Lipid Disorders

LONDON – A low-carbohydrate, high-fat (LCHF) diet reduced the progression of nonalcoholic fatty liver disease (NAFLD), and despite no calorie restriction, participants with both NAFLD and type 2 diabetes lost 5.8% of their body weight, according to a randomized controlled study.

“Based on these results, the LCHF diet may be recommended to people with NAFLD and type 2 diabetes,” said Camilla Dalby Hansen, MD, department of gastroenterology and hepatology, Odense University Hospital, Denmark, who presented the data at the International Liver Congress (ILC) 2022.  

“Basically, if you have fat in your liver, you will benefit from eating fat,” she said.

The LCHF diet was compared with a low-fat, high-carbohydrate diet more typically followed for these conditions. The low-fat diet was also found to reduce the progression of NAFLD, but to a lesser extent than the LCHF diet.

Dr. Dalby Hansen called their study one of the most extensive investigations of the LCHF diet in patients with type 2 diabetes and fatty liver disease.

“Combining this [reduction in NAFLD score] with the huge weight loss, the lower HbA1c [blood sugar], the lowering of blood pressure in women, the rise in HDL levels, and reduction in triglycerides – all in all, this diet is very promising,” she said.

Stephen Harrison, MD, visiting professor, University of Oxford, United Kingdom, medical director of Pinnacle Clinical Research and president of Summit Clinical Research, San Antonio, commended Dr. Dalby Hansen on her methodology, which included before-and-after liver biopsies. “It’s a heinous effort to do paired liver biopsies in a lifestyle modification trial. That’s huge.”

“This study tells me that the way we manage patients doesn’t change – it is still lifestyle modification,” said Dr. Harrison, who was not involved with the study. “It’s eat less [rather] than more. It’s exercise and try to lose weight. In the long term, we give patients benefit, and we show that the disease has improved, and we offer something that means they can maintain a healthy life.”

He added that the relatively small and short trial was informative.

“They improved the NAFLD activity score [NAS],” he said. “I don’t know by how much. There was no change in fibrosis, but we wouldn’t expect this at 6 months.”

“It’s provocative work, and it gives us healthy information about how we can help manage our patients from a lifestyle perspective,” he concluded.
 

‘Do not lose weight. Eat until you are full’

In the study, 110 participants with type 2 diabetes and NAFLD, aged 18-78 years, were allocated to the LCHF diet, and 55 were allocated to the low-fat diet for 6 months.

The researchers performed liver biopsies at baseline and 6 months, which were blinded for scoring.  

Participants had ongoing dietitian consultations, with follow-up visits at 3 and 6 months. Compliance was reported continuously through an online food diary platform.

The primary endpoint was change in glycemic control as measured by A1c level over 6 months. The secondary endpoints comprised the proportion of participants with changes in the NAS of at least 2 points over 6 months. Both these measures were compared between the two dietary groups.

The two groups were matched at baseline, with a mean age of 55-57 years, 58% were women, 89% with metabolic syndrome, and a mean BMI 34 kg/m².

In baseline liver disease, F1 level fibrosis was the most common (58%), followed by hepatic steatosis (S1, 47%; S2, 32%), with a median NAS of 3, and 19% had nonalcoholic steatohepatitis.

The special thing about these diets was that participants were told to “not lose weight, but eat until you are full,” remarked Dr. Dalby Hansen.

Those on the LCHF diet consumed an average of 61% energy from fat, 13% from carbohydrates, and 23% from protein, compared with the low-fat diet, which comprised an average of 29% energy from fat, 46% from carbohydrates, and 21% from protein.

“It’s a lot of fat and corresponds to a quarter of a liter of olive oil per day,” said Dr. Dalby Hansen. “They really had to change their mindset a lot, because it was difficult for them to start eating all these fats, especially since we’ve all been told for decades that it isn’t good. But we supported them, and they got into it.”

The LCHF diet was primarily comprised of unsaturated fats – for example, avocado, oil, nuts, and seeds – but also included saturated fats, such as cheese, cream, and high-fat dairy products. Participants were free to eat unsaturated and saturated fats, but Dr. Dalby Hansen and her team advised participants that “good” unsaturated fats were preferable.

“Also, this diet contained vegetables but no bread, no potatoes, no rice, and no pasta. It was low in carbohydrates, below 20%,” she added.
 

Improved glycemic control, reduced liver fat

“We found that the LCHF diet improved diabetes control, it reduced the fat in the liver, and, even though they’re eating as many calories as they were used to until they were full, they lost 5.8% of body weight,” said Dr. Dalby Hansen in reporting the results. Participants in the low-fat group lost only 1.8% of body weight.

However, mean calorie intake dropped in both groups, by –2.2% in the LCHF group and –8.7% in the low-fat group. 

“The LCHF diet improved the primary outcome of A1c by 9.5 mmol/mol, which is similar to some anti-diabetic medications, such as DPP-4 inhibitors and SGLT2 inhibitors,” she said.

The low-fat group reduced A1c by 3.4 mmol/mol, resulting in a between-group difference of 6.1 mmol/mol.

“Upon follow-up of 3 months, after stopping the diets, on average the participants in both groups returned their HbA1c levels to nearly baseline values,” she said. Results were adjusted for weight loss and baseline values.

Both diets also improved the NAS. The proportion of participants who improved their NAS score by 2 or more points was 22% in the LCHF group versus 17% in the low-fat group (P = 0.58). Additionally, in the LCHF group, 70% of participants improved their score by 1 or more points, compared with 49% in the low-fat group and fewer in the LCHF group experienced a worsening of their score (1% vs. 23%, respectively).

One participant on LCHF had high triglycerides of 12 mmol/L after 3 months. Overall, the low-density lipoprotein increased marginally by 0.2 mmol per liter in the high-fat group, said Dr. Dalby Hansen.

Dr. Dalby Hansen noted some limitations. The findings might not be applicable in more severe NAFLD, dietary assessment relied on self-reporting, no food was provided, and participants had to cook themselves. It was also an open-label study because of the nature of the intervention.
 

Some hope for more sustainable dieting

Many diets are difficult to adhere to, remarked Dr. Dalby Hansen. “We thought this [diet] might be easier to comply with in the longer term, and we hope that these results might provide patients with more options.”

She added that most people who started the diet adapted and complied with it. “However, it might not be for everyone, but I think we can say that if people try, and it fits into their lives, then they go for it.”

However, “it is not about going out and eating whatever fat and how much of it you want. It’s important that you cut the carbohydrates too,” she said. “With this approach, we really saw amazing results.”

Dr. Dalby Hansen added that having various diets available, including the LCHF one, meant that as clinicians they could empower patients to take control of their metabolic health.

“We can ask them directly, ‘What would fit into their life?’” she said. “We know that one size does not fit at all, and I believe that if we could engage patients more, then they can take control of their own situation.”

Asked whether these findings were enough to change guidelines, Zobair Younossi, MD, professor and chairman, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., remarked that it was the sugar at work here.

“Dietary fat – it’s not the same as fat in the liver, and this diet has more to do with the sugar levels,” he said.

“I’m always reluctant to take results from a short-term study without long-term follow-up,” Dr. Younossi said. “I want to know will patients live longer, and long-term data are needed for this. Until I have that strong evidence that outcomes are going to change, or at least some sign that the outcome is going to change, it is too early to change any guidelines.”

Dr. Dalby Hansen reports no relevant financial relationships. Dr. Harrison reported financial relationships with numerous pharmaceutical companies. Dr. Younossi reports the following financial relationships: research funds and/or consultant to Abbott, Allergan, Bristol Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk.

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

LONDON – A low-carbohydrate, high-fat (LCHF) diet reduced the progression of nonalcoholic fatty liver disease (NAFLD), and despite no calorie restriction, participants with both NAFLD and type 2 diabetes lost 5.8% of their body weight, according to a randomized controlled study.

“Based on these results, the LCHF diet may be recommended to people with NAFLD and type 2 diabetes,” said Camilla Dalby Hansen, MD, department of gastroenterology and hepatology, Odense University Hospital, Denmark, who presented the data at the International Liver Congress (ILC) 2022.  

“Basically, if you have fat in your liver, you will benefit from eating fat,” she said.

The LCHF diet was compared with a low-fat, high-carbohydrate diet more typically followed for these conditions. The low-fat diet was also found to reduce the progression of NAFLD, but to a lesser extent than the LCHF diet.

Dr. Dalby Hansen called their study one of the most extensive investigations of the LCHF diet in patients with type 2 diabetes and fatty liver disease.

“Combining this [reduction in NAFLD score] with the huge weight loss, the lower HbA1c [blood sugar], the lowering of blood pressure in women, the rise in HDL levels, and reduction in triglycerides – all in all, this diet is very promising,” she said.

Stephen Harrison, MD, visiting professor, University of Oxford, United Kingdom, medical director of Pinnacle Clinical Research and president of Summit Clinical Research, San Antonio, commended Dr. Dalby Hansen on her methodology, which included before-and-after liver biopsies. “It’s a heinous effort to do paired liver biopsies in a lifestyle modification trial. That’s huge.”

“This study tells me that the way we manage patients doesn’t change – it is still lifestyle modification,” said Dr. Harrison, who was not involved with the study. “It’s eat less [rather] than more. It’s exercise and try to lose weight. In the long term, we give patients benefit, and we show that the disease has improved, and we offer something that means they can maintain a healthy life.”

He added that the relatively small and short trial was informative.

“They improved the NAFLD activity score [NAS],” he said. “I don’t know by how much. There was no change in fibrosis, but we wouldn’t expect this at 6 months.”

“It’s provocative work, and it gives us healthy information about how we can help manage our patients from a lifestyle perspective,” he concluded.
 

‘Do not lose weight. Eat until you are full’

In the study, 110 participants with type 2 diabetes and NAFLD, aged 18-78 years, were allocated to the LCHF diet, and 55 were allocated to the low-fat diet for 6 months.

The researchers performed liver biopsies at baseline and 6 months, which were blinded for scoring.  

Participants had ongoing dietitian consultations, with follow-up visits at 3 and 6 months. Compliance was reported continuously through an online food diary platform.

The primary endpoint was change in glycemic control as measured by A1c level over 6 months. The secondary endpoints comprised the proportion of participants with changes in the NAS of at least 2 points over 6 months. Both these measures were compared between the two dietary groups.

The two groups were matched at baseline, with a mean age of 55-57 years, 58% were women, 89% with metabolic syndrome, and a mean BMI 34 kg/m².

In baseline liver disease, F1 level fibrosis was the most common (58%), followed by hepatic steatosis (S1, 47%; S2, 32%), with a median NAS of 3, and 19% had nonalcoholic steatohepatitis.

The special thing about these diets was that participants were told to “not lose weight, but eat until you are full,” remarked Dr. Dalby Hansen.

Those on the LCHF diet consumed an average of 61% energy from fat, 13% from carbohydrates, and 23% from protein, compared with the low-fat diet, which comprised an average of 29% energy from fat, 46% from carbohydrates, and 21% from protein.

“It’s a lot of fat and corresponds to a quarter of a liter of olive oil per day,” said Dr. Dalby Hansen. “They really had to change their mindset a lot, because it was difficult for them to start eating all these fats, especially since we’ve all been told for decades that it isn’t good. But we supported them, and they got into it.”

The LCHF diet was primarily comprised of unsaturated fats – for example, avocado, oil, nuts, and seeds – but also included saturated fats, such as cheese, cream, and high-fat dairy products. Participants were free to eat unsaturated and saturated fats, but Dr. Dalby Hansen and her team advised participants that “good” unsaturated fats were preferable.

“Also, this diet contained vegetables but no bread, no potatoes, no rice, and no pasta. It was low in carbohydrates, below 20%,” she added.
 

Improved glycemic control, reduced liver fat

“We found that the LCHF diet improved diabetes control, it reduced the fat in the liver, and, even though they’re eating as many calories as they were used to until they were full, they lost 5.8% of body weight,” said Dr. Dalby Hansen in reporting the results. Participants in the low-fat group lost only 1.8% of body weight.

However, mean calorie intake dropped in both groups, by –2.2% in the LCHF group and –8.7% in the low-fat group. 

“The LCHF diet improved the primary outcome of A1c by 9.5 mmol/mol, which is similar to some anti-diabetic medications, such as DPP-4 inhibitors and SGLT2 inhibitors,” she said.

The low-fat group reduced A1c by 3.4 mmol/mol, resulting in a between-group difference of 6.1 mmol/mol.

“Upon follow-up of 3 months, after stopping the diets, on average the participants in both groups returned their HbA1c levels to nearly baseline values,” she said. Results were adjusted for weight loss and baseline values.

Both diets also improved the NAS. The proportion of participants who improved their NAS score by 2 or more points was 22% in the LCHF group versus 17% in the low-fat group (P = 0.58). Additionally, in the LCHF group, 70% of participants improved their score by 1 or more points, compared with 49% in the low-fat group and fewer in the LCHF group experienced a worsening of their score (1% vs. 23%, respectively).

One participant on LCHF had high triglycerides of 12 mmol/L after 3 months. Overall, the low-density lipoprotein increased marginally by 0.2 mmol per liter in the high-fat group, said Dr. Dalby Hansen.

Dr. Dalby Hansen noted some limitations. The findings might not be applicable in more severe NAFLD, dietary assessment relied on self-reporting, no food was provided, and participants had to cook themselves. It was also an open-label study because of the nature of the intervention.
 

Some hope for more sustainable dieting

Many diets are difficult to adhere to, remarked Dr. Dalby Hansen. “We thought this [diet] might be easier to comply with in the longer term, and we hope that these results might provide patients with more options.”

She added that most people who started the diet adapted and complied with it. “However, it might not be for everyone, but I think we can say that if people try, and it fits into their lives, then they go for it.”

However, “it is not about going out and eating whatever fat and how much of it you want. It’s important that you cut the carbohydrates too,” she said. “With this approach, we really saw amazing results.”

Dr. Dalby Hansen added that having various diets available, including the LCHF one, meant that as clinicians they could empower patients to take control of their metabolic health.

“We can ask them directly, ‘What would fit into their life?’” she said. “We know that one size does not fit at all, and I believe that if we could engage patients more, then they can take control of their own situation.”

Asked whether these findings were enough to change guidelines, Zobair Younossi, MD, professor and chairman, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., remarked that it was the sugar at work here.

“Dietary fat – it’s not the same as fat in the liver, and this diet has more to do with the sugar levels,” he said.

“I’m always reluctant to take results from a short-term study without long-term follow-up,” Dr. Younossi said. “I want to know will patients live longer, and long-term data are needed for this. Until I have that strong evidence that outcomes are going to change, or at least some sign that the outcome is going to change, it is too early to change any guidelines.”

Dr. Dalby Hansen reports no relevant financial relationships. Dr. Harrison reported financial relationships with numerous pharmaceutical companies. Dr. Younossi reports the following financial relationships: research funds and/or consultant to Abbott, Allergan, Bristol Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk.

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

LONDON – A low-carbohydrate, high-fat (LCHF) diet reduced the progression of nonalcoholic fatty liver disease (NAFLD), and despite no calorie restriction, participants with both NAFLD and type 2 diabetes lost 5.8% of their body weight, according to a randomized controlled study.

“Based on these results, the LCHF diet may be recommended to people with NAFLD and type 2 diabetes,” said Camilla Dalby Hansen, MD, department of gastroenterology and hepatology, Odense University Hospital, Denmark, who presented the data at the International Liver Congress (ILC) 2022.  

“Basically, if you have fat in your liver, you will benefit from eating fat,” she said.

The LCHF diet was compared with a low-fat, high-carbohydrate diet more typically followed for these conditions. The low-fat diet was also found to reduce the progression of NAFLD, but to a lesser extent than the LCHF diet.

Dr. Dalby Hansen called their study one of the most extensive investigations of the LCHF diet in patients with type 2 diabetes and fatty liver disease.

“Combining this [reduction in NAFLD score] with the huge weight loss, the lower HbA1c [blood sugar], the lowering of blood pressure in women, the rise in HDL levels, and reduction in triglycerides – all in all, this diet is very promising,” she said.

Stephen Harrison, MD, visiting professor, University of Oxford, United Kingdom, medical director of Pinnacle Clinical Research and president of Summit Clinical Research, San Antonio, commended Dr. Dalby Hansen on her methodology, which included before-and-after liver biopsies. “It’s a heinous effort to do paired liver biopsies in a lifestyle modification trial. That’s huge.”

“This study tells me that the way we manage patients doesn’t change – it is still lifestyle modification,” said Dr. Harrison, who was not involved with the study. “It’s eat less [rather] than more. It’s exercise and try to lose weight. In the long term, we give patients benefit, and we show that the disease has improved, and we offer something that means they can maintain a healthy life.”

He added that the relatively small and short trial was informative.

“They improved the NAFLD activity score [NAS],” he said. “I don’t know by how much. There was no change in fibrosis, but we wouldn’t expect this at 6 months.”

“It’s provocative work, and it gives us healthy information about how we can help manage our patients from a lifestyle perspective,” he concluded.
 

‘Do not lose weight. Eat until you are full’

In the study, 110 participants with type 2 diabetes and NAFLD, aged 18-78 years, were allocated to the LCHF diet, and 55 were allocated to the low-fat diet for 6 months.

The researchers performed liver biopsies at baseline and 6 months, which were blinded for scoring.  

Participants had ongoing dietitian consultations, with follow-up visits at 3 and 6 months. Compliance was reported continuously through an online food diary platform.

