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FDA expands inclisiran statin-adjunct indication to include primary prevention
Novartis has announced.
The first-in-class small interfering RNA (siRNA) agent was approved in 2021 as an adjunct to statins for patients with clinical cardiovascular disease or heterozygous familial hypercholesterolemia. The indications now include patients taking statins for primary dyslipidemia who have high-risk comorbidities such as diabetes but who do not have a history of cardiovascular events, the company said.
Inclisiran, with a mechanism of action unique among drugs for dyslipidemia, works by “silencing” RNA involved in the synthesis of proprotein convertase subtilisin/kexin type 9. The protein helps regulate the number of LDL cholesterol cell-surface receptors.
Novartis said it has “global rights to develop, manufacture and commercialize Leqvio under a license and collaboration agreement with Alnylam Pharmaceuticals.”
A version of this article first appeared on Medscape.com.
Novartis has announced.
The first-in-class small interfering RNA (siRNA) agent was approved in 2021 as an adjunct to statins for patients with clinical cardiovascular disease or heterozygous familial hypercholesterolemia. The indications now include patients taking statins for primary dyslipidemia who have high-risk comorbidities such as diabetes but who do not have a history of cardiovascular events, the company said.
Inclisiran, with a mechanism of action unique among drugs for dyslipidemia, works by “silencing” RNA involved in the synthesis of proprotein convertase subtilisin/kexin type 9. The protein helps regulate the number of LDL cholesterol cell-surface receptors.
Novartis said it has “global rights to develop, manufacture and commercialize Leqvio under a license and collaboration agreement with Alnylam Pharmaceuticals.”
A version of this article first appeared on Medscape.com.
Novartis has announced.
The first-in-class small interfering RNA (siRNA) agent was approved in 2021 as an adjunct to statins for patients with clinical cardiovascular disease or heterozygous familial hypercholesterolemia. The indications now include patients taking statins for primary dyslipidemia who have high-risk comorbidities such as diabetes but who do not have a history of cardiovascular events, the company said.
Inclisiran, with a mechanism of action unique among drugs for dyslipidemia, works by “silencing” RNA involved in the synthesis of proprotein convertase subtilisin/kexin type 9. The protein helps regulate the number of LDL cholesterol cell-surface receptors.
Novartis said it has “global rights to develop, manufacture and commercialize Leqvio under a license and collaboration agreement with Alnylam Pharmaceuticals.”
A version of this article first appeared on Medscape.com.
SAFE algorithm detects liver disease in general population
VIENNA – An algorithm, the Steatosis-Associated Fibrosis Estimator (SAFE), was developed to detect clinically significant fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). It is effective at detecting chronic liver disease from all causes with or without NAFLD in the general population, according the results of a U.S. population-based study. The algorithm was designed for use in primary care to help slow the steep rise in liver disease burden.
On the basis of the SAFE score, 61.3% of participants were at low risk for clinically significant fibrosis; 11.2% were at high risk; and 27.5% were at intermediate risk. Upon validation, very few of the low-risk participants had liver fibrosis, while nearly a third of those with a high-risk score had clinically significant fibrosis. In addition, a high percentage of the patients with high-risk SAFE scores had viral hepatitis and elevations in ferritin level.
“This is the first time that there has been a test that provides a score to detect low-risk liver disease in primary care,” said Ray Kim, MD, from Stanford (Calif.) University, senior investigator, who was speaking to this news organization at the annual International Liver Congress sponsored by the European Association for the Study of the Liver
“Primary care doctors currently detect liver disease through a serendipitous abnormal finding on ultrasound or blood tests that detect elevated transaminases, and then the patient is referred to a hepatologist, who figures out what is really going on,” said Dr. Kim.
“This approach is limited, so we need to get SAFE into primary care so these doctors can automatically calculate their scores, and if the patient is over 100 [high risk of chronic liver disease], then they need help [referral to a hepatologist].”
Liver deaths sharply rising
Public health data show that more people are dying of liver disease today than previously. Deaths in the United States have doubled over the past 20 years, said Dr. Kim. “If our mission is to help these patients and prevent death, [things are] moving in the wrong direction.”
He stressed that in order to change the direction, “primary care doctors need to engage with the issue and have appropriate tools to identify people with liver disease.”
Most often, the reason for this rise in deaths is that cases are being diagnosed at advanced stages of disease in which reversibility is limited, he added. “We want to move upstream where people might have early-stage disease and where we can intervene and make a difference.”
In an effort to help earlier detection of liver disease, the SAFE score was developed and validated by Dr. Kim and his colleagues to detect clinically significant (greater than stage 2) fibrosis in patients with NAFLD in primary care. The score is based upon age, body mass index, diabetes, platelet level, aspartate and alanine aminotransferase levels, and globulin level. A score of less than zero signifies that a patient is at low risk for liver fibrosis, while a score greater than 100 signifies a high risk of fibrosis. A score between 0 and 99 denotes intermediate risk of fibrosis.
“Unlike other noninvasive tests that detect advanced fibrosis, this one detects early-stage fibrosis. We’ve shown that the SAFE estimator is better than all other blood-based markers,” explained Dr. Kim.
Applying SAFE to the general population
In the study presented here at EASL, Dr. Kim aimed to expand the horizon for SAFE testing to the U.S. general population and to assess whether SAFE was effective in screening for chronic liver disease regardless of steatosis of the liver.
Together with first author Nakia Chung, MD, also from Stanford University, Dr. Kim applied the SAFE score to data from 7,156 participants of the National Health and Nutrition Examination Survey (NHANES) for 2017-2020. NHANES is representative of the noninstitutionalized, civilian population of the United States. It includes broad demographic, clinical, and laboratory data, including transient elastography data. FibroScans were first used in 2017, so the investigators had 3 years of FibroScan data with which to validate the score.
The researchers extrapolated the NHANES sample data to the U.S. population. They found that the proportion of adults with steatosis (CAP score > 274 dB/m) and significant fibrosis (LSM > 8.0 kPa) was 42.7% (95% confidence interval, 41.0%- 44.3%) and 8.9% (7.6%-10.2%), respectively. In addition, 11.3% (10.2%-12.5%) of the adult U.S. population demonstrated a significant amount of alcohol use, 2.3% (1.4%-3.3%) showed evidence of hepatitis B or C, and 5.4% (4.6%-6.2%) had elevated serum ferritin levels.
The researchers then stratified the patients according to previously defined SAFE tiers of low, intermediate, and high risk and projected findings to the U.S. general population.
“When we applied our score to the general population, we found multiple abnormalities in the high-risk groups [SAFE >100] having Fibroscan data that are consistent with stage 2 or higher fibrosis regardless of etiology, “Dr. Kim pointed out.
Results also showed that very few patients with SAFE less than 0 had liver fibrosis (4% among those with liver stiffness measure [LSM] > 8kPa, and 0.8% with LSM > 12kPa). Among those with SAFE > 100, nearly a third (31.5%) had LSM of > 8kPa, and 16.5% had LSM > 12kPa.
In addition to fibrosis, liver abnormalities were common among patients with SAFE greater than 100, including steatosis (68.0%), viral hepatitis (7.0%), and abnormal ferritin levels (12.9%); 10.8% of these patients used alcohol.
“Right now, some patients are referred, but on examination and FibroScan, they might actually be okay, so it it’s a waste of time and money for everyone. We can preempt all of this by doing a blood test and focusing on those people who really need a scan,” said Dr. Kim.
The researcher is now working with primary care colleagues to help further develop and integrate SAFE into the primary care setting.
Fibrosis score in patients with metabolic dysfunction
Also presenting at the same session on population health was Willem Pieter Brouwer, MD, PhD, from Erasmus University Medical Center, Rotterdam, the Netherlands. He reported results of a validation study of a new risk score – the Metabolic Dysfunction-Associated Fibrosis–5 (MAF-5) score – for use for people with metabolic dysfunction who are recommended for screening for liver fibrosis.
“We believe the MAF-5 score may be a good alternative to the FIB-4 [a liver fibrosis biomarker] for use in the referral pathway for liver health evaluation,” remarked Dr. Brouwer. “The clinical practice guidelines recommend using FIB-4 scores, but these have a poor-moderate performance in the population setting.
“We developed and validated our score in a population of 5,500 from the NHANES 2017-2020 cycle and validated the score in populations from Rotterdam, which is a cohort of elderly participants, and in fibrosis among patients with biopsy-proven NAFLD from Colombia and Belgium,” he explained.
