-up of 13 years, 2,128 participants died, including 488 who died of cardiovascular causes.

The incidence rate of all-cause mortality per 1,000 person-years was 57.6 in adults with diabetes and peripheral neuropathy, 34.3 in adults with peripheral neuropathy but no diabetes, 27.1 in adults with diabetes but no peripheral neuropathy, and 13.0 in adults without diabetes or peripheral neuropathy.

Among participants with diabetes, the leading cause of death was cardiovascular disease (31% of deaths), whereas among participants without diabetes, the leading cause of death was malignant neoplasms (27% of deaths).

After adjustment for age, sex, race, or ethnicity, and risk factors such as cardiovascular disease, peripheral neuropathy was significantly associated with all-cause mortality (hazard ratio [HR], 1.49) and cardiovascular mortality (HR, 1.66) in participants with diabetes. In participants without diabetes, peripheral neuropathy was significantly associated with all-cause mortality (HR, 1.31), but its association with cardiovascular mortality was not statistically significant.

The association between peripheral neuropathy and all-cause mortality persisted in a sensitivity analysis that focused on adults with normoglycemia.
 

Related conditions

The study confirms findings from prior studies that examined the prevalence of loss of peripheral sensation in populations of older adults with and without diabetes, said Elsa S. Strotmeyer, PhD, MPH, associate professor of epidemiology at the University of Pittsburgh. “The clinical significance of the loss of peripheral sensation in older adults without diabetes is not fully appreciated,” she said.

A limitation of the study is that peripheral neuropathy was not a clinical diagnosis. “Monofilament testing at the foot is a quick clinical screen for decreased lower-extremity sensation that likely is a result of sensory peripheral nerve decline,” Dr. Strotmeyer said.

Another limitation is that death certificates are less accurate than medical records for determining cause of death.

“Past studies have indicated that peripheral nerve decline is related to common conditions in aging such as the metabolic syndrome and cardiovascular disease, cancer treatment, and physical function loss,” Dr. Strotmeyer said. “Therefore it is not surprising that is related to mortality as these conditions in aging are associated with increased mortality. Loss of peripheral sensation at the foot may also be related to fall injuries, and mortality from fall injuries has increased dramatically in older adults over the past several decades.”

Prior research has suggested that monofilament testing may play a role in screening for fall risk in older adults without diabetes, Dr. Strotmeyer added.

“For older adults both with and without diabetes, past studies have recommended monofilament testing be incorporated in geriatric screening for fall risk. Therefore, this article expands implications of clinical importance to understanding the pathology and consequences of loss of sensation at the foot in older patients,” she said.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute. Dr. Hicks, Dr. Selvin, and a coauthor, Kunihiro Matsushita, MD, PhD, disclosed NIH grants. In addition, Dr. Selvin disclosed personal fees from Novo Nordisk and grants from the Foundation for the National Institutes of Health outside the submitted work, and Dr. Matsushita disclosed grants and personal fees from Fukuda Denshi outside the submitted work. Dr. Strotmeyer receives funding from the National Institute on Aging and the National Institute of Arthritis and Musculoskeletal and Skin Diseases and is chair of the health sciences section of the Gerontological Society of America.

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