The primary endpoint was change in glycemic control as measured by A1c level over 6 months. The secondary endpoints comprised the proportion of participants with changes in the NAS of at least 2 points over 6 months. Both these measures were compared between the two dietary groups.

The two groups were matched at baseline, with a mean age of 55-57 years, 58% were women, 89% with metabolic syndrome, and a mean BMI 34 kg/m².

In baseline liver disease, F1 level fibrosis was the most common (58%), followed by hepatic steatosis (S1, 47%; S2, 32%), with a median NAS of 3, and 19% had nonalcoholic steatohepatitis.

The special thing about these diets was that participants were told to “not lose weight, but eat until you are full,” remarked Dr. Dalby Hansen.

Those on the LCHF diet consumed an average of 61% energy from fat, 13% from carbohydrates, and 23% from protein, compared with the low-fat diet, which comprised an average of 29% energy from fat, 46% from carbohydrates, and 21% from protein.

“It’s a lot of fat and corresponds to a quarter of a liter of olive oil per day,” said Dr. Dalby Hansen. “They really had to change their mindset a lot, because it was difficult for them to start eating all these fats, especially since we’ve all been told for decades that it isn’t good. But we supported them, and they got into it.”

The LCHF diet was primarily comprised of unsaturated fats – for example, avocado, oil, nuts, and seeds – but also included saturated fats, such as cheese, cream, and high-fat dairy products. Participants were free to eat unsaturated and saturated fats, but Dr. Dalby Hansen and her team advised participants that “good” unsaturated fats were preferable.

“Also, this diet contained vegetables but no bread, no potatoes, no rice, and no pasta. It was low in carbohydrates, below 20%,” she added.
 

Improved glycemic control, reduced liver fat

“We found that the LCHF diet improved diabetes control, it reduced the fat in the liver, and, even though they’re eating as many calories as they were used to until they were full, they lost 5.8% of body weight,” said Dr. Dalby Hansen in reporting the results. Participants in the low-fat group lost only 1.8% of body weight.

However, mean calorie intake dropped in both groups, by –2.2% in the LCHF group and –8.7% in the low-fat group. 

“The LCHF diet improved the primary outcome of A1c by 9.5 mmol/mol, which is similar to some anti-diabetic medications, such as DPP-4 inhibitors and SGLT2 inhibitors,” she said.

The low-fat group reduced A1c by 3.4 mmol/mol, resulting in a between-group difference of 6.1 mmol/mol.

“Upon follow-up of 3 months, after stopping the diets, on average the participants in both groups returned their HbA1c levels to nearly baseline values,” she said. Results were adjusted for weight loss and baseline values.

Both diets also improved the NAS. The proportion of participants who improved their NAS score by 2 or more points was 22% in the LCHF group versus 17% in the low-fat group (P = 0.58). Additionally, in the LCHF group, 70% of participants improved their score by 1 or more points, compared with 49% in the low-fat group and fewer in the LCHF group experienced a worsening of their score (1% vs. 23%, respectively).

One participant on LCHF had high triglycerides of 12 mmol/L after 3 months. Overall, the low-density lipoprotein increased marginally by 0.2 mmol per liter in the high-fat group, said Dr. Dalby Hansen.

Dr. Dalby Hansen noted some limitations. The findings might not be applicable in more severe NAFLD, dietary assessment relied on self-reporting, no food was provided, and participants had to cook themselves. It was also an open-label study because of the nature of the intervention.
 

Some hope for more sustainable dieting

Many diets are difficult to adhere to, remarked Dr. Dalby Hansen. “We thought this [diet] might be easier to comply with in the longer term, and we hope that these results might provide patients with more options.”

She added that most people who started the diet adapted and complied with it. “However, it might not be for everyone, but I think we can say that if people try, and it fits into their lives, then they go for it.”

However, “it is not about going out and eating whatever fat and how much of it you want. It’s important that you cut the carbohydrates too,” she said. “With this approach, we really saw amazing results.”

Dr. Dalby Hansen added that having various diets available, including the LCHF one, meant that as clinicians they could empower patients to take control of their metabolic health.

“We can ask them directly, ‘What would fit into their life?’” she said. “We know that one size does not fit at all, and I believe that if we could engage patients more, then they can take control of their own situation.”

Asked whether these findings were enough to change guidelines, Zobair Younossi, MD, professor and chairman, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., remarked that it was the sugar at work here.

“Dietary fat – it’s not the same as fat in the liver, and this diet has more to do with the sugar levels,” he said.

“I’m always reluctant to take results from a short-term study without long-term follow-up,” Dr. Younossi said. “I want to know will patients live longer, and long-term data are needed for this. Until I have that strong evidence that outcomes are going to change, or at least some sign that the outcome is going to change, it is too early to change any guidelines.”

Dr. Dalby Hansen reports no relevant financial relationships. Dr. Harrison reported financial relationships with numerous pharmaceutical companies. Dr. Younossi reports the following financial relationships: research funds and/or consultant to Abbott, Allergan, Bristol Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk.

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

LONDON – Weight loss, lipid reductions, and “robust improvements” in lipid species associated with nonalcoholic fatty liver disease were achieved in patients who were treated with pemvidutide in a first-in-human, phase 1 clinical trial reported at the annual International Liver Congress, sponsored by the European Association for the Study of the Liver.

The presenting study investigator, Stephen A. Harrison, MD, said that pemvidutide, which is also being developed for the treatment of obesity, appeared to be well tolerated. There were no serious or severe adverse events, and no patient had to discontinue treatment because of side effects.

Sara Freeman/MDedge News

Overall, “pemvidutide represents a promising new agent,” said Dr. Harrison, medical director of Pinnacle Research in San Antonio, Texas.
 

Dual incretin effect

Pemvidutide is a “balanced” dual agonist of glucagon-like peptide 1 (GLP-1) and glucagon, Dr. Harrison explained in his oral abstract.

“With glucagon, we are working to drive energy expenditure up, and with GLP-1, we’re decreasing food intake,” Dr. Harrison said.

What might set pemvidutide apart from other incretins lies within its structure, Dr. Harrison suggested. The structure has two main regions – one with greater GLP-1 specificity and the other with greater glucagon specificity, and these two areas are linked by a propriety technology called a EuPort^™ domain. This is an area which allows the drug to bind to albumin, which increases its serum half-life and enables weekly dosing while slowing its entry into the bloodstream.

“Ultimately, we think that this has impacts, hypothetically, on tolerability and potentially mitigating the need for dose escalation,” said Dr. Harrison.
 

Weight loss results

The phase 1 study Dr. Harrison presented had a randomized, double-blind, placebo-controlled design with single and multiple ascending doses (SAD/MAD) of pemvidutide being tested. He presented data on the MAD phase only, noting that the SAD phase had been used to determine what doses to use in the latter.

Seventy individuals with a body mass index of between 25 and 40 kg/m² were recruited and 34 of these were enrolled in the MAD phase of the study. Three doses of pemvidutide were used, given subcutaneously once a week for 12 weeks: Seven participants received 1.2 mg, 9 were given 1.8 mg, 11 had 2.4 mg, and 7 subjects were treated with placebo. Dr. Harrison noted that there were no caloric restrictions in the trial and no lifestyle modifications or interventions.

The average age of study participants ranged from 27 to 35 years and the mean BMI was 30-31 kg/m² across each group, with their lipid parameters in the upper range of normal.

Clear weight loss reductions were seen across all the pemvidutide groups versus placebo, with the greatest percentage changes in weight loss seen with the two higher doses used. At week 12, there was a 4.9%, 10.3% and 9.0% weight loss in the 1.2-mg, 1.8-mg and 2.4-mg pemvidutide groups compared to 1.6% in placebo-treated individuals.

All patients in the 1.8-mg group achieved a 5% or greater weight loss, Dr. Harrison observed, but there “was a plateauing” effect with the 2.4-mg dose with 89% of patients achieving this target. In comparison, a third of patients on the lowest dose and 20% of those on placebo achieved this target.

The trajectory of weight loss seen in the trial suggests that “the rate of weight loss would continue beyond 12 weeks if we were to continue the therapy” Dr. Harrison said.
 

Lipid changes and liver fat reductions

Levels of serum lipids from baseline to week 12 fell to a greater extent with pemvidutide treatment than with placebo, in the range of –27% for total cholesterol in the two highest dose groups, –25% for LDL-cholesterol for those groups, –37% for triglycerides for the 1.2- and 1.8-mg groups, and reductions in apolipoprotein B were seen.

“We saw an initial decline in HDL [high-density lipoprotein],” Dr. Harrison said, noting that “this is consistent with prior studies looking at rapid weight loss, and over time, this mitigates as you continue to treat at least based on other mechanisms of action or other drugs with similar mechanisms.”

Pemvidutide treatment was also associated with increased lipid oxidation and decreased lipid synthesis, and “there was a robust decrease in lipids implicated in NASH inflammation,” Dr. Harrison pointed out.

Importantly, in five of eight participants who had high levels of liver fat at baseline – defined as a 5% or greater magnetic resonance imaging–derived proton-density-fat-fraction (MRI-PDFF) – showed a decrease to undetectable limits (1.5% or less). This was a greater than 90% reduction in liver fat, Dr. Harrison said. All five patients were in the 1.8-mg and 2.4-mg groups.

As for side effects, these were “predominantly upper GI, with nausea and vomiting.” These were mild in most cases, but he pointed out that five patients treated with the 1.8-mg dose experienced moderate nausea and three experienced moderate vomiting. Mild diarrhea and constipation were also seen in two of patients given this dose but was not reported in any of the other groups.

During the discussion following the presentation, it was pointed out that there was no clear dose-dependent effect considering the 1.8-mg dose seemed to have a stronger effect in some areas than the 2.4-mg dose. That’s a fair point, Dr. Harrison responded, reiterating it was a small study with a short treatment duration, but that there did look like a plateauing effect, “at least in patients with a mean BMI of between 30 and 31.”

Dr. Harrison was asked about potential effects on insulin levels and if that was a worry because, if glucagon is stimulated, it could increase insulin. That in turn might encourage insulin resistance and promote worse outcomes.

“If you look outside of just this program, glucagon agonism has been dosed in a lot of patients over time, and we haven’t seen that,” Dr. Harrison replied. Pemvidutide is an agonist rather than antagonist, so perhaps the [nonalcoholic steatohepatitis]–inducing effects seen before with glucagon antagonism won’t occur, he suggested.

Dr. Harrison disclosed ties to Altimmune (the study sponsor), Akero, Axcella, Bristol Myers Squibb, Cirius, CiVi Biopharma, Conatus, Corcept, CymaBay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, HistoIndex, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, NorthSea, Pfizer, Sagimet, Viking, and 89Bio.

LONDON – Weight loss, lipid reductions, and “robust improvements” in lipid species associated with nonalcoholic fatty liver disease were achieved in patients who were treated with pemvidutide in a first-in-human, phase 1 clinical trial reported at the annual International Liver Congress, sponsored by the European Association for the Study of the Liver.

The presenting study investigator, Stephen A. Harrison, MD, said that pemvidutide, which is also being developed for the treatment of obesity, appeared to be well tolerated. There were no serious or severe adverse events, and no patient had to discontinue treatment because of side effects.

Sara Freeman/MDedge News

Overall, “pemvidutide represents a promising new agent,” said Dr. Harrison, medical director of Pinnacle Research in San Antonio, Texas.
 

Dual incretin effect

Pemvidutide is a “balanced” dual agonist of glucagon-like peptide 1 (GLP-1) and glucagon, Dr. Harrison explained in his oral abstract.

“With glucagon, we are working to drive energy expenditure up, and with GLP-1, we’re decreasing food intake,” Dr. Harrison said.

What might set pemvidutide apart from other incretins lies within its structure, Dr. Harrison suggested. The structure has two main regions – one with greater GLP-1 specificity and the other with greater glucagon specificity, and these two areas are linked by a propriety technology called a EuPort^™ domain. This is an area which allows the drug to bind to albumin, which increases its serum half-life and enables weekly dosing while slowing its entry into the bloodstream.

“Ultimately, we think that this has impacts, hypothetically, on tolerability and potentially mitigating the need for dose escalation,” said Dr. Harrison.
 

Weight loss results

The phase 1 study Dr. Harrison presented had a randomized, double-blind, placebo-controlled design with single and multiple ascending doses (SAD/MAD) of pemvidutide being tested. He presented data on the MAD phase only, noting that the SAD phase had been used to determine what doses to use in the latter.

Seventy individuals with a body mass index of between 25 and 40 kg/m² were recruited and 34 of these were enrolled in the MAD phase of the study. Three doses of pemvidutide were used, given subcutaneously once a week for 12 weeks: Seven participants received 1.2 mg, 9 were given 1.8 mg, 11 had 2.4 mg, and 7 subjects were treated with placebo. Dr. Harrison noted that there were no caloric restrictions in the trial and no lifestyle modifications or interventions.

The average age of study participants ranged from 27 to 35 years and the mean BMI was 30-31 kg/m² across each group, with their lipid parameters in the upper range of normal.

Clear weight loss reductions were seen across all the pemvidutide groups versus placebo, with the greatest percentage changes in weight loss seen with the two higher doses used. At week 12, there was a 4.9%, 10.3% and 9.0% weight loss in the 1.2-mg, 1.8-mg and 2.4-mg pemvidutide groups compared to 1.6% in placebo-treated individuals.

All patients in the 1.8-mg group achieved a 5% or greater weight loss, Dr. Harrison observed, but there “was a plateauing” effect with the 2.4-mg dose with 89% of patients achieving this target. In comparison, a third of patients on the lowest dose and 20% of those on placebo achieved this target.

The trajectory of weight loss seen in the trial suggests that “the rate of weight loss would continue beyond 12 weeks if we were to continue the therapy” Dr. Harrison said.
 

Lipid changes and liver fat reductions

Levels of serum lipids from baseline to week 12 fell to a greater extent with pemvidutide treatment than with placebo, in the range of –27% for total cholesterol in the two highest dose groups, –25% for LDL-cholesterol for those groups, –37% for triglycerides for the 1.2- and 1.8-mg groups, and reductions in apolipoprotein B were seen.

“We saw an initial decline in HDL [high-density lipoprotein],” Dr. Harrison said, noting that “this is consistent with prior studies looking at rapid weight loss, and over time, this mitigates as you continue to treat at least based on other mechanisms of action or other drugs with similar mechanisms.”

Pemvidutide treatment was also associated with increased lipid oxidation and decreased lipid synthesis, and “there was a robust decrease in lipids implicated in NASH inflammation,” Dr. Harrison pointed out.

Importantly, in five of eight participants who had high levels of liver fat at baseline – defined as a 5% or greater magnetic resonance imaging–derived proton-density-fat-fraction (MRI-PDFF) – showed a decrease to undetectable limits (1.5% or less). This was a greater than 90% reduction in liver fat, Dr. Harrison said. All five patients were in the 1.8-mg and 2.4-mg groups.

As for side effects, these were “predominantly upper GI, with nausea and vomiting.” These were mild in most cases, but he pointed out that five patients treated with the 1.8-mg dose experienced moderate nausea and three experienced moderate vomiting. Mild diarrhea and constipation were also seen in two of patients given this dose but was not reported in any of the other groups.

During the discussion following the presentation, it was pointed out that there was no clear dose-dependent effect considering the 1.8-mg dose seemed to have a stronger effect in some areas than the 2.4-mg dose. That’s a fair point, Dr. Harrison responded, reiterating it was a small study with a short treatment duration, but that there did look like a plateauing effect, “at least in patients with a mean BMI of between 30 and 31.”

Dr. Harrison was asked about potential effects on insulin levels and if that was a worry because, if glucagon is stimulated, it could increase insulin. That in turn might encourage insulin resistance and promote worse outcomes.

“If you look outside of just this program, glucagon agonism has been dosed in a lot of patients over time, and we haven’t seen that,” Dr. Harrison replied. Pemvidutide is an agonist rather than antagonist, so perhaps the [nonalcoholic steatohepatitis]–inducing effects seen before with glucagon antagonism won’t occur, he suggested.

Dr. Harrison disclosed ties to Altimmune (the study sponsor), Akero, Axcella, Bristol Myers Squibb, Cirius, CiVi Biopharma, Conatus, Corcept, CymaBay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, HistoIndex, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, NorthSea, Pfizer, Sagimet, Viking, and 89Bio.

LONDON – Weight loss, lipid reductions, and “robust improvements” in lipid species associated with nonalcoholic fatty liver disease were achieved in patients who were treated with pemvidutide in a first-in-human, phase 1 clinical trial reported at the annual International Liver Congress, sponsored by the European Association for the Study of the Liver.

The presenting study investigator, Stephen A. Harrison, MD, said that pemvidutide, which is also being developed for the treatment of obesity, appeared to be well tolerated. There were no serious or severe adverse events, and no patient had to discontinue treatment because of side effects.

Sara Freeman/MDedge News

Overall, “pemvidutide represents a promising new agent,” said Dr. Harrison, medical director of Pinnacle Research in San Antonio, Texas.
 

Dual incretin effect

Pemvidutide is a “balanced” dual agonist of glucagon-like peptide 1 (GLP-1) and glucagon, Dr. Harrison explained in his oral abstract.

“With glucagon, we are working to drive energy expenditure up, and with GLP-1, we’re decreasing food intake,” Dr. Harrison said.

What might set pemvidutide apart from other incretins lies within its structure, Dr. Harrison suggested. The structure has two main regions – one with greater GLP-1 specificity and the other with greater glucagon specificity, and these two areas are linked by a propriety technology called a EuPort^™ domain. This is an area which allows the drug to bind to albumin, which increases its serum half-life and enables weekly dosing while slowing its entry into the bloodstream.