He also validated the score against different existing scoring systems and different methods of measuring liver stiffness and validated it for prognostic use to predict all-cause mortality in the NHANES III cohort.
Dr. Brouwer removed age as a factor of his new MAF-5 score; the score is thus stable for patients of all ages and is suitable for detecting liver disease in younger patients. “This is very important because these patients are currently underserved and have the most years of life to win.”
Referring to the SAFE score discussed by Dr. Kim, as well as other scores, he said, “The FIB-4, SAFE, and NFS [NAFLD fibrosis score] all include age in the scores, which causes problems and limitations in aging populations, as more and more patients will be referred due to an increasing score. Hence, the elderly are mostly all referred for liver checkups.”
Dr. Kim and Dr. Brouwer have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VIENNA – An algorithm, the Steatosis-Associated Fibrosis Estimator (SAFE), was developed to detect clinically significant fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). It is effective at detecting chronic liver disease from all causes with or without NAFLD in the general population, according the results of a U.S. population-based study. The algorithm was designed for use in primary care to help slow the steep rise in liver disease burden.
On the basis of the SAFE score, 61.3% of participants were at low risk for clinically significant fibrosis; 11.2% were at high risk; and 27.5% were at intermediate risk. Upon validation, very few of the low-risk participants had liver fibrosis, while nearly a third of those with a high-risk score had clinically significant fibrosis. In addition, a high percentage of the patients with high-risk SAFE scores had viral hepatitis and elevations in ferritin level.
“This is the first time that there has been a test that provides a score to detect low-risk liver disease in primary care,” said Ray Kim, MD, from Stanford (Calif.) University, senior investigator, who was speaking to this news organization at the annual International Liver Congress sponsored by the European Association for the Study of the Liver
“Primary care doctors currently detect liver disease through a serendipitous abnormal finding on ultrasound or blood tests that detect elevated transaminases, and then the patient is referred to a hepatologist, who figures out what is really going on,” said Dr. Kim.
“This approach is limited, so we need to get SAFE into primary care so these doctors can automatically calculate their scores, and if the patient is over 100 [high risk of chronic liver disease], then they need help [referral to a hepatologist].”
Liver deaths sharply rising
Public health data show that more people are dying of liver disease today than previously. Deaths in the United States have doubled over the past 20 years, said Dr. Kim. “If our mission is to help these patients and prevent death, [things are] moving in the wrong direction.”
He stressed that in order to change the direction, “primary care doctors need to engage with the issue and have appropriate tools to identify people with liver disease.”
Most often, the reason for this rise in deaths is that cases are being diagnosed at advanced stages of disease in which reversibility is limited, he added. “We want to move upstream where people might have early-stage disease and where we can intervene and make a difference.”
In an effort to help earlier detection of liver disease, the SAFE score was developed and validated by Dr. Kim and his colleagues to detect clinically significant (greater than stage 2) fibrosis in patients with NAFLD in primary care. The score is based upon age, body mass index, diabetes, platelet level, aspartate and alanine aminotransferase levels, and globulin level. A score of less than zero signifies that a patient is at low risk for liver fibrosis, while a score greater than 100 signifies a high risk of fibrosis. A score between 0 and 99 denotes intermediate risk of fibrosis.
“Unlike other noninvasive tests that detect advanced fibrosis, this one detects early-stage fibrosis. We’ve shown that the SAFE estimator is better than all other blood-based markers,” explained Dr. Kim.
Applying SAFE to the general population
In the study presented here at EASL, Dr. Kim aimed to expand the horizon for SAFE testing to the U.S. general population and to assess whether SAFE was effective in screening for chronic liver disease regardless of steatosis of the liver.
Together with first author Nakia Chung, MD, also from Stanford University, Dr. Kim applied the SAFE score to data from 7,156 participants of the National Health and Nutrition Examination Survey (NHANES) for 2017-2020. NHANES is representative of the noninstitutionalized, civilian population of the United States. It includes broad demographic, clinical, and laboratory data, including transient elastography data. FibroScans were first used in 2017, so the investigators had 3 years of FibroScan data with which to validate the score.
The researchers extrapolated the NHANES sample data to the U.S. population. They found that the proportion of adults with steatosis (CAP score > 274 dB/m) and significant fibrosis (LSM > 8.0 kPa) was 42.7% (95% confidence interval, 41.0%- 44.3%) and 8.9% (7.6%-10.2%), respectively. In addition, 11.3% (10.2%-12.5%) of the adult U.S. population demonstrated a significant amount of alcohol use, 2.3% (1.4%-3.3%) showed evidence of hepatitis B or C, and 5.4% (4.6%-6.2%) had elevated serum ferritin levels.
The researchers then stratified the patients according to previously defined SAFE tiers of low, intermediate, and high risk and projected findings to the U.S. general population.
“When we applied our score to the general population, we found multiple abnormalities in the high-risk groups [SAFE >100] having Fibroscan data that are consistent with stage 2 or higher fibrosis regardless of etiology, “Dr. Kim pointed out.
Results also showed that very few patients with SAFE less than 0 had liver fibrosis (4% among those with liver stiffness measure [LSM] > 8kPa, and 0.8% with LSM > 12kPa). Among those with SAFE > 100, nearly a third (31.5%) had LSM of > 8kPa, and 16.5% had LSM > 12kPa.
In addition to fibrosis, liver abnormalities were common among patients with SAFE greater than 100, including steatosis (68.0%), viral hepatitis (7.0%), and abnormal ferritin levels (12.9%); 10.8% of these patients used alcohol.
“Right now, some patients are referred, but on examination and FibroScan, they might actually be okay, so it it’s a waste of time and money for everyone. We can preempt all of this by doing a blood test and focusing on those people who really need a scan,” said Dr. Kim.
The researcher is now working with primary care colleagues to help further develop and integrate SAFE into the primary care setting.
Fibrosis score in patients with metabolic dysfunction
Also presenting at the same session on population health was Willem Pieter Brouwer, MD, PhD, from Erasmus University Medical Center, Rotterdam, the Netherlands. He reported results of a validation study of a new risk score – the Metabolic Dysfunction-Associated Fibrosis–5 (MAF-5) score – for use for people with metabolic dysfunction who are recommended for screening for liver fibrosis.
“We believe the MAF-5 score may be a good alternative to the FIB-4 [a liver fibrosis biomarker] for use in the referral pathway for liver health evaluation,” remarked Dr. Brouwer. “The clinical practice guidelines recommend using FIB-4 scores, but these have a poor-moderate performance in the population setting.
“We developed and validated our score in a population of 5,500 from the NHANES 2017-2020 cycle and validated the score in populations from Rotterdam, which is a cohort of elderly participants, and in fibrosis among patients with biopsy-proven NAFLD from Colombia and Belgium,” he explained.
He also validated the score against different existing scoring systems and different methods of measuring liver stiffness and validated it for prognostic use to predict all-cause mortality in the NHANES III cohort.
Dr. Brouwer removed age as a factor of his new MAF-5 score; the score is thus stable for patients of all ages and is suitable for detecting liver disease in younger patients. “This is very important because these patients are currently underserved and have the most years of life to win.”
Referring to the SAFE score discussed by Dr. Kim, as well as other scores, he said, “The FIB-4, SAFE, and NFS [NAFLD fibrosis score] all include age in the scores, which causes problems and limitations in aging populations, as more and more patients will be referred due to an increasing score. Hence, the elderly are mostly all referred for liver checkups.”
Dr. Kim and Dr. Brouwer have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VIENNA – An algorithm, the Steatosis-Associated Fibrosis Estimator (SAFE), was developed to detect clinically significant fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). It is effective at detecting chronic liver disease from all causes with or without NAFLD in the general population, according the results of a U.S. population-based study. The algorithm was designed for use in primary care to help slow the steep rise in liver disease burden.
On the basis of the SAFE score, 61.3% of participants were at low risk for clinically significant fibrosis; 11.2% were at high risk; and 27.5% were at intermediate risk. Upon validation, very few of the low-risk participants had liver fibrosis, while nearly a third of those with a high-risk score had clinically significant fibrosis. In addition, a high percentage of the patients with high-risk SAFE scores had viral hepatitis and elevations in ferritin level.