“Ultimately, we think that this has impacts, hypothetically, on tolerability and potentially mitigating the need for dose escalation,” said Dr. Harrison.
 

Weight loss results

The phase 1 study Dr. Harrison presented had a randomized, double-blind, placebo-controlled design with single and multiple ascending doses (SAD/MAD) of pemvidutide being tested. He presented data on the MAD phase only, noting that the SAD phase had been used to determine what doses to use in the latter.

Seventy individuals with a body mass index of between 25 and 40 kg/m² were recruited and 34 of these were enrolled in the MAD phase of the study. Three doses of pemvidutide were used, given subcutaneously once a week for 12 weeks: Seven participants received 1.2 mg, 9 were given 1.8 mg, 11 had 2.4 mg, and 7 subjects were treated with placebo. Dr. Harrison noted that there were no caloric restrictions in the trial and no lifestyle modifications or interventions.

The average age of study participants ranged from 27 to 35 years and the mean BMI was 30-31 kg/m² across each group, with their lipid parameters in the upper range of normal.

Clear weight loss reductions were seen across all the pemvidutide groups versus placebo, with the greatest percentage changes in weight loss seen with the two higher doses used. At week 12, there was a 4.9%, 10.3% and 9.0% weight loss in the 1.2-mg, 1.8-mg and 2.4-mg pemvidutide groups compared to 1.6% in placebo-treated individuals.

All patients in the 1.8-mg group achieved a 5% or greater weight loss, Dr. Harrison observed, but there “was a plateauing” effect with the 2.4-mg dose with 89% of patients achieving this target. In comparison, a third of patients on the lowest dose and 20% of those on placebo achieved this target.

The trajectory of weight loss seen in the trial suggests that “the rate of weight loss would continue beyond 12 weeks if we were to continue the therapy” Dr. Harrison said.
 

Lipid changes and liver fat reductions

Levels of serum lipids from baseline to week 12 fell to a greater extent with pemvidutide treatment than with placebo, in the range of –27% for total cholesterol in the two highest dose groups, –25% for LDL-cholesterol for those groups, –37% for triglycerides for the 1.2- and 1.8-mg groups, and reductions in apolipoprotein B were seen.

“We saw an initial decline in HDL [high-density lipoprotein],” Dr. Harrison said, noting that “this is consistent with prior studies looking at rapid weight loss, and over time, this mitigates as you continue to treat at least based on other mechanisms of action or other drugs with similar mechanisms.”

Pemvidutide treatment was also associated with increased lipid oxidation and decreased lipid synthesis, and “there was a robust decrease in lipids implicated in NASH inflammation,” Dr. Harrison pointed out.

Importantly, in five of eight participants who had high levels of liver fat at baseline – defined as a 5% or greater magnetic resonance imaging–derived proton-density-fat-fraction (MRI-PDFF) – showed a decrease to undetectable limits (1.5% or less). This was a greater than 90% reduction in liver fat, Dr. Harrison said. All five patients were in the 1.8-mg and 2.4-mg groups.

As for side effects, these were “predominantly upper GI, with nausea and vomiting.” These were mild in most cases, but he pointed out that five patients treated with the 1.8-mg dose experienced moderate nausea and three experienced moderate vomiting. Mild diarrhea and constipation were also seen in two of patients given this dose but was not reported in any of the other groups.

During the discussion following the presentation, it was pointed out that there was no clear dose-dependent effect considering the 1.8-mg dose seemed to have a stronger effect in some areas than the 2.4-mg dose. That’s a fair point, Dr. Harrison responded, reiterating it was a small study with a short treatment duration, but that there did look like a plateauing effect, “at least in patients with a mean BMI of between 30 and 31.”

Dr. Harrison was asked about potential effects on insulin levels and if that was a worry because, if glucagon is stimulated, it could increase insulin. That in turn might encourage insulin resistance and promote worse outcomes.

“If you look outside of just this program, glucagon agonism has been dosed in a lot of patients over time, and we haven’t seen that,” Dr. Harrison replied. Pemvidutide is an agonist rather than antagonist, so perhaps the [nonalcoholic steatohepatitis]–inducing effects seen before with glucagon antagonism won’t occur, he suggested.

Dr. Harrison disclosed ties to Altimmune (the study sponsor), Akero, Axcella, Bristol Myers Squibb, Cirius, CiVi Biopharma, Conatus, Corcept, CymaBay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, HistoIndex, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, NorthSea, Pfizer, Sagimet, Viking, and 89Bio.

LONDON – Around the world, nonalcoholic fatty liver disease (NAFLD) has driven an increase in deaths from liver cancer over the past decade, overtaking alcoholic liver disease, hepatitis B, and hepatitis C, according to an analysis of the Global Burden of Disease Study 2019.

A global rise in liver cancer deaths and chronic liver disease reflects changes in underlying health patterns, said Zobair Younossi, MD, MPH, professor and chair, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., who presented the analysis at the International Liver Congress (ILC) 2022.

“NAFLD and NASH [nonalcoholic steatohepatitis] are rapidly becoming the main causes of cirrhosis and liver cancer in the world,” Dr. Younossi told this news organization. “We have known about the increasing prevalence for some time, but now the outcomes in terms of mortality are catching up,” he said.

“The bottom line of this study is that the burden of this disease [NAFLD] is going up, and it will be the most important disease of the next decade or so,” he said, adding that “the largest annual percentage increase in rates of mortality from liver cancer or chronic liver disease cirrhosis is related to NAFLD.”

Specifically, during the decade of 2009-2019, the annual percent change (APC) of +1.33% in the global liver cancer death rate was driven by the fact that the APC for NAFLD was +2.47%. By comparison, the APC for alcoholic liver disease was +1.91%; for hepatitis B, the APC was +0.21%; and for hepatitis C, the APC was +1.12%.

Aleksander Krag, MD, PhD, professor and senior consultant of hepatology and director of Odense Liver Research Centre at SDU and Odense University Hospital, Denmark, who chaired the session in which this presentation was a part, acknowledged the importance of recognizing the contribution of NAFLD to liver cancer mortality.

“Liver diseases are on the rise. They are the fastest rising cause of death in the United Kingdom, faster than heart disease and other cancers. NAFLD in particular is the fastest growing cause of liver cancer, and the leading cause in France and the United States,” he remarked.

Dr. Krag also highlighted the costs of disease management.

“Managing fatty liver disease in Europe is estimated at €35 billion in direct health care, so we need to do something now,” he stressed.

“The global burden of NAFLD is so high that we need both prevention and treatment tools,” Dr. Krag said. “Change to lifestyle is a ‘no-brainer’ and costs governments very little. For the sake of our young people, we need to take this very seriously. At a political level, we can easily implement this, for example, by banning junk food advertisements, but also educating young people and their families. Good drugs will also help.”
 

NAFLD: The liver manifestation of type 2 diabetes

About 25%-30% of the global population have NAFLD, and 3%-5% have NASH. Dr. Younossi highlighted that the U.S. transplant database shows that NAFLD was the second indication for all liver transplants in the country. NAFLD also was a leading cause of liver transplants for patients with hepatocellular carcinoma.

There are around two billion cases of chronic liver disease globally, he said. He noted that over time, there has been an increase in all kinds of liver diseases, as reflected in the annual percent change.

“The global epidemic of obesity and type 2 diabetes is driving the rise in NAFLD, but even among lean people, the prevalence of NAFLD is around 9%,” Dr. Younossi said. “Alongside the eye and kidney complications of diabetes, this is the liver manifestation of type 2 diabetes.”

To assess global liver disease and death, Dr. Younossi and his colleagues turned to the Global Burden of Disease Study, which gathered data from around 7,000 investigators located across 22 different regions of the world, comprising 156 countries.

They calculated the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) in relation to liver cancer and chronic liver disease, including the APC. They linked the data to changes in four liver diseases: NAFLD, alcoholic liver disease, hepatitis B infection, and hepatitis C infection.

The cases of NAFLD reported in the study had been diagnosed by ultrasound or other imaging. Importantly, the prevalence of NAFLD was adjusted for alcohol use in the various national populations, explained Dr. Younossi.

In 2019, they reported that globally, the overall prevalence of liver disease reached 1.69 billion (liver cancer, 0.04%; chronic liver disease, 99.96%), with an incidence of 2.59 million (liver cancer, 20.7%; chronic liver disease, 79.3%), mortality of 1.95 million (liver cancer, 24.8%; chronic liver disease, 75.3%), and DALYs of 58.7 million (liver cancer, 21.3%; chronic liver disease, 78.7%).

Between 2009 and 2019, deaths from liver cancer rose by 27.2%, and deaths from chronic liver disease rose by 10.6%. DALYs from liver cancer rose by 21.9%, and DALYs from chronic liver disease were up by 5.1%.

In contrast to the increase in liver cancer deaths, deaths from chronic liver disease decreased (APC, –0.18%). The decrease was driven by a decrease in hepatitis B (APC, –1.83%). APCs for hepatitis C (+0.37%), alcoholic liver disease (+0.45%), and NAFLD (+1.33%) increased.

“The burden of hepatitis B–related mortality has decreased because we have been so good at vaccinating people,” Dr. Younossi remarked.
 

NAFLD ‘exploding’ in Middle East, North Africa, and East Asia

The increase in NAFLD has been seen in all regions of the world, but a breakdown by region shows that NAFLD is primarily “exploding” with highest prevalence and mortality in the Middle East (mostly Egypt, Iran, and Turkey), North Africa, and East Asia, said Dr. Younossi. In addition, there are large increases in the West and South America.

“We knew that the prevalence was high in the Middle East, but we now know that mortality is also high, so we are connecting these data,” said Dr. Younossi.
 

Awareness lacking

Dr. Younossi pressed the fact that awareness among the general population, primary care providers, and policymakers is very low. “From my perspective, raising awareness of NAFLD is the number one priority, and that is the value of this study.”

He added that more people will become aware as testing becomes more manageable.

“There are some noninvasive tests being developed, so in the future, we won’t have to do liver biopsies to diagnose these patients,” he said. “Currently, there are some excellent treatments being developed.”

“The WHO [World Health Organization] does not mention NAFLD as an important noncommunicable disease, and this too has to change,” Dr. Younossi added.

Dr. Younossi has received research funds and/or has consulted for Abbott, Allergan, Bristol-Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk. Dr. Krag has disclosed no relevant financial relationships.

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

LONDON – Around the world, nonalcoholic fatty liver disease (NAFLD) has driven an increase in deaths from liver cancer over the past decade, overtaking alcoholic liver disease, hepatitis B, and hepatitis C, according to an analysis of the Global Burden of Disease Study 2019.

A global rise in liver cancer deaths and chronic liver disease reflects changes in underlying health patterns, said Zobair Younossi, MD, MPH, professor and chair, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., who presented the analysis at the International Liver Congress (ILC) 2022.

“NAFLD and NASH [nonalcoholic steatohepatitis] are rapidly becoming the main causes of cirrhosis and liver cancer in the world,” Dr. Younossi told this news organization. “We have known about the increasing prevalence for some time, but now the outcomes in terms of mortality are catching up,” he said.

“The bottom line of this study is that the burden of this disease [NAFLD] is going up, and it will be the most important disease of the next decade or so,” he said, adding that “the largest annual percentage increase in rates of mortality from liver cancer or chronic liver disease cirrhosis is related to NAFLD.”

Specifically, during the decade of 2009-2019, the annual percent change (APC) of +1.33% in the global liver cancer death rate was driven by the fact that the APC for NAFLD was +2.47%. By comparison, the APC for alcoholic liver disease was +1.91%; for hepatitis B, the APC was +0.21%; and for hepatitis C, the APC was +1.12%.

Aleksander Krag, MD, PhD, professor and senior consultant of hepatology and director of Odense Liver Research Centre at SDU and Odense University Hospital, Denmark, who chaired the session in which this presentation was a part, acknowledged the importance of recognizing the contribution of NAFLD to liver cancer mortality.

“Liver diseases are on the rise. They are the fastest rising cause of death in the United Kingdom, faster than heart disease and other cancers. NAFLD in particular is the fastest growing cause of liver cancer, and the leading cause in France and the United States,” he remarked.

Dr. Krag also highlighted the costs of disease management.

“Managing fatty liver disease in Europe is estimated at €35 billion in direct health care, so we need to do something now,” he stressed.

“The global burden of NAFLD is so high that we need both prevention and treatment tools,” Dr. Krag said. “Change to lifestyle is a ‘no-brainer’ and costs governments very little. For the sake of our young people, we need to take this very seriously. At a political level, we can easily implement this, for example, by banning junk food advertisements, but also educating young people and their families. Good drugs will also help.”
 

NAFLD: The liver manifestation of type 2 diabetes

About 25%-30% of the global population have NAFLD, and 3%-5% have NASH. Dr. Younossi highlighted that the U.S. transplant database shows that NAFLD was the second indication for all liver transplants in the country. NAFLD also was a leading cause of liver transplants for patients with hepatocellular carcinoma.

There are around two billion cases of chronic liver disease globally, he said. He noted that over time, there has been an increase in all kinds of liver diseases, as reflected in the annual percent change.

“The global epidemic of obesity and type 2 diabetes is driving the rise in NAFLD, but even among lean people, the prevalence of NAFLD is around 9%,” Dr. Younossi said. “Alongside the eye and kidney complications of diabetes, this is the liver manifestation of type 2 diabetes.”

To assess global liver disease and death, Dr. Younossi and his colleagues turned to the Global Burden of Disease Study, which gathered data from around 7,000 investigators located across 22 different regions of the world, comprising 156 countries.

They calculated the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) in relation to liver cancer and chronic liver disease, including the APC. They linked the data to changes in four liver diseases: NAFLD, alcoholic liver disease, hepatitis B infection, and hepatitis C infection.

The cases of NAFLD reported in the study had been diagnosed by ultrasound or other imaging. Importantly, the prevalence of NAFLD was adjusted for alcohol use in the various national populations, explained Dr. Younossi.

In 2019, they reported that globally, the overall prevalence of liver disease reached 1.69 billion (liver cancer, 0.04%; chronic liver disease, 99.96%), with an incidence of 2.59 million (liver cancer, 20.7%; chronic liver disease, 79.3%), mortality of 1.95 million (liver cancer, 24.8%; chronic liver disease, 75.3%), and DALYs of 58.7 million (liver cancer, 21.3%; chronic liver disease, 78.7%).

Between 2009 and 2019, deaths from liver cancer rose by 27.2%, and deaths from chronic liver disease rose by 10.6%. DALYs from liver cancer rose by 21.9%, and DALYs from chronic liver disease were up by 5.1%.

In contrast to the increase in liver cancer deaths, deaths from chronic liver disease decreased (APC, –0.18%). The decrease was driven by a decrease in hepatitis B (APC, –1.83%). APCs for hepatitis C (+0.37%), alcoholic liver disease (+0.45%), and NAFLD (+1.33%) increased.

“The burden of hepatitis B–related mortality has decreased because we have been so good at vaccinating people,” Dr. Younossi remarked.
 

NAFLD ‘exploding’ in Middle East, North Africa, and East Asia

The increase in NAFLD has been seen in all regions of the world, but a breakdown by region shows that NAFLD is primarily “exploding” with highest prevalence and mortality in the Middle East (mostly Egypt, Iran, and Turkey), North Africa, and East Asia, said Dr. Younossi. In addition, there are large increases in the West and South America.

“We knew that the prevalence was high in the Middle East, but we now know that mortality is also high, so we are connecting these data,” said Dr. Younossi.
 

Awareness lacking

Dr. Younossi pressed the fact that awareness among the general population, primary care providers, and policymakers is very low. “From my perspective, raising awareness of NAFLD is the number one priority, and that is the value of this study.”

He added that more people will become aware as testing becomes more manageable.

“There are some noninvasive tests being developed, so in the future, we won’t have to do liver biopsies to diagnose these patients,” he said. “Currently, there are some excellent treatments being developed.”

“The WHO [World Health Organization] does not mention NAFLD as an important noncommunicable disease, and this too has to change,” Dr. Younossi added.

Dr. Younossi has received research funds and/or has consulted for Abbott, Allergan, Bristol-Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk. Dr. Krag has disclosed no relevant financial relationships.

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

LONDON – Around the world, nonalcoholic fatty liver disease (NAFLD) has driven an increase in deaths from liver cancer over the past decade, overtaking alcoholic liver disease, hepatitis B, and hepatitis C, according to an analysis of the Global Burden of Disease Study 2019.

A global rise in liver cancer deaths and chronic liver disease reflects changes in underlying health patterns, said Zobair Younossi, MD, MPH, professor and chair, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., who presented the analysis at the International Liver Congress (ILC) 2022.

“NAFLD and NASH [nonalcoholic steatohepatitis] are rapidly becoming the main causes of cirrhosis and liver cancer in the world,” Dr. Younossi told this news organization. “We have known about the increasing prevalence for some time, but now the outcomes in terms of mortality are catching up,” he said.

“The bottom line of this study is that the burden of this disease [NAFLD] is going up, and it will be the most important disease of the next decade or so,” he said, adding that “the largest annual percentage increase in rates of mortality from liver cancer or chronic liver disease cirrhosis is related to NAFLD.”

Specifically, during the decade of 2009-2019, the annual percent change (APC) of +1.33% in the global liver cancer death rate was driven by the fact that the APC for NAFLD was +2.47%. By comparison, the APC for alcoholic liver disease was +1.91%; for hepatitis B, the APC was +0.21%; and for hepatitis C, the APC was +1.12%.