“This is the first time that there has been a test that provides a score to detect low-risk liver disease in primary care,” said Ray Kim, MD, from Stanford (Calif.) University, senior investigator, who was speaking to this news organization at the annual International Liver Congress sponsored by the European Association for the Study of the Liver
“Primary care doctors currently detect liver disease through a serendipitous abnormal finding on ultrasound or blood tests that detect elevated transaminases, and then the patient is referred to a hepatologist, who figures out what is really going on,” said Dr. Kim.
“This approach is limited, so we need to get SAFE into primary care so these doctors can automatically calculate their scores, and if the patient is over 100 [high risk of chronic liver disease], then they need help [referral to a hepatologist].”
Liver deaths sharply rising
Public health data show that more people are dying of liver disease today than previously. Deaths in the United States have doubled over the past 20 years, said Dr. Kim. “If our mission is to help these patients and prevent death, [things are] moving in the wrong direction.”
He stressed that in order to change the direction, “primary care doctors need to engage with the issue and have appropriate tools to identify people with liver disease.”
Most often, the reason for this rise in deaths is that cases are being diagnosed at advanced stages of disease in which reversibility is limited, he added. “We want to move upstream where people might have early-stage disease and where we can intervene and make a difference.”
In an effort to help earlier detection of liver disease, the SAFE score was developed and validated by Dr. Kim and his colleagues to detect clinically significant (greater than stage 2) fibrosis in patients with NAFLD in primary care. The score is based upon age, body mass index, diabetes, platelet level, aspartate and alanine aminotransferase levels, and globulin level. A score of less than zero signifies that a patient is at low risk for liver fibrosis, while a score greater than 100 signifies a high risk of fibrosis. A score between 0 and 99 denotes intermediate risk of fibrosis.
“Unlike other noninvasive tests that detect advanced fibrosis, this one detects early-stage fibrosis. We’ve shown that the SAFE estimator is better than all other blood-based markers,” explained Dr. Kim.
Applying SAFE to the general population
In the study presented here at EASL, Dr. Kim aimed to expand the horizon for SAFE testing to the U.S. general population and to assess whether SAFE was effective in screening for chronic liver disease regardless of steatosis of the liver.
Together with first author Nakia Chung, MD, also from Stanford University, Dr. Kim applied the SAFE score to data from 7,156 participants of the National Health and Nutrition Examination Survey (NHANES) for 2017-2020. NHANES is representative of the noninstitutionalized, civilian population of the United States. It includes broad demographic, clinical, and laboratory data, including transient elastography data. FibroScans were first used in 2017, so the investigators had 3 years of FibroScan data with which to validate the score.
The researchers extrapolated the NHANES sample data to the U.S. population. They found that the proportion of adults with steatosis (CAP score > 274 dB/m) and significant fibrosis (LSM > 8.0 kPa) was 42.7% (95% confidence interval, 41.0%- 44.3%) and 8.9% (7.6%-10.2%), respectively. In addition, 11.3% (10.2%-12.5%) of the adult U.S. population demonstrated a significant amount of alcohol use, 2.3% (1.4%-3.3%) showed evidence of hepatitis B or C, and 5.4% (4.6%-6.2%) had elevated serum ferritin levels.
The researchers then stratified the patients according to previously defined SAFE tiers of low, intermediate, and high risk and projected findings to the U.S. general population.
“When we applied our score to the general population, we found multiple abnormalities in the high-risk groups [SAFE >100] having Fibroscan data that are consistent with stage 2 or higher fibrosis regardless of etiology, “Dr. Kim pointed out.
Results also showed that very few patients with SAFE less than 0 had liver fibrosis (4% among those with liver stiffness measure [LSM] > 8kPa, and 0.8% with LSM > 12kPa). Among those with SAFE > 100, nearly a third (31.5%) had LSM of > 8kPa, and 16.5% had LSM > 12kPa.
In addition to fibrosis, liver abnormalities were common among patients with SAFE greater than 100, including steatosis (68.0%), viral hepatitis (7.0%), and abnormal ferritin levels (12.9%); 10.8% of these patients used alcohol.
“Right now, some patients are referred, but on examination and FibroScan, they might actually be okay, so it it’s a waste of time and money for everyone. We can preempt all of this by doing a blood test and focusing on those people who really need a scan,” said Dr. Kim.
The researcher is now working with primary care colleagues to help further develop and integrate SAFE into the primary care setting.
Fibrosis score in patients with metabolic dysfunction
Also presenting at the same session on population health was Willem Pieter Brouwer, MD, PhD, from Erasmus University Medical Center, Rotterdam, the Netherlands. He reported results of a validation study of a new risk score – the Metabolic Dysfunction-Associated Fibrosis–5 (MAF-5) score – for use for people with metabolic dysfunction who are recommended for screening for liver fibrosis.
“We believe the MAF-5 score may be a good alternative to the FIB-4 [a liver fibrosis biomarker] for use in the referral pathway for liver health evaluation,” remarked Dr. Brouwer. “The clinical practice guidelines recommend using FIB-4 scores, but these have a poor-moderate performance in the population setting.
“We developed and validated our score in a population of 5,500 from the NHANES 2017-2020 cycle and validated the score in populations from Rotterdam, which is a cohort of elderly participants, and in fibrosis among patients with biopsy-proven NAFLD from Colombia and Belgium,” he explained.
He also validated the score against different existing scoring systems and different methods of measuring liver stiffness and validated it for prognostic use to predict all-cause mortality in the NHANES III cohort.
Dr. Brouwer removed age as a factor of his new MAF-5 score; the score is thus stable for patients of all ages and is suitable for detecting liver disease in younger patients. “This is very important because these patients are currently underserved and have the most years of life to win.”
Referring to the SAFE score discussed by Dr. Kim, as well as other scores, he said, “The FIB-4, SAFE, and NFS [NAFLD fibrosis score] all include age in the scores, which causes problems and limitations in aging populations, as more and more patients will be referred due to an increasing score. Hence, the elderly are mostly all referred for liver checkups.”
Dr. Kim and Dr. Brouwer have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ILC 2023
‘Striking’ benefit of lipid lowering in primary prevention
SAN DIEGO – two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.
The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.
This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.
Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.
“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview.
“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.
But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated.
“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed.
Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.”
“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
‘Wake-up call’
He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”
Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels.
“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”
Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.
He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years.
“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.
“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.
CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.
Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.
Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”
And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.
Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
Greater benefit in primary prevention?
In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.
Other key secondary endpoints also showed impressive reductions.
The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.
Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.
Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.
“It may seem paradoxical, but there is actually some history that this may be the case,” he said.
He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.
He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.
“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.
Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.
“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”
He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
Editorial cautious
In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.
Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.
Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.
“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.
A version of this article first appeared on Medscape.com.
SAN DIEGO – two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.
The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.
This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.
Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.
“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview.
“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.
But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated.
“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed.
Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.”
“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
‘Wake-up call’
He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”
Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels.
“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”
Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.
He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years.
“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.
“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.
CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.
Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.
Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”
And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.
Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
Greater benefit in primary prevention?
In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.
Other key secondary endpoints also showed impressive reductions.
The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.
Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.
Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.
“It may seem paradoxical, but there is actually some history that this may be the case,” he said.
He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.
He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.
“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.
Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.
“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”
He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
Editorial cautious
In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.
Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.
Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.
“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.
A version of this article first appeared on Medscape.com.
SAN DIEGO – two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.
The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.
This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.
Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.
“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview.
“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.
But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated.
“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed.
Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.”
“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
‘Wake-up call’
He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”
Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels.
“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”
Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.
He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years.
“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.
“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.
CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.
Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.
Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”
And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.
Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
Greater benefit in primary prevention?
In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.
Other key secondary endpoints also showed impressive reductions.
The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.
Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.
Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.
“It may seem paradoxical, but there is actually some history that this may be the case,” he said.
He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.
He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.
“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.
Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.
“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”
He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
Editorial cautious
In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.
Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.
Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.
“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.
A version of this article first appeared on Medscape.com.
AT ADA 2023
‘Exciting time for NASH’ with resmetirom phase 3 results
VIENNA – Resolution of nonalcoholic steatohepatitis (NASH), and reduction of fibrosis on liver biopsy were achieved with the oral, thyroid hormone receptor beta-selective agonist resmetirom (Madrigal Pharmaceuticals) in patients with NASH and associated cirrhosis in a pivotal phase 3 clinical trial. The primary results of the MAESTRO-NASH (NCT03900429) trial were reported at the European Association for the Study of the Liver Congress 2023.