Aleksander Krag, MD, PhD, professor and senior consultant of hepatology and director of Odense Liver Research Centre at SDU and Odense University Hospital, Denmark, who chaired the session in which this presentation was a part, acknowledged the importance of recognizing the contribution of NAFLD to liver cancer mortality.

“Liver diseases are on the rise. They are the fastest rising cause of death in the United Kingdom, faster than heart disease and other cancers. NAFLD in particular is the fastest growing cause of liver cancer, and the leading cause in France and the United States,” he remarked.

Dr. Krag also highlighted the costs of disease management.

“Managing fatty liver disease in Europe is estimated at €35 billion in direct health care, so we need to do something now,” he stressed.

“The global burden of NAFLD is so high that we need both prevention and treatment tools,” Dr. Krag said. “Change to lifestyle is a ‘no-brainer’ and costs governments very little. For the sake of our young people, we need to take this very seriously. At a political level, we can easily implement this, for example, by banning junk food advertisements, but also educating young people and their families. Good drugs will also help.”
 

NAFLD: The liver manifestation of type 2 diabetes

About 25%-30% of the global population have NAFLD, and 3%-5% have NASH. Dr. Younossi highlighted that the U.S. transplant database shows that NAFLD was the second indication for all liver transplants in the country. NAFLD also was a leading cause of liver transplants for patients with hepatocellular carcinoma.

There are around two billion cases of chronic liver disease globally, he said. He noted that over time, there has been an increase in all kinds of liver diseases, as reflected in the annual percent change.

“The global epidemic of obesity and type 2 diabetes is driving the rise in NAFLD, but even among lean people, the prevalence of NAFLD is around 9%,” Dr. Younossi said. “Alongside the eye and kidney complications of diabetes, this is the liver manifestation of type 2 diabetes.”

To assess global liver disease and death, Dr. Younossi and his colleagues turned to the Global Burden of Disease Study, which gathered data from around 7,000 investigators located across 22 different regions of the world, comprising 156 countries.

They calculated the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) in relation to liver cancer and chronic liver disease, including the APC. They linked the data to changes in four liver diseases: NAFLD, alcoholic liver disease, hepatitis B infection, and hepatitis C infection.

The cases of NAFLD reported in the study had been diagnosed by ultrasound or other imaging. Importantly, the prevalence of NAFLD was adjusted for alcohol use in the various national populations, explained Dr. Younossi.

In 2019, they reported that globally, the overall prevalence of liver disease reached 1.69 billion (liver cancer, 0.04%; chronic liver disease, 99.96%), with an incidence of 2.59 million (liver cancer, 20.7%; chronic liver disease, 79.3%), mortality of 1.95 million (liver cancer, 24.8%; chronic liver disease, 75.3%), and DALYs of 58.7 million (liver cancer, 21.3%; chronic liver disease, 78.7%).

Between 2009 and 2019, deaths from liver cancer rose by 27.2%, and deaths from chronic liver disease rose by 10.6%. DALYs from liver cancer rose by 21.9%, and DALYs from chronic liver disease were up by 5.1%.

In contrast to the increase in liver cancer deaths, deaths from chronic liver disease decreased (APC, –0.18%). The decrease was driven by a decrease in hepatitis B (APC, –1.83%). APCs for hepatitis C (+0.37%), alcoholic liver disease (+0.45%), and NAFLD (+1.33%) increased.

“The burden of hepatitis B–related mortality has decreased because we have been so good at vaccinating people,” Dr. Younossi remarked.
 

NAFLD ‘exploding’ in Middle East, North Africa, and East Asia

The increase in NAFLD has been seen in all regions of the world, but a breakdown by region shows that NAFLD is primarily “exploding” with highest prevalence and mortality in the Middle East (mostly Egypt, Iran, and Turkey), North Africa, and East Asia, said Dr. Younossi. In addition, there are large increases in the West and South America.

“We knew that the prevalence was high in the Middle East, but we now know that mortality is also high, so we are connecting these data,” said Dr. Younossi.
 

Awareness lacking

Dr. Younossi pressed the fact that awareness among the general population, primary care providers, and policymakers is very low. “From my perspective, raising awareness of NAFLD is the number one priority, and that is the value of this study.”

He added that more people will become aware as testing becomes more manageable.

“There are some noninvasive tests being developed, so in the future, we won’t have to do liver biopsies to diagnose these patients,” he said. “Currently, there are some excellent treatments being developed.”

“The WHO [World Health Organization] does not mention NAFLD as an important noncommunicable disease, and this too has to change,” Dr. Younossi added.

Dr. Younossi has received research funds and/or has consulted for Abbott, Allergan, Bristol-Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk. Dr. Krag has disclosed no relevant financial relationships.

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

Pregnancy termination for medical reasons had been part of the fabric of everyday health care in the United States since the Supreme Court’s 1973 Roe v. Wade decision, which the current high court overturned in a ruling announced on June 24.

That means many clinicians across specialties are entering uncharted territory with the country’s new patchwork of abortion legality. Some specialties, cardiology among them, may feel the impact more than others.

javi_indy/ Thinkstock

“Unfortunately,” Dr. Haythe said, “many of the states that are going to make or have made abortion illegal are not providing that kind of preconception counseling or good prenatal care to women.”

Cardiologists can provide such counseling to their female patients of childbearing age who have high-risk cardiac conditions, “but not everybody knows that they have a heart problem when they get pregnant, and not everybody is getting screened for heart problems when they’re of childbearing age,” Dr. Haythe said.

“Sometimes it’s not clear whether the problems could have been picked up until a woman is pregnant and has started to have symptoms.” For example, “a lot of women with poor access to health care have rheumatic heart disease. They may have no idea that they have severe aortic stenosis, and it’s not until their second trimester that they start to feel really short of breath.” Often that can be treated in the cath lab, “but again, that’s putting the woman and the baby at risk.”

Cardiologists in states where abortion is illegal will still present the option to their patients with high-risk pregnancies, noted Dr. Haythe. But the conversation may sound something like, “you are at very high risk, termination of the pregnancy takes that risk away, but you’ll have to find a state where it’s legal to do that.”

Dr. Park said such a situation, when abortion is recommended but locally unavailable, is much like any other in cardiology for which the patient may want a second opinion. If a center “doesn’t have the capability or the technology to offer a certain treatment, the patient can opt to seek another opinion at another center,” she said. “Patients will often travel out of state to get the care they need.”

A requirement for out-of-state travel to obtain abortions is likely to worsen socioeconomic disparities in health care, Dr. Bond observed, “because we know that those who are low-income won’t be able to afford that travel.”

Dr. Bond is cosignatory on a statement from the Association of Black Cardiologists (ABC) responding to the high court’s ruling in Dobbs v. Jackson. “This decision will isolate the poor, socioeconomically disadvantaged, and minority populations specifically, widening the already large gaps in health care for our most vulnerable communities,” it states.

“The loss of broad protections supporting the medical and often lifesaving procedure of abortions is likely to have a real impact on the maternal mortality rate, especially in those with congenital and/or acquired cardiovascular conditions where evidence-based guidelines advise at times on termination of such high-risk pregnancies.”

The ABC, it states, “believes that every woman, and every person, should be afforded the right to safe, accessible, legal, timely, patient-centered, equitable, and affordable health care.”

The American College of Cardiology (ACC) released a statement on the matter June 24, signed by its president, Edward T.A. Fry, MD, along with five former ACC presidents. “While the ACC has no official policy on abortion, clinical practice guidelines and other clinical guidance tools address the dangers of pregnancy in certain patient populations at higher risk of death or serious cardiac events.”

The college, it states, is “deeply concerned about the potential implications of the Supreme Court decision regarding Roe vs. Wade on the ability of patients and clinicians to engage in important shared discussions about maternal health, or to remove previously available health care options.”

Dr. Bond proposed that a “vocal stance” from medical societies involved in women’s health, “perhaps even a collective stance from our cardiovascular societies and our obstetrics societies,” would also perhaps reach “the masses of doctors in private practice who are dealing with these patients.”

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

Pregnancy termination for medical reasons had been part of the fabric of everyday health care in the United States since the Supreme Court’s 1973 Roe v. Wade decision, which the current high court overturned in a ruling announced on June 24.

That means many clinicians across specialties are entering uncharted territory with the country’s new patchwork of abortion legality. Some specialties, cardiology among them, may feel the impact more than others.

javi_indy/ Thinkstock

“Unfortunately,” Dr. Haythe said, “many of the states that are going to make or have made abortion illegal are not providing that kind of preconception counseling or good prenatal care to women.”

Cardiologists can provide such counseling to their female patients of childbearing age who have high-risk cardiac conditions, “but not everybody knows that they have a heart problem when they get pregnant, and not everybody is getting screened for heart problems when they’re of childbearing age,” Dr. Haythe said.

“Sometimes it’s not clear whether the problems could have been picked up until a woman is pregnant and has started to have symptoms.” For example, “a lot of women with poor access to health care have rheumatic heart disease. They may have no idea that they have severe aortic stenosis, and it’s not until their second trimester that they start to feel really short of breath.” Often that can be treated in the cath lab, “but again, that’s putting the woman and the baby at risk.”

Cardiologists in states where abortion is illegal will still present the option to their patients with high-risk pregnancies, noted Dr. Haythe. But the conversation may sound something like, “you are at very high risk, termination of the pregnancy takes that risk away, but you’ll have to find a state where it’s legal to do that.”

Dr. Park said such a situation, when abortion is recommended but locally unavailable, is much like any other in cardiology for which the patient may want a second opinion. If a center “doesn’t have the capability or the technology to offer a certain treatment, the patient can opt to seek another opinion at another center,” she said. “Patients will often travel out of state to get the care they need.”

A requirement for out-of-state travel to obtain abortions is likely to worsen socioeconomic disparities in health care, Dr. Bond observed, “because we know that those who are low-income won’t be able to afford that travel.”

Dr. Bond is cosignatory on a statement from the Association of Black Cardiologists (ABC) responding to the high court’s ruling in Dobbs v. Jackson. “This decision will isolate the poor, socioeconomically disadvantaged, and minority populations specifically, widening the already large gaps in health care for our most vulnerable communities,” it states.

“The loss of broad protections supporting the medical and often lifesaving procedure of abortions is likely to have a real impact on the maternal mortality rate, especially in those with congenital and/or acquired cardiovascular conditions where evidence-based guidelines advise at times on termination of such high-risk pregnancies.”

The ABC, it states, “believes that every woman, and every person, should be afforded the right to safe, accessible, legal, timely, patient-centered, equitable, and affordable health care.”

The American College of Cardiology (ACC) released a statement on the matter June 24, signed by its president, Edward T.A. Fry, MD, along with five former ACC presidents. “While the ACC has no official policy on abortion, clinical practice guidelines and other clinical guidance tools address the dangers of pregnancy in certain patient populations at higher risk of death or serious cardiac events.”

The college, it states, is “deeply concerned about the potential implications of the Supreme Court decision regarding Roe vs. Wade on the ability of patients and clinicians to engage in important shared discussions about maternal health, or to remove previously available health care options.”

Dr. Bond proposed that a “vocal stance” from medical societies involved in women’s health, “perhaps even a collective stance from our cardiovascular societies and our obstetrics societies,” would also perhaps reach “the masses of doctors in private practice who are dealing with these patients.”

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

Pregnancy termination for medical reasons had been part of the fabric of everyday health care in the United States since the Supreme Court’s 1973 Roe v. Wade decision, which the current high court overturned in a ruling announced on June 24.

That means many clinicians across specialties are entering uncharted territory with the country’s new patchwork of abortion legality. Some specialties, cardiology among them, may feel the impact more than others.

javi_indy/ Thinkstock

“Unfortunately,” Dr. Haythe said, “many of the states that are going to make or have made abortion illegal are not providing that kind of preconception counseling or good prenatal care to women.”

Cardiologists can provide such counseling to their female patients of childbearing age who have high-risk cardiac conditions, “but not everybody knows that they have a heart problem when they get pregnant, and not everybody is getting screened for heart problems when they’re of childbearing age,” Dr. Haythe said.

“Sometimes it’s not clear whether the problems could have been picked up until a woman is pregnant and has started to have symptoms.” For example, “a lot of women with poor access to health care have rheumatic heart disease. They may have no idea that they have severe aortic stenosis, and it’s not until their second trimester that they start to feel really short of breath.” Often that can be treated in the cath lab, “but again, that’s putting the woman and the baby at risk.”

Cardiologists in states where abortion is illegal will still present the option to their patients with high-risk pregnancies, noted Dr. Haythe. But the conversation may sound something like, “you are at very high risk, termination of the pregnancy takes that risk away, but you’ll have to find a state where it’s legal to do that.”

Dr. Park said such a situation, when abortion is recommended but locally unavailable, is much like any other in cardiology for which the patient may want a second opinion. If a center “doesn’t have the capability or the technology to offer a certain treatment, the patient can opt to seek another opinion at another center,” she said. “Patients will often travel out of state to get the care they need.”

A requirement for out-of-state travel to obtain abortions is likely to worsen socioeconomic disparities in health care, Dr. Bond observed, “because we know that those who are low-income won’t be able to afford that travel.”

Dr. Bond is cosignatory on a statement from the Association of Black Cardiologists (ABC) responding to the high court’s ruling in Dobbs v. Jackson. “This decision will isolate the poor, socioeconomically disadvantaged, and minority populations specifically, widening the already large gaps in health care for our most vulnerable communities,” it states.

“The loss of broad protections supporting the medical and often lifesaving procedure of abortions is likely to have a real impact on the maternal mortality rate, especially in those with congenital and/or acquired cardiovascular conditions where evidence-based guidelines advise at times on termination of such high-risk pregnancies.”

The ABC, it states, “believes that every woman, and every person, should be afforded the right to safe, accessible, legal, timely, patient-centered, equitable, and affordable health care.”

The American College of Cardiology (ACC) released a statement on the matter June 24, signed by its president, Edward T.A. Fry, MD, along with five former ACC presidents. “While the ACC has no official policy on abortion, clinical practice guidelines and other clinical guidance tools address the dangers of pregnancy in certain patient populations at higher risk of death or serious cardiac events.”

The college, it states, is “deeply concerned about the potential implications of the Supreme Court decision regarding Roe vs. Wade on the ability of patients and clinicians to engage in important shared discussions about maternal health, or to remove previously available health care options.”

Dr. Bond proposed that a “vocal stance” from medical societies involved in women’s health, “perhaps even a collective stance from our cardiovascular societies and our obstetrics societies,” would also perhaps reach “the masses of doctors in private practice who are dealing with these patients.”

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

There is not enough evidence to recommend for or against taking most vitamin and mineral supplements to prevent heart disease, stroke, and cancer, a new report by the U.S. Preventive Services Task Force concludes.

However, there are two vitamins – vitamin E and beta-carotene – that the task force recommends against for the prevention of heart disease, stroke, and cancer. Evidence shows that there is no benefit to taking vitamin E and that beta-carotene can increase the risk for lung cancer in people already at risk, such as smokers and those with occupational exposure to asbestos.

sodapix/thinkstockphotos.com

These are the main findings of the USPSTF’s final recommendation statement on vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer. The statement was published in JAMA.

“This is essentially the same recommendation that the task force made in 2014,” USPSTF member John Wong, MD, professor of medicine at Tufts University, Boston, said in an interview.

“We recognize that over half of people in the U.S. take a vitamin supplement of some sort every day and 30% take a vitamin/mineral combination. We wanted to review the evidence again to see if there was any benefit in terms of reducing the risk of cardiovascular disease or cancer or increasing the chances of living longer,” Dr. Wong explained.

“We looked hard for evidence, reviewing 84 studies in total. But we did not find sufficient evidence in favor of taking or not taking vitamins, with the two exceptions of beta-carotene and vitamin E, which we recommend against taking,” he noted.

Although there is evidence of some harm with beta-carotene, the main reason behind the recommendation against taking vitamin E is the consistent evidence of no benefit, Dr. Wong explained.

“While the evidence for some other vitamins is conflicting, there is more consistent evidence of no benefit for vitamin E,” he said.

The bulk of new evidence since the last review in 2014 was predominately for vitamin D supplementation, but despite the inclusion of 32 new randomized, controlled trials and two cohort studies, pooled estimates for all-cause mortality were similar to those in the previous review, with confidence intervals only slightly crossing 1, and point estimates that suggest at most a very small benefit, the task force noted.

“Apart from beta-carotene and vitamin E, after reviewing 84 studies – including 78 randomized controlled trials – in over a million patients, we can find no clear demonstration of benefit or harm of taking vitamins in terms of developing cardiovascular disease or cancer or the effect on all-cause mortality. So, we don’t know whether people should take vitamins or not, and we need more research,” Dr. Wong added.

On the use of a multivitamin supplement, Dr. Wong noted that the complete body of evidence did not find any benefit of taking a multivitamin on cardiovascular or cancer mortality. But there was a small reduction in cancer incidence.

However, he pointed out that the three studies that suggested a reduction in cancer incidence all had issues regarding generalizability.

“The recently published COSMOS trial had an average follow-up of only 3.6 years, which isn’t really long enough when thinking about the prevention of cancer, one of the other studies only used antioxidants, and the third study was conducted only in U.S. male physicians. So those limitations regarding generalizability limited our confidence in making recommendations about multivitamins,” Dr. Wong explained.

But he noted that the task force did not find any significant harms from taking multivitamins.