Both doses of resmetirom – 80 mg and 100 mg – met the primary endpoints of NASH resolution and no worsening of fibrosis on liver biopsy. The key secondary endpoint of LDL cholesterol lowering was also achieved with statistical significance. Likewise, improvement was seen in liver enzymes, and liver and spleen volumes.
In the intent-to-treat population, NASH resolution was achieved in 26% (P < .0001) in the 80-mg resmetirom group, 30% (P < .0001) in the 100-mg group, and 10% in those taking placebo. And ≥ 1-stage improvement in fibrosis with no worsening of the nonalcoholic fatty liver disease activity score (NAS) was achieved by 24% (P < .0002), 26% (P < .0001), and 14% in these groups respectively.
The investigational, liver-directed agent, designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity, was well tolerated overall with a favorable safety profile.
“This is an exciting time for NASH because we are at the forefront of having a drug to treat these patients, and the benefit to patients promises to be huge,” asserted Stephen Harrison, MD, principal investigator of the MAESTRO studies, gastroenterologist and hepatologist, and founder of Pinnacle Clinical Research, San Antonio, in reporting 52-week results.
“This is the first treatment to achieve meaningful effects on both primary liver biopsy endpoints – disease activity and fibrosis – which is absolutely critical because fibrosis pertains to a worse prognosis. [These results] are reasonably likely to predict clinical benefit in a phase 3 trial in patients with NASH,” he added.
FDA-chosen endpoints likely to predict clinical outcomes
The ongoing 54-month, phase 3, registrational, double-blind, placebo-controlled trial involved taking liver biopsies from 966 patients at around 200 global sites. Biopsy readings were taken by two pathologists that were then combined into a single treatment effect.
Patients had biopsy-proven NASH with fibrosis stages F1B, F2, or F3, the presence of three or more metabolic risk factors, a FibroScan vibration-controlled transient elastography (VCTE) score of 8.5 kPa or more, baseline MRI proton density fat fraction (MRI-PDFF) of 8% or more, and a NAS score of 4 or more with at least 1 in each NAS component. Around 65% of participants had type 2 diabetes, between 13% and 16% were taking glucagonlike peptide-1 (GLP-1) receptor agonists, and 46%-51% were taking statins.
Patients were randomized 1:1:1 to once-daily resmetirom 80 mg or 100 mg orally or to placebo and treated for 52 weeks.
Both liver histological improvement primary endpoints at week-52 were proposed by the U.S. Food and Drug Administration as reasonably likely to predict clinical benefit and as such support accelerated approval for the treatment of NASH with liver fibrosis. These primary endpoints were NASH resolution (ballooning 0, inflammation 0/1) with ≥ 2-point improvement in NAS with no worsening of fibrosis, and ≥ 1-stage reduction in fibrosis with no worsening of NAS.
Patients on resmetirom showed improvement in NAS components and fibrosis, and less worsening of NAS and fibrosis, compared with placebo. Percentage improvement was seen in 31%, 33%, and 15% of patients on 80 mg resmetirom, 100 mg resmetirom, and placebo respectively; no change was seen in 51%, 48%, and 51% respectively; and worsening was seen in 18%, 19%, and 34% respectively.
The key secondary endpoint of LDL cholesterol lowering was also met. “There was a significant effect of resmetirom 80 and 100 mg on multiple atherogenic lipids/lipoproteins at both week 24 and 52,” reported Dr. Harrison. The 52-week percentage change from baseline in LDL cholesterol was –14%, –20%, and 0% for the 80-mg resmetirom group, the 100-mg group, and the placebo group respectively.
“We also saw a significant reduction in liver enzymes [alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase (GGT)] relative to placebo both in terms of percentage and absolute measures,” Dr. Harrison added. “[And] the change in liver enzymes was associated with the neutral biomarker that increases with resmetirom target engagement.”
Resmetirom at both doses also resulted in a significant effect on MRI-PDFF and Fibroscan CAP. At week 52, 80 mg resmetirom, 100 mg, and placebo led to –42.1%, –51.4% and –10.4% change from baseline in MRI-PDFF, while Fibroscan CAP changed by –39.6%, –41.3%, and –14.5% respectively, reported Dr. Harrison. Liver volume dropped by –21.6% in the 80-mg group and –25.8% in the 100-mg group, compared with –1.0% in the placebo group. Spleen volume changed by –5.9%, –6.1%, and +3.2% respectively.
Liver stiffness, as measured by Fibroscan VCTE at week 52, changed from –3.7 KPa (F1B) to –2.0 KPa (F3) at 80 mg, and from –3.7 KPa (F1B) to –2.5 KPa (F2) and –3.3 KPa (F3) at the 100-mg dose.
Further analysis showed that improvements in fibrosis and NASH resolution were seen across all key subgroups, including baseline fibrosis stage (F2 or F3), NAS (< 6, ≥ 6), type 2 diabetes status, age (< 65 years, ≥ 65 years), and sex.
Safety profile
“The safety profile of resmetirom in the MAESTRO-NASH trial is consistent with previous phase 2/3 trials in which the most common adverse events were diarrhea and nausea at treatment initiation,” said Dr. Harrison.
Study discontinuations in the 100-mg group were increased relative to placebo during the first few weeks of treatment and were similar in all treatment groups up to 52 weeks. Discontinuations of patients on resmetirom 100 mg were mainly gastrointestinal related.
Phase 2 results of the serial liver biopsy trial in adults with biopsy-confirmed NASH showed that resmetirom resolved NASH in a significantly greater percentage of patients and reduced liver enzymes, inflammatory biomarkers, and fibrosis, compared with placebo.
“We’ve been waiting for a long, long time for a therapy for these patients because until now, they have been challenged with lifestyle modifications to lose and maintain weight,” said Dr. Harrison. “There’s been a delay in identifying patients with this disease because we’ve had no treatment, but now that we are on the forefront of a treatment, it allows clinicians to open their minds to the possibility of identifying these patients.”
Dr. Harrison noted that a limitation of these data was the lack of clinical outcomes data to correlate with the biopsy data; however, the MAESTRO-NASH trial will continue to 54 months to accrue and evaluate clinical outcomes.
Milan Mishkovikj, MSc, board director of the European Liver Patients Association, Bitola, North Macedonia, commented on the potential benefit of this drug for patients. “Adhering to a healthy lifestyle is not always easy – not in all countries – so it’s encouraging to have a drug that hopefully is affordable and accessible to us. Now we need to manage the expectations of patients and caregivers.”
EASL’s vice secretary Aleksander Krag, MD, PhD, professor and head of hepatology at University of Southern Denmark, Odense, and Odense University Hospital remarked, “This is so exciting. This phase 3 trial is a real game-changer in the field of fatty liver disease because it has nearly 1,000 patients over 52 weeks of treatment.”
Madrigal Pharmaceuticals plans to submit an application to the FDA by end of the second quarter with a priority review.
Dr. Harrison is founder of Madrigal Pharmaceuticals. Dr. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience, and participated in advisory boards for Norgine and Siemens, all outside the submitted work. He receives royalties from Gyldendal and Echosens. Dr. Mishkovikj has declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VIENNA – Resolution of nonalcoholic steatohepatitis (NASH), and reduction of fibrosis on liver biopsy were achieved with the oral, thyroid hormone receptor beta-selective agonist resmetirom (Madrigal Pharmaceuticals) in patients with NASH and associated cirrhosis in a pivotal phase 3 clinical trial. The primary results of the MAESTRO-NASH (NCT03900429) trial were reported at the European Association for the Study of the Liver Congress 2023.
Both doses of resmetirom – 80 mg and 100 mg – met the primary endpoints of NASH resolution and no worsening of fibrosis on liver biopsy. The key secondary endpoint of LDL cholesterol lowering was also achieved with statistical significance. Likewise, improvement was seen in liver enzymes, and liver and spleen volumes.
In the intent-to-treat population, NASH resolution was achieved in 26% (P < .0001) in the 80-mg resmetirom group, 30% (P < .0001) in the 100-mg group, and 10% in those taking placebo. And ≥ 1-stage improvement in fibrosis with no worsening of the nonalcoholic fatty liver disease activity score (NAS) was achieved by 24% (P < .0002), 26% (P < .0001), and 14% in these groups respectively.
The investigational, liver-directed agent, designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity, was well tolerated overall with a favorable safety profile.
“This is an exciting time for NASH because we are at the forefront of having a drug to treat these patients, and the benefit to patients promises to be huge,” asserted Stephen Harrison, MD, principal investigator of the MAESTRO studies, gastroenterologist and hepatologist, and founder of Pinnacle Clinical Research, San Antonio, in reporting 52-week results.