“There are possible harms from taking high doses of vitamin A and vitamin D, but generally the doses contained in a multivitamin tablet are lower than these. But if the goal for taking a multivitamin is to lower your risk of cancer or cardiovascular disease, we didn’t find sufficient evidence to be able to make a recommendation,” he said.

Asked what he would say to all the people currently taking multivitamins, Dr. Wong responded that he would advise them to have a conversation with a trusted health care professional about their particular circumstances.

“Our statement has quite a narrow focus. It is directed toward community-dwelling, nonpregnant adults. This recommendation does not apply to children, persons who are pregnant or may become pregnant, or persons who are chronically ill, are hospitalized, or have a known nutritional deficiency,” he commented.
 

‘Any benefit likely to be small’

In an editorial accompanying the publication of the USPSTF statement, Jenny Jia, MD; Natalie Cameron, MD; and Jeffrey Linder, MD – all from Northwestern University, Chicago – noted that the current evidence base includes 52 additional studies not available when the last USPSTF recommendation on this topic was published in 2014.

The editorialists pointed out that for multivitamins, proving the absence of a benefit is challenging, but at best, current evidence suggests that any potential benefits of a multivitamin to reduce mortality are likely to be small.

They gave an example of a healthy 65-year-old woman with a 9-year estimated mortality risk of about 8%, and note that taking a multivitamin for 5-10 years might reduce her estimated mortality risk to 7.5% (based on an odds ratio of 0.94).

“In addition to showing small potential benefit, this estimate is based on imperfect evidence, is imprecise, and is highly sensitive to how the data are interpreted and analyzed,” they said.

The editorialists recommended that lifestyle counseling to prevent chronic diseases should continue to focus on evidence-based approaches, including balanced diets that are high in fruits and vegetables and physical activity.

However, they added that healthy eating can be a challenge when the American industrialized food system does not prioritize health, and healthy foods tend to be more expensive, leading to access problems and food insecurity.

The editorialists suggested that, rather than focusing money, time, and attention on supplements, it would be better to emphasize lower-risk, higher-benefit activities, such as getting exercise, maintaining a healthy weight, and avoiding smoking, in addition to following a healthful diet.
 

Possible benefit for older adults?

Commenting on the USPSTF statement, JoAnn Manson, MD, chief, division of preventive medicine, Brigham and Women’s Hospital, Boston, who led the recent COSMOS study, said that vitamin and mineral supplements should not be perceived as a substitute for a healthful diet.

“The emphasis needs to be on getting nutritional needs from a healthy diet that is high in plant-based and whole foods that don’t strip the vitamins and minerals through excessive processing,” she said. “Although it’s easier to pop a pill each day than to focus on healthful dietary patterns, the mixture of phytochemicals, fiber, and all the other nutrients in actual foods just can’t be packaged into a pill. Also, vitamins and minerals tend to be better absorbed from food than from supplements and healthy foods can replace calories from less healthy foods, such as red meat and processed foods.”

However, Dr. Manson noted that the evidence is mounting that taking a tablet containing moderate doses of a wide range of vitamins and minerals is safe and may actually have benefits for some people.

She pointed out that the COSMOS and COSMOS-Mind studies showed benefits of multivitamins in slowing cognitive decline in older adults, but the findings need to be replicated.  

“The USPSTF did see a statistically significant 7% reduction in cancer with multivitamins in their meta-analysis of four randomized trials and a borderline 6% reduction in all-cause mortality,” she noted. “Plus, multivitamins have been shown to be quite safe in several large and long-term randomized trials. I agree the evidence is not sufficient to make a blanket recommendation for everyone to take multivitamins, but the evidence is mounting that this would be a prudent approach for many older adults,” Dr. Manson said.

“Many people view multivitamins as a form of insurance, as a way to hedge their bets,” she added. “Although this is a rational approach, especially for those who have concerns about the adequacy of their diet, it’s important that this mindset not lead to complacency about following healthy lifestyle practices, including healthy eating, regular physical activity, not smoking, making sure that blood pressure and cholesterol levels are well controlled, and many other practices that critically important for health but are more challenging than simply popping a pill each day.”

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

There is not enough evidence to recommend for or against taking most vitamin and mineral supplements to prevent heart disease, stroke, and cancer, a new report by the U.S. Preventive Services Task Force concludes.

However, there are two vitamins – vitamin E and beta-carotene – that the task force recommends against for the prevention of heart disease, stroke, and cancer. Evidence shows that there is no benefit to taking vitamin E and that beta-carotene can increase the risk for lung cancer in people already at risk, such as smokers and those with occupational exposure to asbestos.

sodapix/thinkstockphotos.com

These are the main findings of the USPSTF’s final recommendation statement on vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer. The statement was published in JAMA.

“This is essentially the same recommendation that the task force made in 2014,” USPSTF member John Wong, MD, professor of medicine at Tufts University, Boston, said in an interview.

“We recognize that over half of people in the U.S. take a vitamin supplement of some sort every day and 30% take a vitamin/mineral combination. We wanted to review the evidence again to see if there was any benefit in terms of reducing the risk of cardiovascular disease or cancer or increasing the chances of living longer,” Dr. Wong explained.

“We looked hard for evidence, reviewing 84 studies in total. But we did not find sufficient evidence in favor of taking or not taking vitamins, with the two exceptions of beta-carotene and vitamin E, which we recommend against taking,” he noted.

Although there is evidence of some harm with beta-carotene, the main reason behind the recommendation against taking vitamin E is the consistent evidence of no benefit, Dr. Wong explained.

“While the evidence for some other vitamins is conflicting, there is more consistent evidence of no benefit for vitamin E,” he said.

The bulk of new evidence since the last review in 2014 was predominately for vitamin D supplementation, but despite the inclusion of 32 new randomized, controlled trials and two cohort studies, pooled estimates for all-cause mortality were similar to those in the previous review, with confidence intervals only slightly crossing 1, and point estimates that suggest at most a very small benefit, the task force noted.

“Apart from beta-carotene and vitamin E, after reviewing 84 studies – including 78 randomized controlled trials – in over a million patients, we can find no clear demonstration of benefit or harm of taking vitamins in terms of developing cardiovascular disease or cancer or the effect on all-cause mortality. So, we don’t know whether people should take vitamins or not, and we need more research,” Dr. Wong added.

On the use of a multivitamin supplement, Dr. Wong noted that the complete body of evidence did not find any benefit of taking a multivitamin on cardiovascular or cancer mortality. But there was a small reduction in cancer incidence.

However, he pointed out that the three studies that suggested a reduction in cancer incidence all had issues regarding generalizability.

“The recently published COSMOS trial had an average follow-up of only 3.6 years, which isn’t really long enough when thinking about the prevention of cancer, one of the other studies only used antioxidants, and the third study was conducted only in U.S. male physicians. So those limitations regarding generalizability limited our confidence in making recommendations about multivitamins,” Dr. Wong explained.

But he noted that the task force did not find any significant harms from taking multivitamins.

“There are possible harms from taking high doses of vitamin A and vitamin D, but generally the doses contained in a multivitamin tablet are lower than these. But if the goal for taking a multivitamin is to lower your risk of cancer or cardiovascular disease, we didn’t find sufficient evidence to be able to make a recommendation,” he said.

Asked what he would say to all the people currently taking multivitamins, Dr. Wong responded that he would advise them to have a conversation with a trusted health care professional about their particular circumstances.

“Our statement has quite a narrow focus. It is directed toward community-dwelling, nonpregnant adults. This recommendation does not apply to children, persons who are pregnant or may become pregnant, or persons who are chronically ill, are hospitalized, or have a known nutritional deficiency,” he commented.
 

‘Any benefit likely to be small’

In an editorial accompanying the publication of the USPSTF statement, Jenny Jia, MD; Natalie Cameron, MD; and Jeffrey Linder, MD – all from Northwestern University, Chicago – noted that the current evidence base includes 52 additional studies not available when the last USPSTF recommendation on this topic was published in 2014.

The editorialists pointed out that for multivitamins, proving the absence of a benefit is challenging, but at best, current evidence suggests that any potential benefits of a multivitamin to reduce mortality are likely to be small.

They gave an example of a healthy 65-year-old woman with a 9-year estimated mortality risk of about 8%, and note that taking a multivitamin for 5-10 years might reduce her estimated mortality risk to 7.5% (based on an odds ratio of 0.94).

“In addition to showing small potential benefit, this estimate is based on imperfect evidence, is imprecise, and is highly sensitive to how the data are interpreted and analyzed,” they said.

The editorialists recommended that lifestyle counseling to prevent chronic diseases should continue to focus on evidence-based approaches, including balanced diets that are high in fruits and vegetables and physical activity.

However, they added that healthy eating can be a challenge when the American industrialized food system does not prioritize health, and healthy foods tend to be more expensive, leading to access problems and food insecurity.

The editorialists suggested that, rather than focusing money, time, and attention on supplements, it would be better to emphasize lower-risk, higher-benefit activities, such as getting exercise, maintaining a healthy weight, and avoiding smoking, in addition to following a healthful diet.
 

Possible benefit for older adults?

Commenting on the USPSTF statement, JoAnn Manson, MD, chief, division of preventive medicine, Brigham and Women’s Hospital, Boston, who led the recent COSMOS study, said that vitamin and mineral supplements should not be perceived as a substitute for a healthful diet.

“The emphasis needs to be on getting nutritional needs from a healthy diet that is high in plant-based and whole foods that don’t strip the vitamins and minerals through excessive processing,” she said. “Although it’s easier to pop a pill each day than to focus on healthful dietary patterns, the mixture of phytochemicals, fiber, and all the other nutrients in actual foods just can’t be packaged into a pill. Also, vitamins and minerals tend to be better absorbed from food than from supplements and healthy foods can replace calories from less healthy foods, such as red meat and processed foods.”

However, Dr. Manson noted that the evidence is mounting that taking a tablet containing moderate doses of a wide range of vitamins and minerals is safe and may actually have benefits for some people.

She pointed out that the COSMOS and COSMOS-Mind studies showed benefits of multivitamins in slowing cognitive decline in older adults, but the findings need to be replicated.  

“The USPSTF did see a statistically significant 7% reduction in cancer with multivitamins in their meta-analysis of four randomized trials and a borderline 6% reduction in all-cause mortality,” she noted. “Plus, multivitamins have been shown to be quite safe in several large and long-term randomized trials. I agree the evidence is not sufficient to make a blanket recommendation for everyone to take multivitamins, but the evidence is mounting that this would be a prudent approach for many older adults,” Dr. Manson said.

“Many people view multivitamins as a form of insurance, as a way to hedge their bets,” she added. “Although this is a rational approach, especially for those who have concerns about the adequacy of their diet, it’s important that this mindset not lead to complacency about following healthy lifestyle practices, including healthy eating, regular physical activity, not smoking, making sure that blood pressure and cholesterol levels are well controlled, and many other practices that critically important for health but are more challenging than simply popping a pill each day.”

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

There is not enough evidence to recommend for or against taking most vitamin and mineral supplements to prevent heart disease, stroke, and cancer, a new report by the U.S. Preventive Services Task Force concludes.

However, there are two vitamins – vitamin E and beta-carotene – that the task force recommends against for the prevention of heart disease, stroke, and cancer. Evidence shows that there is no benefit to taking vitamin E and that beta-carotene can increase the risk for lung cancer in people already at risk, such as smokers and those with occupational exposure to asbestos.

sodapix/thinkstockphotos.com

These are the main findings of the USPSTF’s final recommendation statement on vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer. The statement was published in JAMA.

“This is essentially the same recommendation that the task force made in 2014,” USPSTF member John Wong, MD, professor of medicine at Tufts University, Boston, said in an interview.

“We recognize that over half of people in the U.S. take a vitamin supplement of some sort every day and 30% take a vitamin/mineral combination. We wanted to review the evidence again to see if there was any benefit in terms of reducing the risk of cardiovascular disease or cancer or increasing the chances of living longer,” Dr. Wong explained.

“We looked hard for evidence, reviewing 84 studies in total. But we did not find sufficient evidence in favor of taking or not taking vitamins, with the two exceptions of beta-carotene and vitamin E, which we recommend against taking,” he noted.

Although there is evidence of some harm with beta-carotene, the main reason behind the recommendation against taking vitamin E is the consistent evidence of no benefit, Dr. Wong explained.

“While the evidence for some other vitamins is conflicting, there is more consistent evidence of no benefit for vitamin E,” he said.

The bulk of new evidence since the last review in 2014 was predominately for vitamin D supplementation, but despite the inclusion of 32 new randomized, controlled trials and two cohort studies, pooled estimates for all-cause mortality were similar to those in the previous review, with confidence intervals only slightly crossing 1, and point estimates that suggest at most a very small benefit, the task force noted.

“Apart from beta-carotene and vitamin E, after reviewing 84 studies – including 78 randomized controlled trials – in over a million patients, we can find no clear demonstration of benefit or harm of taking vitamins in terms of developing cardiovascular disease or cancer or the effect on all-cause mortality. So, we don’t know whether people should take vitamins or not, and we need more research,” Dr. Wong added.

On the use of a multivitamin supplement, Dr. Wong noted that the complete body of evidence did not find any benefit of taking a multivitamin on cardiovascular or cancer mortality. But there was a small reduction in cancer incidence.

However, he pointed out that the three studies that suggested a reduction in cancer incidence all had issues regarding generalizability.

“The recently published COSMOS trial had an average follow-up of only 3.6 years, which isn’t really long enough when thinking about the prevention of cancer, one of the other studies only used antioxidants, and the third study was conducted only in U.S. male physicians. So those limitations regarding generalizability limited our confidence in making recommendations about multivitamins,” Dr. Wong explained.

But he noted that the task force did not find any significant harms from taking multivitamins.

“There are possible harms from taking high doses of vitamin A and vitamin D, but generally the doses contained in a multivitamin tablet are lower than these. But if the goal for taking a multivitamin is to lower your risk of cancer or cardiovascular disease, we didn’t find sufficient evidence to be able to make a recommendation,” he said.

Asked what he would say to all the people currently taking multivitamins, Dr. Wong responded that he would advise them to have a conversation with a trusted health care professional about their particular circumstances.

“Our statement has quite a narrow focus. It is directed toward community-dwelling, nonpregnant adults. This recommendation does not apply to children, persons who are pregnant or may become pregnant, or persons who are chronically ill, are hospitalized, or have a known nutritional deficiency,” he commented.
 

‘Any benefit likely to be small’

In an editorial accompanying the publication of the USPSTF statement, Jenny Jia, MD; Natalie Cameron, MD; and Jeffrey Linder, MD – all from Northwestern University, Chicago – noted that the current evidence base includes 52 additional studies not available when the last USPSTF recommendation on this topic was published in 2014.

The editorialists pointed out that for multivitamins, proving the absence of a benefit is challenging, but at best, current evidence suggests that any potential benefits of a multivitamin to reduce mortality are likely to be small.

They gave an example of a healthy 65-year-old woman with a 9-year estimated mortality risk of about 8%, and note that taking a multivitamin for 5-10 years might reduce her estimated mortality risk to 7.5% (based on an odds ratio of 0.94).

“In addition to showing small potential benefit, this estimate is based on imperfect evidence, is imprecise, and is highly sensitive to how the data are interpreted and analyzed,” they said.

The editorialists recommended that lifestyle counseling to prevent chronic diseases should continue to focus on evidence-based approaches, including balanced diets that are high in fruits and vegetables and physical activity.

However, they added that healthy eating can be a challenge when the American industrialized food system does not prioritize health, and healthy foods tend to be more expensive, leading to access problems and food insecurity.

The editorialists suggested that, rather than focusing money, time, and attention on supplements, it would be better to emphasize lower-risk, higher-benefit activities, such as getting exercise, maintaining a healthy weight, and avoiding smoking, in addition to following a healthful diet.
 

Possible benefit for older adults?

Commenting on the USPSTF statement, JoAnn Manson, MD, chief, division of preventive medicine, Brigham and Women’s Hospital, Boston, who led the recent COSMOS study, said that vitamin and mineral supplements should not be perceived as a substitute for a healthful diet.

“The emphasis needs to be on getting nutritional needs from a healthy diet that is high in plant-based and whole foods that don’t strip the vitamins and minerals through excessive processing,” she said. “Although it’s easier to pop a pill each day than to focus on healthful dietary patterns, the mixture of phytochemicals, fiber, and all the other nutrients in actual foods just can’t be packaged into a pill. Also, vitamins and minerals tend to be better absorbed from food than from supplements and healthy foods can replace calories from less healthy foods, such as red meat and processed foods.”

However, Dr. Manson noted that the evidence is mounting that taking a tablet containing moderate doses of a wide range of vitamins and minerals is safe and may actually have benefits for some people.

She pointed out that the COSMOS and COSMOS-Mind studies showed benefits of multivitamins in slowing cognitive decline in older adults, but the findings need to be replicated.  

“The USPSTF did see a statistically significant 7% reduction in cancer with multivitamins in their meta-analysis of four randomized trials and a borderline 6% reduction in all-cause mortality,” she noted. “Plus, multivitamins have been shown to be quite safe in several large and long-term randomized trials. I agree the evidence is not sufficient to make a blanket recommendation for everyone to take multivitamins, but the evidence is mounting that this would be a prudent approach for many older adults,” Dr. Manson said.

“Many people view multivitamins as a form of insurance, as a way to hedge their bets,” she added. “Although this is a rational approach, especially for those who have concerns about the adequacy of their diet, it’s important that this mindset not lead to complacency about following healthy lifestyle practices, including healthy eating, regular physical activity, not smoking, making sure that blood pressure and cholesterol levels are well controlled, and many other practices that critically important for health but are more challenging than simply popping a pill each day.”

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

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

Adding remnant cholesterol to guideline prediction models should improve the identification of individuals who would benefit the most from statin treatment for the primary prevention of heart disease, a new study suggests.

The study, which followed almost 42,000 Danish individuals without a history of ischemic cardiovascular disease, diabetes, or statin use for more than 10 years, found that elevated remnant cholesterol appropriately reclassified up to 40% of those who later experienced myocardial infarction and ischemic heart disease.

“The clinical implications of our study include that doctors and patients should be aware of remnant cholesterol levels to prevent future risk of MI and ischemic heart disease,” the authors conclude.

They suggest that the development of a cardiovascular risk algorithm, including remnant cholesterol together with LDL cholesterol, would help to better identify high-risk individuals who could be candidates for statins in a primary prevention setting.

They note that physicians are encouraged to evaluate non-HDL cholesterol and/or apolipoprotein B rather than LDL cholesterol and certainly not yet remnant cholesterol, possibly because of the limited availability of remnant cholesterol values in some parts of the world.

However, they point out that remnant cholesterol can be calculated with a standard lipid profile without additional cost, which is currently already the standard procedure in the greater Copenhagen area.

“This means that the use of remnant cholesterol is easy to introduce into daily clinical practice,” they say.

The study was published online in the Journal of the American College of Cardiology.

The authors, Takahito Doi, MD, Anne Langsted, MD, and Børge Nordestgaard, from Copenhagen University Hospital, Denmark, explain that remnant cholesterol is total cholesterol minus LDL-cholesterol minus HDL-cholesterol and includes the cholesterol content of the triglyceride-rich very-low-density lipoproteins, intermediate-density lipoproteins, and chylomicron remnants in the nonfasting state.

“When these particles enter the arterial wall, they are taken up by macrophages to produce foam cells, and therefore elevated remnant cholesterol likely enhance accumulation of cholesterol in the arterial wall, leading to progression of atherosclerosis and in consequence ischemic heart disease,” they note.  

They point out that most guidelines for assessment of the 10-year risk of ischemic heart and atherosclerotic cardiovascular disease include levels of total and HDL cholesterol, but remnant cholesterol levels are not included.

They conducted the current study to investigate whether elevated remnant cholesterol would lead to appropriate reclassification of individuals who later experienced MI or ischemic heart disease.

The researchers analyzed data from the Copenhagen General Population Study, which recruited individuals from the White Danish general population from 2003-2015 and followed them until 2018. Information on lifestyle, health, and medication, including statin therapy, was obtained through a questionnaire, and participants underwent physical examinations and had nonfasting blood samples drawn for biochemical measurements.

For the current study, they included 41,928 individuals aged 40-100 years enrolled before 2009 without a history of ischemic cardiovascular disease, diabetes, and statin use at baseline. The median follow-up time was 12 years. Information on diagnoses of MI and ischemic heart disease was collected from the national Danish Causes of Death Registry and all hospital admissions and diagnoses entered in the national Danish Patient Registry.

During the first 10 years of follow-up there were 1,063 MIs and 1,460 ischemic heart disease events (death of ischemic heart disease, nonfatal MI, and coronary revascularization).

Results showed that in models based on conventional risk factors estimating risk of heart disease of above or below 5% in 10 years, adding remnant cholesterol at levels above the 95th percentile, appropriately reclassified 23% of individuals who had an MI and 21% of individuals who had an ischemic heart disease event.

Using remnant cholesterol levels above the 75th percentile appropriately reclassified 10% of those who had an MI and 8% of those who had an ischemic heart disease event. No events were reclassified incorrectly.

Using measurements of remnant cholesterol also improved reclassification of individuals with heart disease risk above or below 7.5% or 10% in 10 years.

When reclassifications were combined from below to above 5%, 7.5%, and 10% risk of events, 42% of individuals with MI and 41% with ischemic heart disease events were reclassified appropriately.

In an editorial accompanying publication of the study in JACC, Peter Wilson, MD, Emory University School of Medicine, Atlanta, and Alan Remaley, MD, National Heart, Lung, and Blood Institute, say these findings rekindle interest in atherogenic nonfasting lipid measurements and emphasize an important role for elevated nonfasting remnant cholesterol as a value-added predictor of ischemic events.

An indirect measure of triglycerides

Dr. Wilson explained that remnant cholesterol is an indirect measure of triglycerides beyond LDL levels, and it is thus including a new lipid measurement in risk prediction.

“We are completely focused on LDL cholesterol,” he said. “This opens it up a bit by adding in another measure that takes into account triglycerides as well as LDL.”

He also pointed out that use of a nonfasting sample is another advantage of measuring remnant cholesterol.  

“An accurate measure of LDL needs a fasting sample, which is a nuisance, whereas remnant cholesterol can be measured in a nonfasting blood sample, so it is more convenient,” Dr. Wilson said.

While this study shows this measure is helpful for risk prediction in the primary prevention population, Dr. Wilson believes remnant cholesterol could be most useful in helping to guide further medication choice in patients who are already taking statins.

“Statins mainly target LDL, but if we can also measure nonfasting triglycerides this will be helpful. It may help us select some patients who may need a different type of drug to use in addition to statins that lowers triglycerides,” he said.  

This work was supported by the Global Excellence Programme, the Research Fund for the Capital Region of Denmark, the Japanese College of Cardiology Overseas Research Fellowship, and the Scandinavia Japan Sasakawa Foundation. Mr. Nordestgaard has reported consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Amarin, Kowa, Denka, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics. Dr. Doi has reported talks sponsored by MSD.

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

Adding remnant cholesterol to guideline prediction models should improve the identification of individuals who would benefit the most from statin treatment for the primary prevention of heart disease, a new study suggests.

The study, which followed almost 42,000 Danish individuals without a history of ischemic cardiovascular disease, diabetes, or statin use for more than 10 years, found that elevated remnant cholesterol appropriately reclassified up to 40% of those who later experienced myocardial infarction and ischemic heart disease.

“The clinical implications of our study include that doctors and patients should be aware of remnant cholesterol levels to prevent future risk of MI and ischemic heart disease,” the authors conclude.

They suggest that the development of a cardiovascular risk algorithm, including remnant cholesterol together with LDL cholesterol, would help to better identify high-risk individuals who could be candidates for statins in a primary prevention setting.

They note that physicians are encouraged to evaluate non-HDL cholesterol and/or apolipoprotein B rather than LDL cholesterol and certainly not yet remnant cholesterol, possibly because of the limited availability of remnant cholesterol values in some parts of the world.

However, they point out that remnant cholesterol can be calculated with a standard lipid profile without additional cost, which is currently already the standard procedure in the greater Copenhagen area.

“This means that the use of remnant cholesterol is easy to introduce into daily clinical practice,” they say.

The study was published online in the Journal of the American College of Cardiology.

The authors, Takahito Doi, MD, Anne Langsted, MD, and Børge Nordestgaard, from Copenhagen University Hospital, Denmark, explain that remnant cholesterol is total cholesterol minus LDL-cholesterol minus HDL-cholesterol and includes the cholesterol content of the triglyceride-rich very-low-density lipoproteins, intermediate-density lipoproteins, and chylomicron remnants in the nonfasting state.

“When these particles enter the arterial wall, they are taken up by macrophages to produce foam cells, and therefore elevated remnant cholesterol likely enhance accumulation of cholesterol in the arterial wall, leading to progression of atherosclerosis and in consequence ischemic heart disease,” they note.  

They point out that most guidelines for assessment of the 10-year risk of ischemic heart and atherosclerotic cardiovascular disease include levels of total and HDL cholesterol, but remnant cholesterol levels are not included.

They conducted the current study to investigate whether elevated remnant cholesterol would lead to appropriate reclassification of individuals who later experienced MI or ischemic heart disease.

The researchers analyzed data from the Copenhagen General Population Study, which recruited individuals from the White Danish general population from 2003-2015 and followed them until 2018. Information on lifestyle, health, and medication, including statin therapy, was obtained through a questionnaire, and participants underwent physical examinations and had nonfasting blood samples drawn for biochemical measurements.

For the current study, they included 41,928 individuals aged 40-100 years enrolled before 2009 without a history of ischemic cardiovascular disease, diabetes, and statin use at baseline. The median follow-up time was 12 years. Information on diagnoses of MI and ischemic heart disease was collected from the national Danish Causes of Death Registry and all hospital admissions and diagnoses entered in the national Danish Patient Registry.

During the first 10 years of follow-up there were 1,063 MIs and 1,460 ischemic heart disease events (death of ischemic heart disease, nonfatal MI, and coronary revascularization).

Results showed that in models based on conventional risk factors estimating risk of heart disease of above or below 5% in 10 years, adding remnant cholesterol at levels above the 95th percentile, appropriately reclassified 23% of individuals who had an MI and 21% of individuals who had an ischemic heart disease event.

Using remnant cholesterol levels above the 75th percentile appropriately reclassified 10% of those who had an MI and 8% of those who had an ischemic heart disease event. No events were reclassified incorrectly.

Using measurements of remnant cholesterol also improved reclassification of individuals with heart disease risk above or below 7.5% or 10% in 10 years.

When reclassifications were combined from below to above 5%, 7.5%, and 10% risk of events, 42% of individuals with MI and 41% with ischemic heart disease events were reclassified appropriately.

In an editorial accompanying publication of the study in JACC, Peter Wilson, MD, Emory University School of Medicine, Atlanta, and Alan Remaley, MD, National Heart, Lung, and Blood Institute, say these findings rekindle interest in atherogenic nonfasting lipid measurements and emphasize an important role for elevated nonfasting remnant cholesterol as a value-added predictor of ischemic events.

An indirect measure of triglycerides

Dr. Wilson explained that remnant cholesterol is an indirect measure of triglycerides beyond LDL levels, and it is thus including a new lipid measurement in risk prediction.

“We are completely focused on LDL cholesterol,” he said. “This opens it up a bit by adding in another measure that takes into account triglycerides as well as LDL.”

He also pointed out that use of a nonfasting sample is another advantage of measuring remnant cholesterol.  

“An accurate measure of LDL needs a fasting sample, which is a nuisance, whereas remnant cholesterol can be measured in a nonfasting blood sample, so it is more convenient,” Dr. Wilson said.

While this study shows this measure is helpful for risk prediction in the primary prevention population, Dr. Wilson believes remnant cholesterol could be most useful in helping to guide further medication choice in patients who are already taking statins.

“Statins mainly target LDL, but if we can also measure nonfasting triglycerides this will be helpful. It may help us select some patients who may need a different type of drug to use in addition to statins that lowers triglycerides,” he said.  

This work was supported by the Global Excellence Programme, the Research Fund for the Capital Region of Denmark, the Japanese College of Cardiology Overseas Research Fellowship, and the Scandinavia Japan Sasakawa Foundation. Mr. Nordestgaard has reported consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Amarin, Kowa, Denka, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics. Dr. Doi has reported talks sponsored by MSD.

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

Adding remnant cholesterol to guideline prediction models should improve the identification of individuals who would benefit the most from statin treatment for the primary prevention of heart disease, a new study suggests.

The study, which followed almost 42,000 Danish individuals without a history of ischemic cardiovascular disease, diabetes, or statin use for more than 10 years, found that elevated remnant cholesterol appropriately reclassified up to 40% of those who later experienced myocardial infarction and ischemic heart disease.

“The clinical implications of our study include that doctors and patients should be aware of remnant cholesterol levels to prevent future risk of MI and ischemic heart disease,” the authors conclude.

They suggest that the development of a cardiovascular risk algorithm, including remnant cholesterol together with LDL cholesterol, would help to better identify high-risk individuals who could be candidates for statins in a primary prevention setting.

They note that physicians are encouraged to evaluate non-HDL cholesterol and/or apolipoprotein B rather than LDL cholesterol and certainly not yet remnant cholesterol, possibly because of the limited availability of remnant cholesterol values in some parts of the world.

However, they point out that remnant cholesterol can be calculated with a standard lipid profile without additional cost, which is currently already the standard procedure in the greater Copenhagen area.

“This means that the use of remnant cholesterol is easy to introduce into daily clinical practice,” they say.

The study was published online in the Journal of the American College of Cardiology.

The authors, Takahito Doi, MD, Anne Langsted, MD, and Børge Nordestgaard, from Copenhagen University Hospital, Denmark, explain that remnant cholesterol is total cholesterol minus LDL-cholesterol minus HDL-cholesterol and includes the cholesterol content of the triglyceride-rich very-low-density lipoproteins, intermediate-density lipoproteins, and chylomicron remnants in the nonfasting state.

“When these particles enter the arterial wall, they are taken up by macrophages to produce foam cells, and therefore elevated remnant cholesterol likely enhance accumulation of cholesterol in the arterial wall, leading to progression of atherosclerosis and in consequence ischemic heart disease,” they note.  

They point out that most guidelines for assessment of the 10-year risk of ischemic heart and atherosclerotic cardiovascular disease include levels of total and HDL cholesterol, but remnant cholesterol levels are not included.

They conducted the current study to investigate whether elevated remnant cholesterol would lead to appropriate reclassification of individuals who later experienced MI or ischemic heart disease.

The researchers analyzed data from the Copenhagen General Population Study, which recruited individuals from the White Danish general population from 2003-2015 and followed them until 2018. Information on lifestyle, health, and medication, including statin therapy, was obtained through a questionnaire, and participants underwent physical examinations and had nonfasting blood samples drawn for biochemical measurements.

For the current study, they included 41,928 individuals aged 40-100 years enrolled before 2009 without a history of ischemic cardiovascular disease, diabetes, and statin use at baseline. The median follow-up time was 12 years. Information on diagnoses of MI and ischemic heart disease was collected from the national Danish Causes of Death Registry and all hospital admissions and diagnoses entered in the national Danish Patient Registry.

During the first 10 years of follow-up there were 1,063 MIs and 1,460 ischemic heart disease events (death of ischemic heart disease, nonfatal MI, and coronary revascularization).

Results showed that in models based on conventional risk factors estimating risk of heart disease of above or below 5% in 10 years, adding remnant cholesterol at levels above the 95th percentile, appropriately reclassified 23% of individuals who had an MI and 21% of individuals who had an ischemic heart disease event.

Using remnant cholesterol levels above the 75th percentile appropriately reclassified 10% of those who had an MI and 8% of those who had an ischemic heart disease event. No events were reclassified incorrectly.

Using measurements of remnant cholesterol also improved reclassification of individuals with heart disease risk above or below 7.5% or 10% in 10 years.

When reclassifications were combined from below to above 5%, 7.5%, and 10% risk of events, 42% of individuals with MI and 41% with ischemic heart disease events were reclassified appropriately.

In an editorial accompanying publication of the study in JACC, Peter Wilson, MD, Emory University School of Medicine, Atlanta, and Alan Remaley, MD, National Heart, Lung, and Blood Institute, say these findings rekindle interest in atherogenic nonfasting lipid measurements and emphasize an important role for elevated nonfasting remnant cholesterol as a value-added predictor of ischemic events.

An indirect measure of triglycerides

Dr. Wilson explained that remnant cholesterol is an indirect measure of triglycerides beyond LDL levels, and it is thus including a new lipid measurement in risk prediction.

“We are completely focused on LDL cholesterol,” he said. “This opens it up a bit by adding in another measure that takes into account triglycerides as well as LDL.”

He also pointed out that use of a nonfasting sample is another advantage of measuring remnant cholesterol.  

“An accurate measure of LDL needs a fasting sample, which is a nuisance, whereas remnant cholesterol can be measured in a nonfasting blood sample, so it is more convenient,” Dr. Wilson said.

While this study shows this measure is helpful for risk prediction in the primary prevention population, Dr. Wilson believes remnant cholesterol could be most useful in helping to guide further medication choice in patients who are already taking statins.

“Statins mainly target LDL, but if we can also measure nonfasting triglycerides this will be helpful. It may help us select some patients who may need a different type of drug to use in addition to statins that lowers triglycerides,” he said.  

This work was supported by the Global Excellence Programme, the Research Fund for the Capital Region of Denmark, the Japanese College of Cardiology Overseas Research Fellowship, and the Scandinavia Japan Sasakawa Foundation. Mr. Nordestgaard has reported consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Amarin, Kowa, Denka, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics. Dr. Doi has reported talks sponsored by MSD.

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

The Food and Drug Administration has approved a supplemental indication for setmelanotide (Imcivree, Rhythm Pharmaceuticals) injection for chronic weight management in adults and pediatric patients age 6 and older with obesity due to Bardet-Biedl Syndrome (BBS).

Olivier Le Moal/Getty Images

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is the first FDA-approved therapy for BBS, a rare genetic disorder that impairs a hunger signal along the melanocortin-4 receptor (MC4R) pathway.

BBS affects an estimated 1,500-2,500 people in the United States.

Individuals with BBS typically have obesity that starts at age 1 along with insatiable hunger (hyperphagia). Available weight management options are generally unsuccessful.

Other symptoms may include retinal degeneration, reduced kidney function, or extra digits of the hands or feet.

Setmelanotide received priority review, orphan drug designation, and breakthrough designation for this new indication.

As previously reported, in November 2020, the FDA approved setmelanotide for weight management in adults and children as young as 6 years with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing – who also have impaired hunger signaling from the brain.

These individuals have a normal weight at birth but develop persistent, severe obesity within months due to hyperphagia.