“This is the first treatment to achieve meaningful effects on both primary liver biopsy endpoints – disease activity and fibrosis – which is absolutely critical because fibrosis pertains to a worse prognosis. [These results] are reasonably likely to predict clinical benefit in a phase 3 trial in patients with NASH,” he added.
FDA-chosen endpoints likely to predict clinical outcomes
The ongoing 54-month, phase 3, registrational, double-blind, placebo-controlled trial involved taking liver biopsies from 966 patients at around 200 global sites. Biopsy readings were taken by two pathologists that were then combined into a single treatment effect.
Patients had biopsy-proven NASH with fibrosis stages F1B, F2, or F3, the presence of three or more metabolic risk factors, a FibroScan vibration-controlled transient elastography (VCTE) score of 8.5 kPa or more, baseline MRI proton density fat fraction (MRI-PDFF) of 8% or more, and a NAS score of 4 or more with at least 1 in each NAS component. Around 65% of participants had type 2 diabetes, between 13% and 16% were taking glucagonlike peptide-1 (GLP-1) receptor agonists, and 46%-51% were taking statins.
Patients were randomized 1:1:1 to once-daily resmetirom 80 mg or 100 mg orally or to placebo and treated for 52 weeks.
Both liver histological improvement primary endpoints at week-52 were proposed by the U.S. Food and Drug Administration as reasonably likely to predict clinical benefit and as such support accelerated approval for the treatment of NASH with liver fibrosis. These primary endpoints were NASH resolution (ballooning 0, inflammation 0/1) with ≥ 2-point improvement in NAS with no worsening of fibrosis, and ≥ 1-stage reduction in fibrosis with no worsening of NAS.
Patients on resmetirom showed improvement in NAS components and fibrosis, and less worsening of NAS and fibrosis, compared with placebo. Percentage improvement was seen in 31%, 33%, and 15% of patients on 80 mg resmetirom, 100 mg resmetirom, and placebo respectively; no change was seen in 51%, 48%, and 51% respectively; and worsening was seen in 18%, 19%, and 34% respectively.
The key secondary endpoint of LDL cholesterol lowering was also met. “There was a significant effect of resmetirom 80 and 100 mg on multiple atherogenic lipids/lipoproteins at both week 24 and 52,” reported Dr. Harrison. The 52-week percentage change from baseline in LDL cholesterol was –14%, –20%, and 0% for the 80-mg resmetirom group, the 100-mg group, and the placebo group respectively.
“We also saw a significant reduction in liver enzymes [alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase (GGT)] relative to placebo both in terms of percentage and absolute measures,” Dr. Harrison added. “[And] the change in liver enzymes was associated with the neutral biomarker that increases with resmetirom target engagement.”
Resmetirom at both doses also resulted in a significant effect on MRI-PDFF and Fibroscan CAP. At week 52, 80 mg resmetirom, 100 mg, and placebo led to –42.1%, –51.4% and –10.4% change from baseline in MRI-PDFF, while Fibroscan CAP changed by –39.6%, –41.3%, and –14.5% respectively, reported Dr. Harrison. Liver volume dropped by –21.6% in the 80-mg group and –25.8% in the 100-mg group, compared with –1.0% in the placebo group. Spleen volume changed by –5.9%, –6.1%, and +3.2% respectively.
Liver stiffness, as measured by Fibroscan VCTE at week 52, changed from –3.7 KPa (F1B) to –2.0 KPa (F3) at 80 mg, and from –3.7 KPa (F1B) to –2.5 KPa (F2) and –3.3 KPa (F3) at the 100-mg dose.
Further analysis showed that improvements in fibrosis and NASH resolution were seen across all key subgroups, including baseline fibrosis stage (F2 or F3), NAS (< 6, ≥ 6), type 2 diabetes status, age (< 65 years, ≥ 65 years), and sex.
Safety profile
“The safety profile of resmetirom in the MAESTRO-NASH trial is consistent with previous phase 2/3 trials in which the most common adverse events were diarrhea and nausea at treatment initiation,” said Dr. Harrison.
Study discontinuations in the 100-mg group were increased relative to placebo during the first few weeks of treatment and were similar in all treatment groups up to 52 weeks. Discontinuations of patients on resmetirom 100 mg were mainly gastrointestinal related.
Phase 2 results of the serial liver biopsy trial in adults with biopsy-confirmed NASH showed that resmetirom resolved NASH in a significantly greater percentage of patients and reduced liver enzymes, inflammatory biomarkers, and fibrosis, compared with placebo.
“We’ve been waiting for a long, long time for a therapy for these patients because until now, they have been challenged with lifestyle modifications to lose and maintain weight,” said Dr. Harrison. “There’s been a delay in identifying patients with this disease because we’ve had no treatment, but now that we are on the forefront of a treatment, it allows clinicians to open their minds to the possibility of identifying these patients.”
Dr. Harrison noted that a limitation of these data was the lack of clinical outcomes data to correlate with the biopsy data; however, the MAESTRO-NASH trial will continue to 54 months to accrue and evaluate clinical outcomes.
Milan Mishkovikj, MSc, board director of the European Liver Patients Association, Bitola, North Macedonia, commented on the potential benefit of this drug for patients. “Adhering to a healthy lifestyle is not always easy – not in all countries – so it’s encouraging to have a drug that hopefully is affordable and accessible to us. Now we need to manage the expectations of patients and caregivers.”
EASL’s vice secretary Aleksander Krag, MD, PhD, professor and head of hepatology at University of Southern Denmark, Odense, and Odense University Hospital remarked, “This is so exciting. This phase 3 trial is a real game-changer in the field of fatty liver disease because it has nearly 1,000 patients over 52 weeks of treatment.”
Madrigal Pharmaceuticals plans to submit an application to the FDA by end of the second quarter with a priority review.
Dr. Harrison is founder of Madrigal Pharmaceuticals. Dr. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience, and participated in advisory boards for Norgine and Siemens, all outside the submitted work. He receives royalties from Gyldendal and Echosens. Dr. Mishkovikj has declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VIENNA – Resolution of nonalcoholic steatohepatitis (NASH), and reduction of fibrosis on liver biopsy were achieved with the oral, thyroid hormone receptor beta-selective agonist resmetirom (Madrigal Pharmaceuticals) in patients with NASH and associated cirrhosis in a pivotal phase 3 clinical trial. The primary results of the MAESTRO-NASH (NCT03900429) trial were reported at the European Association for the Study of the Liver Congress 2023.
Both doses of resmetirom – 80 mg and 100 mg – met the primary endpoints of NASH resolution and no worsening of fibrosis on liver biopsy. The key secondary endpoint of LDL cholesterol lowering was also achieved with statistical significance. Likewise, improvement was seen in liver enzymes, and liver and spleen volumes.
In the intent-to-treat population, NASH resolution was achieved in 26% (P < .0001) in the 80-mg resmetirom group, 30% (P < .0001) in the 100-mg group, and 10% in those taking placebo. And ≥ 1-stage improvement in fibrosis with no worsening of the nonalcoholic fatty liver disease activity score (NAS) was achieved by 24% (P < .0002), 26% (P < .0001), and 14% in these groups respectively.
The investigational, liver-directed agent, designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity, was well tolerated overall with a favorable safety profile.
“This is an exciting time for NASH because we are at the forefront of having a drug to treat these patients, and the benefit to patients promises to be huge,” asserted Stephen Harrison, MD, principal investigator of the MAESTRO studies, gastroenterologist and hepatologist, and founder of Pinnacle Clinical Research, San Antonio, in reporting 52-week results.
“This is the first treatment to achieve meaningful effects on both primary liver biopsy endpoints – disease activity and fibrosis – which is absolutely critical because fibrosis pertains to a worse prognosis. [These results] are reasonably likely to predict clinical benefit in a phase 3 trial in patients with NASH,” he added.
FDA-chosen endpoints likely to predict clinical outcomes
The ongoing 54-month, phase 3, registrational, double-blind, placebo-controlled trial involved taking liver biopsies from 966 patients at around 200 global sites. Biopsy readings were taken by two pathologists that were then combined into a single treatment effect.
Patients had biopsy-proven NASH with fibrosis stages F1B, F2, or F3, the presence of three or more metabolic risk factors, a FibroScan vibration-controlled transient elastography (VCTE) score of 8.5 kPa or more, baseline MRI proton density fat fraction (MRI-PDFF) of 8% or more, and a NAS score of 4 or more with at least 1 in each NAS component. Around 65% of participants had type 2 diabetes, between 13% and 16% were taking glucagonlike peptide-1 (GLP-1) receptor agonists, and 46%-51% were taking statins.
Patients were randomized 1:1:1 to once-daily resmetirom 80 mg or 100 mg orally or to placebo and treated for 52 weeks.
Both liver histological improvement primary endpoints at week-52 were proposed by the U.S. Food and Drug Administration as reasonably likely to predict clinical benefit and as such support accelerated approval for the treatment of NASH with liver fibrosis. These primary endpoints were NASH resolution (ballooning 0, inflammation 0/1) with ≥ 2-point improvement in NAS with no worsening of fibrosis, and ≥ 1-stage reduction in fibrosis with no worsening of NAS.
Patients on resmetirom showed improvement in NAS components and fibrosis, and less worsening of NAS and fibrosis, compared with placebo. Percentage improvement was seen in 31%, 33%, and 15% of patients on 80 mg resmetirom, 100 mg resmetirom, and placebo respectively; no change was seen in 51%, 48%, and 51% respectively; and worsening was seen in 18%, 19%, and 34% respectively.
The key secondary endpoint of LDL cholesterol lowering was also met. “There was a significant effect of resmetirom 80 and 100 mg on multiple atherogenic lipids/lipoproteins at both week 24 and 52,” reported Dr. Harrison. The 52-week percentage change from baseline in LDL cholesterol was –14%, –20%, and 0% for the 80-mg resmetirom group, the 100-mg group, and the placebo group respectively.
“We also saw a significant reduction in liver enzymes [alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase (GGT)] relative to placebo both in terms of percentage and absolute measures,” Dr. Harrison added. “[And] the change in liver enzymes was associated with the neutral biomarker that increases with resmetirom target engagement.”
Resmetirom at both doses also resulted in a significant effect on MRI-PDFF and Fibroscan CAP. At week 52, 80 mg resmetirom, 100 mg, and placebo led to –42.1%, –51.4% and –10.4% change from baseline in MRI-PDFF, while Fibroscan CAP changed by –39.6%, –41.3%, and –14.5% respectively, reported Dr. Harrison. Liver volume dropped by –21.6% in the 80-mg group and –25.8% in the 100-mg group, compared with –1.0% in the placebo group. Spleen volume changed by –5.9%, –6.1%, and +3.2% respectively.
Liver stiffness, as measured by Fibroscan VCTE at week 52, changed from –3.7 KPa (F1B) to –2.0 KPa (F3) at 80 mg, and from –3.7 KPa (F1B) to –2.5 KPa (F2) and –3.3 KPa (F3) at the 100-mg dose.
Further analysis showed that improvements in fibrosis and NASH resolution were seen across all key subgroups, including baseline fibrosis stage (F2 or F3), NAS (< 6, ≥ 6), type 2 diabetes status, age (< 65 years, ≥ 65 years), and sex.
Safety profile
“The safety profile of resmetirom in the MAESTRO-NASH trial is consistent with previous phase 2/3 trials in which the most common adverse events were diarrhea and nausea at treatment initiation,” said Dr. Harrison.
Study discontinuations in the 100-mg group were increased relative to placebo during the first few weeks of treatment and were similar in all treatment groups up to 52 weeks. Discontinuations of patients on resmetirom 100 mg were mainly gastrointestinal related.
Phase 2 results of the serial liver biopsy trial in adults with biopsy-confirmed NASH showed that resmetirom resolved NASH in a significantly greater percentage of patients and reduced liver enzymes, inflammatory biomarkers, and fibrosis, compared with placebo.
“We’ve been waiting for a long, long time for a therapy for these patients because until now, they have been challenged with lifestyle modifications to lose and maintain weight,” said Dr. Harrison. “There’s been a delay in identifying patients with this disease because we’ve had no treatment, but now that we are on the forefront of a treatment, it allows clinicians to open their minds to the possibility of identifying these patients.”
Dr. Harrison noted that a limitation of these data was the lack of clinical outcomes data to correlate with the biopsy data; however, the MAESTRO-NASH trial will continue to 54 months to accrue and evaluate clinical outcomes.
Milan Mishkovikj, MSc, board director of the European Liver Patients Association, Bitola, North Macedonia, commented on the potential benefit of this drug for patients. “Adhering to a healthy lifestyle is not always easy – not in all countries – so it’s encouraging to have a drug that hopefully is affordable and accessible to us. Now we need to manage the expectations of patients and caregivers.”
EASL’s vice secretary Aleksander Krag, MD, PhD, professor and head of hepatology at University of Southern Denmark, Odense, and Odense University Hospital remarked, “This is so exciting. This phase 3 trial is a real game-changer in the field of fatty liver disease because it has nearly 1,000 patients over 52 weeks of treatment.”
Madrigal Pharmaceuticals plans to submit an application to the FDA by end of the second quarter with a priority review.
Dr. Harrison is founder of Madrigal Pharmaceuticals. Dr. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience, and participated in advisory boards for Norgine and Siemens, all outside the submitted work. He receives royalties from Gyldendal and Echosens. Dr. Mishkovikj has declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NAFLD increases risk for severe infections
People with nonalcoholic fatty liver disease (NAFLD) are more likely to develop severe infections requiring hospitalization, according to findings from a large Swedish cohort study.
The increased risk was equal to one extra severe infection in every six patients with NAFLD by 20 years after diagnosis, wrote Fahim Ebrahimi, MD, of the Karolinska Institute in Stockholm, and coauthors.
“Accumulating evidence suggests that NAFLD can affect multiple organ systems, which is not surprising, as the liver has multiple functions – regulating metabolism and being a central organ of the immune system,” Dr. Ebrahimi said in an interview.
The study was published online in Clinical Gastroenterology and Hepatology.
“Up to a fifth of cells in the liver are immune cells that process numerous antigens and pathogens from the gastrointestinal tract,” Dr. Ebrahimi noted. “We were intrigued by experimental studies showing that, in NAFLD, many of these key immune cells become dysfunctional at various levels, which may affect disease progression, but at the same time also increase the susceptibility to viral, bacterial, and fungal infections.”
Patients with NAFLD have metabolic risk factors known to increase infection risk, but a smaller study by a different research group had found that NAFLD could independently predispose patients to bacterial infections.
To further explore a connection between NAFLD and infection risk, the researchers looked at data for 12,133 Swedish adults with simple steatosis, nonfibrotic steatohepatitis, noncirrhotic fibrosis, or cirrhosis caused by NAFLD confirmed by liver biopsies performed between 1969 and 2017.
Each patient was matched to five or more contemporary controls from the general population by age, sex, and region of residence. The authors conducted an additional analysis that also adjusted for education, country of birth, and baseline clinical comorbidities, including diabetes, obesity, dyslipidemia, and hypertension, as well as hospitalization preceding the biopsy and chronic obstructive pulmonary disease.
The primary endpoint was severe infections requiring hospital admission. Secondary endpoints included seven prespecified infection subgroups: sepsis; respiratory tract; most gastrointestinal infections; bacterial peritonitis; urogenital; muscle, skin, and soft tissue; and other infections.
Elevated risk at all NAFLD stages
Dr. Ebrahimi and colleagues found that over a median follow-up of 14 years, patients with NAFLD had a higher incidence of severe infections – most often respiratory or urinary tract infections – compared with those without NAFLD (32% vs. 17%, respectively).
Biopsy-confirmed NAFLD was also associated with a 71% higher hazard and a 20-year absolute excess risk of 17.3% for severe infections requiring hospital admission versus comparators. The elevated risk showed up in patients with steatosis and increased with the severity of NAFLD. Simple steatosis saw a 64% higher risk (adjusted hazard ratio, 1.64; 95% confidence interval, 1.55-1.73), whereas patients with cirrhosis saw a more than twofold higher risk, compared with controls (aHR, 2.32; 95% CI, 1.92-2.82).
When Dr. Ebrahimi and colleagues adjusted for parameters of the metabolic syndrome, they found an independent increased risk for severe infection. For patients with NAFLD, the increased risk may come from greater susceptibility to infections in general or to a more severe course of infections.
“Our study clearly demonstrates the complexity and high disease burden associated with NAFLD,” Dr. Ebrahimi said. “We are beginning to understand the different layers involved and will eventually move away from a liver-centric view to a more holistic view of the disease.”