The FDA approval of Imcivree for BBS “represents a significant milestone for Rhythm [Pharmaceuticals], validating our strategy of developing Imcivree for people with hyperphagia and severe obesity caused by rare MC4R-pathway diseases and allowing us to provide our precision therapy to an established community of patients living with BBS and their families who are eagerly awaiting a new treatment option,” said David Meeker, MD, chair, president and CEO of Rhythm, in a press release.
 

Safety, effectiveness in 66-week trial in 44 patients

The safety and effectiveness of setmelanotidewas evaluated in a 66-week phase 3 clinical trial that enrolled 44 patients age 6 and older who had a diagnosis of BBS and obesity – defined as a body mass index greater than or equal to 30 kg/m2 or greater than or equal to 97th percentile for pediatric patients.

After an initial 14-week, randomized, double-blind, placebo-controlled treatment period, patients entered a 52-week, open-label period.

The trial met its primary endpoint and all key secondary endpoints, with statistically significant reductions in weight and hunger at 52 weeks on therapy.

• After 52 weeks of treatment, patients taking setmelanotide lost, on average, 7.9% of their initial BMI.
• 61% of patients lost 5% or more of their initial BMI, and 39% lost 10% or more of their initial BMI.
• In the 14-week, placebo-controlled treatment, on average, BMI dropped by 4.6% in the 22 patients treated with the study drug and dropped 0.1% in the 22 patients treated with placebo.
• At 52 weeks, the 14 patients aged 12 and older who were able to self-report their hunger had a significant –2.1 mean change in hunger score.

Setmelanotide is associated with the following warnings and precautions:

• Spontaneous penile erections in males and sexual adverse reactions in females. Instruct males with erection lasting longer than 4 hours to seek emergency medical attention.
• Depression and suicidal ideation. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors. Consider discontinuing the drug if patients have suicidal thoughts or behaviors or clinically significant or persistent depression symptoms.
• Skin pigmentation and darkening of preexisting nevi (moles). Examine skin before and during treatment.
• Setmelanotide is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low-birth-weight infants treated with benzyl alcohol-preserved drugs.

The most common adverse reactions (with an incidence greater than or equal to 20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection.

The FDA did not approve the company’s supplemental new drug application for setmelanotide in Alström syndrome.

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

The Food and Drug Administration has approved a supplemental indication for setmelanotide (Imcivree, Rhythm Pharmaceuticals) injection for chronic weight management in adults and pediatric patients age 6 and older with obesity due to Bardet-Biedl Syndrome (BBS).

Olivier Le Moal/Getty Images

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is the first FDA-approved therapy for BBS, a rare genetic disorder that impairs a hunger signal along the melanocortin-4 receptor (MC4R) pathway.

BBS affects an estimated 1,500-2,500 people in the United States.

Individuals with BBS typically have obesity that starts at age 1 along with insatiable hunger (hyperphagia). Available weight management options are generally unsuccessful.

Other symptoms may include retinal degeneration, reduced kidney function, or extra digits of the hands or feet.

Setmelanotide received priority review, orphan drug designation, and breakthrough designation for this new indication.

As previously reported, in November 2020, the FDA approved setmelanotide for weight management in adults and children as young as 6 years with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing – who also have impaired hunger signaling from the brain.

These individuals have a normal weight at birth but develop persistent, severe obesity within months due to hyperphagia.

The FDA approval of Imcivree for BBS “represents a significant milestone for Rhythm [Pharmaceuticals], validating our strategy of developing Imcivree for people with hyperphagia and severe obesity caused by rare MC4R-pathway diseases and allowing us to provide our precision therapy to an established community of patients living with BBS and their families who are eagerly awaiting a new treatment option,” said David Meeker, MD, chair, president and CEO of Rhythm, in a press release.
 

Safety, effectiveness in 66-week trial in 44 patients

The safety and effectiveness of setmelanotidewas evaluated in a 66-week phase 3 clinical trial that enrolled 44 patients age 6 and older who had a diagnosis of BBS and obesity – defined as a body mass index greater than or equal to 30 kg/m2 or greater than or equal to 97th percentile for pediatric patients.

After an initial 14-week, randomized, double-blind, placebo-controlled treatment period, patients entered a 52-week, open-label period.

The trial met its primary endpoint and all key secondary endpoints, with statistically significant reductions in weight and hunger at 52 weeks on therapy.

• After 52 weeks of treatment, patients taking setmelanotide lost, on average, 7.9% of their initial BMI.
• 61% of patients lost 5% or more of their initial BMI, and 39% lost 10% or more of their initial BMI.
• In the 14-week, placebo-controlled treatment, on average, BMI dropped by 4.6% in the 22 patients treated with the study drug and dropped 0.1% in the 22 patients treated with placebo.
• At 52 weeks, the 14 patients aged 12 and older who were able to self-report their hunger had a significant –2.1 mean change in hunger score.

Setmelanotide is associated with the following warnings and precautions:

• Spontaneous penile erections in males and sexual adverse reactions in females. Instruct males with erection lasting longer than 4 hours to seek emergency medical attention.
• Depression and suicidal ideation. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors. Consider discontinuing the drug if patients have suicidal thoughts or behaviors or clinically significant or persistent depression symptoms.
• Skin pigmentation and darkening of preexisting nevi (moles). Examine skin before and during treatment.
• Setmelanotide is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low-birth-weight infants treated with benzyl alcohol-preserved drugs.

The most common adverse reactions (with an incidence greater than or equal to 20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection.

The FDA did not approve the company’s supplemental new drug application for setmelanotide in Alström syndrome.

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

The Food and Drug Administration has approved a supplemental indication for setmelanotide (Imcivree, Rhythm Pharmaceuticals) injection for chronic weight management in adults and pediatric patients age 6 and older with obesity due to Bardet-Biedl Syndrome (BBS).

Olivier Le Moal/Getty Images

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is the first FDA-approved therapy for BBS, a rare genetic disorder that impairs a hunger signal along the melanocortin-4 receptor (MC4R) pathway.

BBS affects an estimated 1,500-2,500 people in the United States.

Individuals with BBS typically have obesity that starts at age 1 along with insatiable hunger (hyperphagia). Available weight management options are generally unsuccessful.

Other symptoms may include retinal degeneration, reduced kidney function, or extra digits of the hands or feet.

Setmelanotide received priority review, orphan drug designation, and breakthrough designation for this new indication.

As previously reported, in November 2020, the FDA approved setmelanotide for weight management in adults and children as young as 6 years with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing – who also have impaired hunger signaling from the brain.

These individuals have a normal weight at birth but develop persistent, severe obesity within months due to hyperphagia.

The FDA approval of Imcivree for BBS “represents a significant milestone for Rhythm [Pharmaceuticals], validating our strategy of developing Imcivree for people with hyperphagia and severe obesity caused by rare MC4R-pathway diseases and allowing us to provide our precision therapy to an established community of patients living with BBS and their families who are eagerly awaiting a new treatment option,” said David Meeker, MD, chair, president and CEO of Rhythm, in a press release.
 

Safety, effectiveness in 66-week trial in 44 patients

The safety and effectiveness of setmelanotidewas evaluated in a 66-week phase 3 clinical trial that enrolled 44 patients age 6 and older who had a diagnosis of BBS and obesity – defined as a body mass index greater than or equal to 30 kg/m2 or greater than or equal to 97th percentile for pediatric patients.

After an initial 14-week, randomized, double-blind, placebo-controlled treatment period, patients entered a 52-week, open-label period.

The trial met its primary endpoint and all key secondary endpoints, with statistically significant reductions in weight and hunger at 52 weeks on therapy.

• After 52 weeks of treatment, patients taking setmelanotide lost, on average, 7.9% of their initial BMI.
• 61% of patients lost 5% or more of their initial BMI, and 39% lost 10% or more of their initial BMI.
• In the 14-week, placebo-controlled treatment, on average, BMI dropped by 4.6% in the 22 patients treated with the study drug and dropped 0.1% in the 22 patients treated with placebo.
• At 52 weeks, the 14 patients aged 12 and older who were able to self-report their hunger had a significant –2.1 mean change in hunger score.

Setmelanotide is associated with the following warnings and precautions:

• Spontaneous penile erections in males and sexual adverse reactions in females. Instruct males with erection lasting longer than 4 hours to seek emergency medical attention.
• Depression and suicidal ideation. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors. Consider discontinuing the drug if patients have suicidal thoughts or behaviors or clinically significant or persistent depression symptoms.
• Skin pigmentation and darkening of preexisting nevi (moles). Examine skin before and during treatment.
• Setmelanotide is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low-birth-weight infants treated with benzyl alcohol-preserved drugs.

The most common adverse reactions (with an incidence greater than or equal to 20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection.

The FDA did not approve the company’s supplemental new drug application for setmelanotide in Alström syndrome.

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

Out-of-pocket (OOP) costs for Medicare enrollees receiving quadruple drug therapy for heart failure with reduced ejection fraction were “substantially higher than regimens limited to generically available medications,” according to a new analysis of prescription drug plans.

“Despite the clinical benefit of quadruple therapy” consisting of beta-blockers, angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors, “coverage was restricted primarily through cost sharing, and estimated annual OOP costs for beneficiaries were [over $2,000] per year under most plans,” wrote Kamil F. Faridi, MD, and associates. The findings were published in the Journal of the American College of Cardiology.

For just 1 month of quadruple drug therapy for heart failure with reduced ejection fraction (HFrEF), the estimated median OOP cost was $94 for individuals covered by a Medicare prescription drug plan during the second quarter of 2020, with the majority coming from the ARNI (median, $47) and the SGLT2 inhibitor (median, $45). Alternative HFrEF regimens were significantly less costly, ranging from $3 to $47 OOP, the investigators reported.

Almost all of the 4,068 plans participating in Medicare at that time covered quadruple therapy for HFrEF, but more than 99% restricted coverage by instituting cost sharing for medications at tier level 3 and above on the drug formularies. Such restrictions for ARNIs and SGLT2 inhibitors “might not be readily apparent to prescribing physicians,” wrote Dr. Faridi of Yale University, New Haven, Conn., and associates.

Other methods of regulating coverage were less common. Prior authorization of ARNIs was invoked by about a quarter of the plans, but none required authorization for any of the other drugs involved, and few plans used step therapy-requirements involving lower-cost alternatives, they noted.

“The use of cost sharing restricts access through high OOP costs for patients. Furthermore, these policies likely disadvantage relatively poorer patients (although the poorest Medicare patients will tend to be dual-enrolled in Medicaid and protected from cost sharing),” Jason H. Wasfy, MD, and Anna C. O’Kelly, MD, said in an accompanying editorial comment .

Since acceptable cost-effectiveness has been demonstrated for dapagliflozin, an SGLT1 inhibitor, and for the ARNIs, and because these medications have no generic equivalents, health plans should “use the discretion they have under Medicare Part D to reduce cost sharing for patients with HFrEF,” Dr. Wasfy and Dr. O’Kelly wrote, adding that the current study “demonstrates that without consensus on cost effectiveness from the societal perspective, costs can be imposed directly on patients in ways that slow uptake of cost-effective drugs.”

Data for all Medicare Advantage plans (n = 3,167) and standalone Part D plans (n = 901) came from the Medicare Prescription Drug Plan Formulary and Pricing Information Files. Annual OOP costs were estimated “using each phase of a 2020 Medicare part D standard benefit,” including deductible, standard coverage, coverage gap, and catastrophic coverage, the investigators explained.

Dr. Faridi and associates did not report any direct funding sources for their study. Dr Faridi received a grant from the National Institutes of Health outside the scope of the present work, and other investigators disclosed ties to the Food and Drug Administration, the Centers for Medicare and Medicaid Services, Johnson & Johnson, AstraZeneca, Boehringer Ingelheim, Amgen, Cytokinetics, and the Institute for Clinical and Economic Review.

Dr. Wasfy is supported by the American Heart Association and has received consulting fees from Pfizer and honoraria from the Institute for Clinical and Economic Review. Dr. O’Kelly has no relevant disclosures.

Out-of-pocket (OOP) costs for Medicare enrollees receiving quadruple drug therapy for heart failure with reduced ejection fraction were “substantially higher than regimens limited to generically available medications,” according to a new analysis of prescription drug plans.

“Despite the clinical benefit of quadruple therapy” consisting of beta-blockers, angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors, “coverage was restricted primarily through cost sharing, and estimated annual OOP costs for beneficiaries were [over $2,000] per year under most plans,” wrote Kamil F. Faridi, MD, and associates. The findings were published in the Journal of the American College of Cardiology.

For just 1 month of quadruple drug therapy for heart failure with reduced ejection fraction (HFrEF), the estimated median OOP cost was $94 for individuals covered by a Medicare prescription drug plan during the second quarter of 2020, with the majority coming from the ARNI (median, $47) and the SGLT2 inhibitor (median, $45). Alternative HFrEF regimens were significantly less costly, ranging from $3 to $47 OOP, the investigators reported.

Almost all of the 4,068 plans participating in Medicare at that time covered quadruple therapy for HFrEF, but more than 99% restricted coverage by instituting cost sharing for medications at tier level 3 and above on the drug formularies. Such restrictions for ARNIs and SGLT2 inhibitors “might not be readily apparent to prescribing physicians,” wrote Dr. Faridi of Yale University, New Haven, Conn., and associates.

Other methods of regulating coverage were less common. Prior authorization of ARNIs was invoked by about a quarter of the plans, but none required authorization for any of the other drugs involved, and few plans used step therapy-requirements involving lower-cost alternatives, they noted.

“The use of cost sharing restricts access through high OOP costs for patients. Furthermore, these policies likely disadvantage relatively poorer patients (although the poorest Medicare patients will tend to be dual-enrolled in Medicaid and protected from cost sharing),” Jason H. Wasfy, MD, and Anna C. O’Kelly, MD, said in an accompanying editorial comment .

Since acceptable cost-effectiveness has been demonstrated for dapagliflozin, an SGLT1 inhibitor, and for the ARNIs, and because these medications have no generic equivalents, health plans should “use the discretion they have under Medicare Part D to reduce cost sharing for patients with HFrEF,” Dr. Wasfy and Dr. O’Kelly wrote, adding that the current study “demonstrates that without consensus on cost effectiveness from the societal perspective, costs can be imposed directly on patients in ways that slow uptake of cost-effective drugs.”

Data for all Medicare Advantage plans (n = 3,167) and standalone Part D plans (n = 901) came from the Medicare Prescription Drug Plan Formulary and Pricing Information Files. Annual OOP costs were estimated “using each phase of a 2020 Medicare part D standard benefit,” including deductible, standard coverage, coverage gap, and catastrophic coverage, the investigators explained.

Dr. Faridi and associates did not report any direct funding sources for their study. Dr Faridi received a grant from the National Institutes of Health outside the scope of the present work, and other investigators disclosed ties to the Food and Drug Administration, the Centers for Medicare and Medicaid Services, Johnson & Johnson, AstraZeneca, Boehringer Ingelheim, Amgen, Cytokinetics, and the Institute for Clinical and Economic Review.

Dr. Wasfy is supported by the American Heart Association and has received consulting fees from Pfizer and honoraria from the Institute for Clinical and Economic Review. Dr. O’Kelly has no relevant disclosures.

Out-of-pocket (OOP) costs for Medicare enrollees receiving quadruple drug therapy for heart failure with reduced ejection fraction were “substantially higher than regimens limited to generically available medications,” according to a new analysis of prescription drug plans.

“Despite the clinical benefit of quadruple therapy” consisting of beta-blockers, angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors, “coverage was restricted primarily through cost sharing, and estimated annual OOP costs for beneficiaries were [over $2,000] per year under most plans,” wrote Kamil F. Faridi, MD, and associates. The findings were published in the Journal of the American College of Cardiology.

For just 1 month of quadruple drug therapy for heart failure with reduced ejection fraction (HFrEF), the estimated median OOP cost was $94 for individuals covered by a Medicare prescription drug plan during the second quarter of 2020, with the majority coming from the ARNI (median, $47) and the SGLT2 inhibitor (median, $45). Alternative HFrEF regimens were significantly less costly, ranging from $3 to $47 OOP, the investigators reported.

Almost all of the 4,068 plans participating in Medicare at that time covered quadruple therapy for HFrEF, but more than 99% restricted coverage by instituting cost sharing for medications at tier level 3 and above on the drug formularies. Such restrictions for ARNIs and SGLT2 inhibitors “might not be readily apparent to prescribing physicians,” wrote Dr. Faridi of Yale University, New Haven, Conn., and associates.

Other methods of regulating coverage were less common. Prior authorization of ARNIs was invoked by about a quarter of the plans, but none required authorization for any of the other drugs involved, and few plans used step therapy-requirements involving lower-cost alternatives, they noted.

“The use of cost sharing restricts access through high OOP costs for patients. Furthermore, these policies likely disadvantage relatively poorer patients (although the poorest Medicare patients will tend to be dual-enrolled in Medicaid and protected from cost sharing),” Jason H. Wasfy, MD, and Anna C. O’Kelly, MD, said in an accompanying editorial comment .

Since acceptable cost-effectiveness has been demonstrated for dapagliflozin, an SGLT1 inhibitor, and for the ARNIs, and because these medications have no generic equivalents, health plans should “use the discretion they have under Medicare Part D to reduce cost sharing for patients with HFrEF,” Dr. Wasfy and Dr. O’Kelly wrote, adding that the current study “demonstrates that without consensus on cost effectiveness from the societal perspective, costs can be imposed directly on patients in ways that slow uptake of cost-effective drugs.”

Data for all Medicare Advantage plans (n = 3,167) and standalone Part D plans (n = 901) came from the Medicare Prescription Drug Plan Formulary and Pricing Information Files. Annual OOP costs were estimated “using each phase of a 2020 Medicare part D standard benefit,” including deductible, standard coverage, coverage gap, and catastrophic coverage, the investigators explained.

Dr. Faridi and associates did not report any direct funding sources for their study. Dr Faridi received a grant from the National Institutes of Health outside the scope of the present work, and other investigators disclosed ties to the Food and Drug Administration, the Centers for Medicare and Medicaid Services, Johnson & Johnson, AstraZeneca, Boehringer Ingelheim, Amgen, Cytokinetics, and the Institute for Clinical and Economic Review.

Dr. Wasfy is supported by the American Heart Association and has received consulting fees from Pfizer and honoraria from the Institute for Clinical and Economic Review. Dr. O’Kelly has no relevant disclosures.

The U.S. National Lipid Association has issued a new scientific statement on the management of patients with statin intolerance, which recommends different strategies to help patients stay on statin medications, and also suggests alternatives that can be used in patients who really cannot tolerate statin drugs.

The statement was published online in the Journal of Clinical Lipidology.  

It notes that, although statins are generally well tolerated, statin intolerance is reported in 5%-30% of patients and contributes to reduced statin adherence and persistence, as well as higher risk for adverse cardiovascular outcomes.

RogerAshford/Thinkstock

The statement acknowledges the importance of identifying modifiable risk factors for statin intolerance and recognizes the possibility of a “nocebo” effect, basically the patient expectation of harm resulting in perceived side effects.

To identify a tolerable statin regimen, it recommends that clinicians consider using several different strategies (different statin, dose, and/or dosing frequency), and to classify a patient as having statin intolerance, a minimum of two statins should have been attempted, including at least one at the lowest-approved daily dosage.

The statement says that nonstatin therapy may be required for patients who cannot reach therapeutic objectives with lifestyle and maximal tolerated statin therapy, and in these cases, therapies with outcomes data from randomized trials showing reduced cardiovascular events are favored.

In high and very high-risk patients who are statin intolerant, clinicians should consider initiating nonstatin therapy while additional attempts are made to identify a tolerable statin in order to limit the time of exposure to elevated levels of atherogenic lipoproteins, it suggests.

“There is strong evidence that statins reduce risk of cardiovascular events particularly in patients with atherosclerotic cardiovascular disease, but recent research shows that only about half of patients with ASCVD are on a statin,” Kevin C. Maki, PhD, coauthor of the statement and current president of the National Lipid Association, said in an interview.

“There is an urgent problem with underutilization of statins and undertreatment of ASCVD. And we know that perceived side effects associated with statins are a common reason for discontinuation of these drugs and the consequent failure to manage ASCVD adequately,” he said.  

Dr. Maki noted that the NLA’s first message is that, when experiencing symptoms taking statins, a large majority of patients can still tolerate a statin. “They can try a different agent or a different dose. But for those who still can’t tolerate a statin, we then recommend nonstatin therapies and we favor those therapies with evidence from randomized trials.”

He pointed out that many patients who believe they are experiencing side effects from taking statins still experience the same effects on a placebo, a condition known as the nocebo effect.

“Several studies have shown that the nocebo effect is very common and accounts for more than half of perceived statin side effects. It is therefore estimated that many of the complaints of statin intolerance are probably not directly related to the pharmacodynamic actions of the drugs,” Dr. Maki said.

One recent study on the nocebo effect, the SAMSON study, suggested that 90% of symptoms attributed to statins were elicited by placebo tablets too.

But Dr. Maki added that it can be a losing battle for the clinician if patients think their symptoms are related to taking a statin.

“We suggest that clinicians inform patients that most people can tolerate a statin – maybe with a different agent or an alternative dose – and it is really important to lower LDL cholesterol as that will lower the risk of MI and stroke, so we need to find a regimen that works for each individual,” he said. “Most people can find a regimen that works. If this means taking a lower dose of a statin, they can take some additional therapy as well. This is a better situation than stopping taking statins altogether and allowing ASCVD to progress.”

Dr. Maki stressed that statins should still be the first choice as they are effective, taken orally, and inexpensive.

“Other medications do not have all these advantages. For example, PCSK9 inhibitors are very effective but they are expensive and injectable,” he noted. “And while ezetimibe [Zetia] is now generic so inexpensive, it has a more modest effect on LDL-lowering compared to statins, so by itself it is not normally enough for most patients to get to their target LDL, but it is an option for use in combination with a statin.”

He added that the NLA message is to do everything possible to keep patients on a statin, especially patients with preexisting ASCVD.

“We would like these patients to be on high-intensity statins. If they really can’t tolerate this, then they could be on a low-intensity statin plus an additional agent.”

Commenting on the NLA statement, SAMSON study coauthor James Howard, MB BChir, PhD, Imperial College London, said he had reservations about some of the recommendations.

“Whilst I think it is great news that the existence and importance of the nocebo effect is increasingly recognized in international guidelines and statements, I think we need to be very careful about recommending reduced doses and frequencies of statins,” Dr. Howard said.

“Studies such as SAMSON and StatinWISE indicate the vast majority of side effects reported by patients taking statins are not caused by the statin molecule, but instead are caused by either the nocebo effect, or ever-present background symptoms that are wrongly attributed to the statins,” he commented. “Therefore, to recommend that the correct approach in a patient with a history of MI suffering symptoms on 80 mg of atorvastatin is to reduce the dose or try alternate daily dosing. This reinforces the view that these drugs are side-effect prone and need to be carefully titrated.”

Dr. Howard suggested that patients should be educated on the possibility of the nocebo effect or background symptoms and encouraged to retrial statins at the same dose. “If that doesn’t work, then formal recording with a symptom diary might help patients recognize background symptoms,” he added.

Dr. Howard noted that, if symptoms still persist, an “n-of-1” trial could be conducted, in which the patient rotates between multiple periods of taking a statin and a placebo, but he acknowledged that this is expensive and time consuming. 

Also commenting, Steve Nissen, MD, Cleveland Clinic, said he thought the NLA statement was “reasonable and thoughtful.”

“Regardless of whether the symptoms are due to the nocebo effect or not, some patients will just not take a statin no matter how hard you try to convince them to persevere, so we do need alternatives,” Dr. Nissen said.

He noted that current alternatives would include the PCSK9 inhibitors and ezetimibe, but a future candidate could be the oral bempedoic acid (Nexletol), which is currently being evaluated in a large outcomes trial (CLEAR Outcomes).

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

The U.S. National Lipid Association has issued a new scientific statement on the management of patients with statin intolerance, which recommends different strategies to help patients stay on statin medications, and also suggests alternatives that can be used in patients who really cannot tolerate statin drugs.

The statement was published online in the Journal of Clinical Lipidology.  

It notes that, although statins are generally well tolerated, statin intolerance is reported in 5%-30% of patients and contributes to reduced statin adherence and persistence, as well as higher risk for adverse cardiovascular outcomes.

RogerAshford/Thinkstock

The statement acknowledges the importance of identifying modifiable risk factors for statin intolerance and recognizes the possibility of a “nocebo” effect, basically the patient expectation of harm resulting in perceived side effects.

To identify a tolerable statin regimen, it recommends that clinicians consider using several different strategies (different statin, dose, and/or dosing frequency), and to classify a patient as having statin intolerance, a minimum of two statins should have been attempted, including at least one at the lowest-approved daily dosage.

The statement says that nonstatin therapy may be required for patients who cannot reach therapeutic objectives with lifestyle and maximal tolerated statin therapy, and in these cases, therapies with outcomes data from randomized trials showing reduced cardiovascular events are favored.

In high and very high-risk patients who are statin intolerant, clinicians should consider initiating nonstatin therapy while additional attempts are made to identify a tolerable statin in order to limit the time of exposure to elevated levels of atherogenic lipoproteins, it suggests.

“There is strong evidence that statins reduce risk of cardiovascular events particularly in patients with atherosclerotic cardiovascular disease, but recent research shows that only about half of patients with ASCVD are on a statin,” Kevin C. Maki, PhD, coauthor of the statement and current president of the National Lipid Association, said in an interview.

“There is an urgent problem with underutilization of statins and undertreatment of ASCVD. And we know that perceived side effects associated with statins are a common reason for discontinuation of these drugs and the consequent failure to manage ASCVD adequately,” he said.  

Dr. Maki noted that the NLA’s first message is that, when experiencing symptoms taking statins, a large majority of patients can still tolerate a statin. “They can try a different agent or a different dose. But for those who still can’t tolerate a statin, we then recommend nonstatin therapies and we favor those therapies with evidence from randomized trials.”

He pointed out that many patients who believe they are experiencing side effects from taking statins still experience the same effects on a placebo, a condition known as the nocebo effect.

“Several studies have shown that the nocebo effect is very common and accounts for more than half of perceived statin side effects. It is therefore estimated that many of the complaints of statin intolerance are probably not directly related to the pharmacodynamic actions of the drugs,” Dr. Maki said.

One recent study on the nocebo effect, the SAMSON study, suggested that 90% of symptoms attributed to statins were elicited by placebo tablets too.

But Dr. Maki added that it can be a losing battle for the clinician if patients think their symptoms are related to taking a statin.

“We suggest that clinicians inform patients that most people can tolerate a statin – maybe with a different agent or an alternative dose – and it is really important to lower LDL cholesterol as that will lower the risk of MI and stroke, so we need to find a regimen that works for each individual,” he said. “Most people can find a regimen that works. If this means taking a lower dose of a statin, they can take some additional therapy as well. This is a better situation than stopping taking statins altogether and allowing ASCVD to progress.”

Dr. Maki stressed that statins should still be the first choice as they are effective, taken orally, and inexpensive.

“Other medications do not have all these advantages. For example, PCSK9 inhibitors are very effective but they are expensive and injectable,” he noted. “And while ezetimibe [Zetia] is now generic so inexpensive, it has a more modest effect on LDL-lowering compared to statins, so by itself it is not normally enough for most patients to get to their target LDL, but it is an option for use in combination with a statin.”

He added that the NLA message is to do everything possible to keep patients on a statin, especially patients with preexisting ASCVD.

“We would like these patients to be on high-intensity statins. If they really can’t tolerate this, then they could be on a low-intensity statin plus an additional agent.”

Commenting on the NLA statement, SAMSON study coauthor James Howard, MB BChir, PhD, Imperial College London, said he had reservations about some of the recommendations.

“Whilst I think it is great news that the existence and importance of the nocebo effect is increasingly recognized in international guidelines and statements, I think we need to be very careful about recommending reduced doses and frequencies of statins,” Dr. Howard said.

“Studies such as SAMSON and StatinWISE indicate the vast majority of side effects reported by patients taking statins are not caused by the statin molecule, but instead are caused by either the nocebo effect, or ever-present background symptoms that are wrongly attributed to the statins,” he commented. “Therefore, to recommend that the correct approach in a patient with a history of MI suffering symptoms on 80 mg of atorvastatin is to reduce the dose or try alternate daily dosing. This reinforces the view that these drugs are side-effect prone and need to be carefully titrated.”

Dr. Howard suggested that patients should be educated on the possibility of the nocebo effect or background symptoms and encouraged to retrial statins at the same dose. “If that doesn’t work, then formal recording with a symptom diary might help patients recognize background symptoms,” he added.

Dr. Howard noted that, if symptoms still persist, an “n-of-1” trial could be conducted, in which the patient rotates between multiple periods of taking a statin and a placebo, but he acknowledged that this is expensive and time consuming. 

Also commenting, Steve Nissen, MD, Cleveland Clinic, said he thought the NLA statement was “reasonable and thoughtful.”

“Regardless of whether the symptoms are due to the nocebo effect or not, some patients will just not take a statin no matter how hard you try to convince them to persevere, so we do need alternatives,” Dr. Nissen said.

He noted that current alternatives would include the PCSK9 inhibitors and ezetimibe, but a future candidate could be the oral bempedoic acid (Nexletol), which is currently being evaluated in a large outcomes trial (CLEAR Outcomes).

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

The U.S. National Lipid Association has issued a new scientific statement on the management of patients with statin intolerance, which recommends different strategies to help patients stay on statin medications, and also suggests alternatives that can be used in patients who really cannot tolerate statin drugs.

The statement was published online in the Journal of Clinical Lipidology.  

It notes that, although statins are generally well tolerated, statin intolerance is reported in 5%-30% of patients and contributes to reduced statin adherence and persistence, as well as higher risk for adverse cardiovascular outcomes.

RogerAshford/Thinkstock

The statement acknowledges the importance of identifying modifiable risk factors for statin intolerance and recognizes the possibility of a “nocebo” effect, basically the patient expectation of harm resulting in perceived side effects.

To identify a tolerable statin regimen, it recommends that clinicians consider using several different strategies (different statin, dose, and/or dosing frequency), and to classify a patient as having statin intolerance, a minimum of two statins should have been attempted, including at least one at the lowest-approved daily dosage.

The statement says that nonstatin therapy may be required for patients who cannot reach therapeutic objectives with lifestyle and maximal tolerated statin therapy, and in these cases, therapies with outcomes data from randomized trials showing reduced cardiovascular events are favored.

In high and very high-risk patients who are statin intolerant, clinicians should consider initiating nonstatin therapy while additional attempts are made to identify a tolerable statin in order to limit the time of exposure to elevated levels of atherogenic lipoproteins, it suggests.

“There is strong evidence that statins reduce risk of cardiovascular events particularly in patients with atherosclerotic cardiovascular disease, but recent research shows that only about half of patients with ASCVD are on a statin,” Kevin C. Maki, PhD, coauthor of the statement and current president of the National Lipid Association, said in an interview.

“There is an urgent problem with underutilization of statins and undertreatment of ASCVD. And we know that perceived side effects associated with statins are a common reason for discontinuation of these drugs and the consequent failure to manage ASCVD adequately,” he said.  

Dr. Maki noted that the NLA’s first message is that, when experiencing symptoms taking statins, a large majority of patients can still tolerate a statin. “They can try a different agent or a different dose. But for those who still can’t tolerate a statin, we then recommend nonstatin therapies and we favor those therapies with evidence from randomized trials.”

He pointed out that many patients who believe they are experiencing side effects from taking statins still experience the same effects on a placebo, a condition known as the nocebo effect.

“Several studies have shown that the nocebo effect is very common and accounts for more than half of perceived statin side effects. It is therefore estimated that many of the complaints of statin intolerance are probably not directly related to the pharmacodynamic actions of the drugs,” Dr. Maki said.

One recent study on the nocebo effect, the SAMSON study, suggested that 90% of symptoms attributed to statins were elicited by placebo tablets too.

But Dr. Maki added that it can be a losing battle for the clinician if patients think their symptoms are related to taking a statin.

“We suggest that clinicians inform patients that most people can tolerate a statin – maybe with a different agent or an alternative dose – and it is really important to lower LDL cholesterol as that will lower the risk of MI and stroke, so we need to find a regimen that works for each individual,” he said. “Most people can find a regimen that works. If this means taking a lower dose of a statin, they can take some additional therapy as well. This is a better situation than stopping taking statins altogether and allowing ASCVD to progress.”

Dr. Maki stressed that statins should still be the first choice as they are effective, taken orally, and inexpensive.

“Other medications do not have all these advantages. For example, PCSK9 inhibitors are very effective but they are expensive and injectable,” he noted. “And while ezetimibe [Zetia] is now generic so inexpensive, it has a more modest effect on LDL-lowering compared to statins, so by itself it is not normally enough for most patients to get to their target LDL, but it is an option for use in combination with a statin.”

He added that the NLA message is to do everything possible to keep patients on a statin, especially patients with preexisting ASCVD.

“We would like these patients to be on high-intensity statins. If they really can’t tolerate this, then they could be on a low-intensity statin plus an additional agent.”

Commenting on the NLA statement, SAMSON study coauthor James Howard, MB BChir, PhD, Imperial College London, said he had reservations about some of the recommendations.

“Whilst I think it is great news that the existence and importance of the nocebo effect is increasingly recognized in international guidelines and statements, I think we need to be very careful about recommending reduced doses and frequencies of statins,” Dr. Howard said.

“Studies such as SAMSON and StatinWISE indicate the vast majority of side effects reported by patients taking statins are not caused by the statin molecule, but instead are caused by either the nocebo effect, or ever-present background symptoms that are wrongly attributed to the statins,” he commented. “Therefore, to recommend that the correct approach in a patient with a history of MI suffering symptoms on 80 mg of atorvastatin is to reduce the dose or try alternate daily dosing. This reinforces the view that these drugs are side-effect prone and need to be carefully titrated.”

Dr. Howard suggested that patients should be educated on the possibility of the nocebo effect or background symptoms and encouraged to retrial statins at the same dose. “If that doesn’t work, then formal recording with a symptom diary might help patients recognize background symptoms,” he added.

Dr. Howard noted that, if symptoms still persist, an “n-of-1” trial could be conducted, in which the patient rotates between multiple periods of taking a statin and a placebo, but he acknowledged that this is expensive and time consuming. 

Also commenting, Steve Nissen, MD, Cleveland Clinic, said he thought the NLA statement was “reasonable and thoughtful.”

“Regardless of whether the symptoms are due to the nocebo effect or not, some patients will just not take a statin no matter how hard you try to convince them to persevere, so we do need alternatives,” Dr. Nissen said.

He noted that current alternatives would include the PCSK9 inhibitors and ezetimibe, but a future candidate could be the oral bempedoic acid (Nexletol), which is currently being evaluated in a large outcomes trial (CLEAR Outcomes).

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