Clinicians caring for patients with NAFLD need to be aware of the increased risk for infection, Dr. Ebrahimi said. They also should assess their patients’ vaccination status, and seek to control modifiable risk factors, such as diabetes.
Nancy Reau, MD, of Rush University, Chicago, described the study’s message as important.
“Patients with NAFLD and advancing liver disease are at risk for severe infections,” Dr. Reau said. “When we consider the fact that patients with advanced liver disease tend to die from infectious complications, awareness leading to early recognition and efficient treatment is imperative.”
The authors acknowledged the following limitations: only severe infections requiring hospitalization could be captured; whether infection led to decompensation or vice versa among patients with cirrhosis could not be determined; and detailed data on smoking, alcohol, vaccinations, body mass, and other potentially relevant measures were not available.
The Swiss National Science Foundation, Syskonen Svensson Foundation, and Bengt Ihre Foundation provided grants to Dr. Ebrahimi or coauthors. One coauthor disclosed previous research funding from Janssen and MSD. Dr. Reau disclosed receiving research support and consulting fees from AbbVie and Gilead, as well as consulting fees from Arbutus, Intercept, and Salix.
A version of this article first appeared on Medscape.com.
People with nonalcoholic fatty liver disease (NAFLD) are more likely to develop severe infections requiring hospitalization, according to findings from a large Swedish cohort study.
The increased risk was equal to one extra severe infection in every six patients with NAFLD by 20 years after diagnosis, wrote Fahim Ebrahimi, MD, of the Karolinska Institute in Stockholm, and coauthors.
“Accumulating evidence suggests that NAFLD can affect multiple organ systems, which is not surprising, as the liver has multiple functions – regulating metabolism and being a central organ of the immune system,” Dr. Ebrahimi said in an interview.
The study was published online in Clinical Gastroenterology and Hepatology.
“Up to a fifth of cells in the liver are immune cells that process numerous antigens and pathogens from the gastrointestinal tract,” Dr. Ebrahimi noted. “We were intrigued by experimental studies showing that, in NAFLD, many of these key immune cells become dysfunctional at various levels, which may affect disease progression, but at the same time also increase the susceptibility to viral, bacterial, and fungal infections.”
Patients with NAFLD have metabolic risk factors known to increase infection risk, but a smaller study by a different research group had found that NAFLD could independently predispose patients to bacterial infections.
To further explore a connection between NAFLD and infection risk, the researchers looked at data for 12,133 Swedish adults with simple steatosis, nonfibrotic steatohepatitis, noncirrhotic fibrosis, or cirrhosis caused by NAFLD confirmed by liver biopsies performed between 1969 and 2017.
Each patient was matched to five or more contemporary controls from the general population by age, sex, and region of residence. The authors conducted an additional analysis that also adjusted for education, country of birth, and baseline clinical comorbidities, including diabetes, obesity, dyslipidemia, and hypertension, as well as hospitalization preceding the biopsy and chronic obstructive pulmonary disease.
The primary endpoint was severe infections requiring hospital admission. Secondary endpoints included seven prespecified infection subgroups: sepsis; respiratory tract; most gastrointestinal infections; bacterial peritonitis; urogenital; muscle, skin, and soft tissue; and other infections.
Elevated risk at all NAFLD stages
Dr. Ebrahimi and colleagues found that over a median follow-up of 14 years, patients with NAFLD had a higher incidence of severe infections – most often respiratory or urinary tract infections – compared with those without NAFLD (32% vs. 17%, respectively).
Biopsy-confirmed NAFLD was also associated with a 71% higher hazard and a 20-year absolute excess risk of 17.3% for severe infections requiring hospital admission versus comparators. The elevated risk showed up in patients with steatosis and increased with the severity of NAFLD. Simple steatosis saw a 64% higher risk (adjusted hazard ratio, 1.64; 95% confidence interval, 1.55-1.73), whereas patients with cirrhosis saw a more than twofold higher risk, compared with controls (aHR, 2.32; 95% CI, 1.92-2.82).
When Dr. Ebrahimi and colleagues adjusted for parameters of the metabolic syndrome, they found an independent increased risk for severe infection. For patients with NAFLD, the increased risk may come from greater susceptibility to infections in general or to a more severe course of infections.
“Our study clearly demonstrates the complexity and high disease burden associated with NAFLD,” Dr. Ebrahimi said. “We are beginning to understand the different layers involved and will eventually move away from a liver-centric view to a more holistic view of the disease.”
Clinicians caring for patients with NAFLD need to be aware of the increased risk for infection, Dr. Ebrahimi said. They also should assess their patients’ vaccination status, and seek to control modifiable risk factors, such as diabetes.
Nancy Reau, MD, of Rush University, Chicago, described the study’s message as important.
“Patients with NAFLD and advancing liver disease are at risk for severe infections,” Dr. Reau said. “When we consider the fact that patients with advanced liver disease tend to die from infectious complications, awareness leading to early recognition and efficient treatment is imperative.”
The authors acknowledged the following limitations: only severe infections requiring hospitalization could be captured; whether infection led to decompensation or vice versa among patients with cirrhosis could not be determined; and detailed data on smoking, alcohol, vaccinations, body mass, and other potentially relevant measures were not available.
The Swiss National Science Foundation, Syskonen Svensson Foundation, and Bengt Ihre Foundation provided grants to Dr. Ebrahimi or coauthors. One coauthor disclosed previous research funding from Janssen and MSD. Dr. Reau disclosed receiving research support and consulting fees from AbbVie and Gilead, as well as consulting fees from Arbutus, Intercept, and Salix.
A version of this article first appeared on Medscape.com.
People with nonalcoholic fatty liver disease (NAFLD) are more likely to develop severe infections requiring hospitalization, according to findings from a large Swedish cohort study.
The increased risk was equal to one extra severe infection in every six patients with NAFLD by 20 years after diagnosis, wrote Fahim Ebrahimi, MD, of the Karolinska Institute in Stockholm, and coauthors.
“Accumulating evidence suggests that NAFLD can affect multiple organ systems, which is not surprising, as the liver has multiple functions – regulating metabolism and being a central organ of the immune system,” Dr. Ebrahimi said in an interview.
The study was published online in Clinical Gastroenterology and Hepatology.
“Up to a fifth of cells in the liver are immune cells that process numerous antigens and pathogens from the gastrointestinal tract,” Dr. Ebrahimi noted. “We were intrigued by experimental studies showing that, in NAFLD, many of these key immune cells become dysfunctional at various levels, which may affect disease progression, but at the same time also increase the susceptibility to viral, bacterial, and fungal infections.”
Patients with NAFLD have metabolic risk factors known to increase infection risk, but a smaller study by a different research group had found that NAFLD could independently predispose patients to bacterial infections.
To further explore a connection between NAFLD and infection risk, the researchers looked at data for 12,133 Swedish adults with simple steatosis, nonfibrotic steatohepatitis, noncirrhotic fibrosis, or cirrhosis caused by NAFLD confirmed by liver biopsies performed between 1969 and 2017.
Each patient was matched to five or more contemporary controls from the general population by age, sex, and region of residence. The authors conducted an additional analysis that also adjusted for education, country of birth, and baseline clinical comorbidities, including diabetes, obesity, dyslipidemia, and hypertension, as well as hospitalization preceding the biopsy and chronic obstructive pulmonary disease.
The primary endpoint was severe infections requiring hospital admission. Secondary endpoints included seven prespecified infection subgroups: sepsis; respiratory tract; most gastrointestinal infections; bacterial peritonitis; urogenital; muscle, skin, and soft tissue; and other infections.
Elevated risk at all NAFLD stages
Dr. Ebrahimi and colleagues found that over a median follow-up of 14 years, patients with NAFLD had a higher incidence of severe infections – most often respiratory or urinary tract infections – compared with those without NAFLD (32% vs. 17%, respectively).
Biopsy-confirmed NAFLD was also associated with a 71% higher hazard and a 20-year absolute excess risk of 17.3% for severe infections requiring hospital admission versus comparators. The elevated risk showed up in patients with steatosis and increased with the severity of NAFLD. Simple steatosis saw a 64% higher risk (adjusted hazard ratio, 1.64; 95% confidence interval, 1.55-1.73), whereas patients with cirrhosis saw a more than twofold higher risk, compared with controls (aHR, 2.32; 95% CI, 1.92-2.82).
When Dr. Ebrahimi and colleagues adjusted for parameters of the metabolic syndrome, they found an independent increased risk for severe infection. For patients with NAFLD, the increased risk may come from greater susceptibility to infections in general or to a more severe course of infections.
“Our study clearly demonstrates the complexity and high disease burden associated with NAFLD,” Dr. Ebrahimi said. “We are beginning to understand the different layers involved and will eventually move away from a liver-centric view to a more holistic view of the disease.”
Clinicians caring for patients with NAFLD need to be aware of the increased risk for infection, Dr. Ebrahimi said. They also should assess their patients’ vaccination status, and seek to control modifiable risk factors, such as diabetes.
Nancy Reau, MD, of Rush University, Chicago, described the study’s message as important.
“Patients with NAFLD and advancing liver disease are at risk for severe infections,” Dr. Reau said. “When we consider the fact that patients with advanced liver disease tend to die from infectious complications, awareness leading to early recognition and efficient treatment is imperative.”
The authors acknowledged the following limitations: only severe infections requiring hospitalization could be captured; whether infection led to decompensation or vice versa among patients with cirrhosis could not be determined; and detailed data on smoking, alcohol, vaccinations, body mass, and other potentially relevant measures were not available.
The Swiss National Science Foundation, Syskonen Svensson Foundation, and Bengt Ihre Foundation provided grants to Dr. Ebrahimi or coauthors. One coauthor disclosed previous research funding from Janssen and MSD. Dr. Reau disclosed receiving research support and consulting fees from AbbVie and Gilead, as well as consulting fees from Arbutus, Intercept, and Salix.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
High Lp(a) tied to higher coronary plaque volume, progression
MANNHEIM, GERMANY – , an observational imaging study shows.
This could explain the greater risk for major adverse cardiovascular events seen in patients with high Lp(a) levels, suggests the research, presented during the annual European Atherosclerosis Society Congress.
The team performed follow-up coronary CT angiography (CCTA) on almost 275 patients who had undergone imaging approximately 10 years earlier, finding that almost one-third had high Lp(a) levels.
At baseline, per cent plaque volumes were 1.8 times greater in high Lp(a) patients versus those with low levels of the protein. After 10 years, plaque volumes were 3.3 times larger in patients with high Lp(a) levels.
Over this period, the rate of increase of plaque volume was 1.9 times greater in patients with high Lp(a) levels.
Study presenter Nick S. Nurmohamed, MD, PhD candidate, department of vascular medicine, Amsterdam University Medical Centers, also showed that high Lp(a) levels were associated with a 2.1-fold increase in rates of MACE.
He said in an interview that this finding could be related to Lp(a) increasing inflammatory signaling in the plaque, “making it more prone to rupture, and we saw that on the CCTA scans,” where high Lp(a) levels were associated with the presence of more high-risk plaques.
He added that in the absence of drugs that target Lp(a) levels directly, the results underline the need to focus on other means of lipid-lowering, as well as “creating awareness that Lp(a) is associated with plaque formation.”
Dr. Nurmohamed said that “for the moment, we have to treat patients with high Lp(a) with other risk-lowering therapies, such as low-density lipoprotein [LDL] cholesterol–lowering drugs, and the management of other risk factors.”
However, he noted that “there are a couple of Lp(a)-lowering medications in trials,” with results expected in the next 2-3 years.
“Then we will have the means to treat those patients, and with CCTA we can identify the patients with the biggest risk,” Dr. Nurmohamed added.
Plaque burden
Philippe Moulin, MD, PhD, head of endocrinology and professor of human nutrition at Faculté Lyon Est, Claude Bernard Lyon (France) 1 University, said that the association between Lp(a) and plaque burden has been seen previously in the literature in a very similar study but with only 1-year follow-up.
Similarly, registry data have suggested that Lp(a) is associated with worsening plaque progression over time.
“Here, with 10-year follow-up, [the study] is much more interesting,” due to its greater statistical power, he said in an interview. It is also “well-documented” and uses an “appropriate” methodology.
But Dr. Moulin underlined that the number of patients with high Lp(a) levels included in the study is relatively small.
Consequently, the researchers were not able to look at the level and rate of progression of atherosclerosis between different quartiles of Lp(a), “so you have no dose-response analysis.”
It also does not “establish causality,” as it remains an observational study, despite being longitudinal, “well done, and so on.”
Dr. Moulin added that the study nevertheless adds “one more stone” to the construct of the idea of high risk around high Lp(a) levels, and “prepares the ground” for the availability of two drugs to decrease Lp(a) levels, expected in 2026 and 2027.
These are expected to substantially reduce Lp(a) levels and achieve a reduction in cardiovascular risk of around 20%-40%, “which would be interesting,” especially as “we have patients who have Lp(a) levels four times above the upper normal value.”
Crucially, they may already have normal LDL cholesterol levels, meaning that, for some patients, “there is clearly a need for such treatment, as long as it is proven that it will decrease cardiovascular risk.”
For the moment, however, the strategy for managing patients with high Lp(a) remains to increase the dose of statin and to have more stringent targets, although Dr. Moulin pointed out that, “when you give statins, you raise slightly Lp(a) levels.”
Dr. Nurmohamed said in an interview that “we know from largely genetic and observational studies that Lp(a) is causally associated with atherosclerotic cardiovascular disease.”
What is less clear is the exact underlying mechanism, he said, noting that there have been several imaging studies in high and low Lp(a) patients that have yielded conflicting results in terms of the relationship with plaque burden.
To investigate the impact of Lp(a) levels on long-term coronary plaque progression, the team invited patients who had taken part in a previous CCTA study to undergo repeat CCTA, regardless of their underlying symptoms.
In all, 299 patients underwent follow-up imaging a median of 10.2 years after their original scan. Plaque volumes were quantified and adjusted for vessel volumes, and the patients were classified as having high (≥ 70 nmol/L) or low (< 70 nmol/L) Lp(a) levels.
After excluding patients who had undergone coronary artery bypass grafting, the team analyzed 274 patients with a mean age at baseline of 57 years. Of these, 159 (58%) were men. High Lp(a) levels were identified in 87 (32%) patients.
The team found that at baseline, patients with high Lp(a) levels had significantly larger percent atheroma volumes than those with low levels, at 3.92% versus 2.17%, or an absolute difference of 1.75% (P = .013).
The difference between the two groups was even greater at the follow-up, when percent atheroma volumes reached 8.75% in patients with high Lp(a) levels versus 3.90% for those with low levels, or an absolute difference of 4.85% (P = .005).
Similar findings were seen when looking separately at percentage of noncalcified and calcified plaque volumes as well as when analyzing for the presence of low-density plaques.
Multivariate analysis taking into account clinical risk factors, statin use, and CT tube voltage found that high Lp(a) levels were associated with a greater percent atheroma volume at baseline, at an odds ratio versus low Lp(a) of 1.83 (95% confidence interval, 0.12-3.54; P = .037).
High Lp(a) levels were also linked to a larger percent atheroma volume on follow-up imaging, at an odds ratio of 3.25 (95% CI, 0.80-5.71; P = .010), and a significantly greater change in atheroma volume from baseline to follow-up imaging, at an odds ratio of 1.86 (95% CI, 0.59-3.14; P = .005)
Finally, the team showed that, after adjusting for clinical risk factors, high baseline Lp(a) levels were associated with an increased risk of MACE during the follow-up period, at a hazard ratio versus low Lp(a) levels of 2.10 (95% CI, 1.01-4.29, P = .048).
No funding was declared. Dr. Nurmohamed is cofounder of Lipid Tools. Other authors declare relationships with Amgen, Novartis, Esperion, Sanofi-Regeneron, Ackee, Cleerly, GW Heart and Vascular Institute, Siemens Healthineers, and HeartFlow.
A version of this article first appeared on Medscape.com.
MANNHEIM, GERMANY – , an observational imaging study shows.
This could explain the greater risk for major adverse cardiovascular events seen in patients with high Lp(a) levels, suggests the research, presented during the annual European Atherosclerosis Society Congress.
The team performed follow-up coronary CT angiography (CCTA) on almost 275 patients who had undergone imaging approximately 10 years earlier, finding that almost one-third had high Lp(a) levels.
At baseline, per cent plaque volumes were 1.8 times greater in high Lp(a) patients versus those with low levels of the protein. After 10 years, plaque volumes were 3.3 times larger in patients with high Lp(a) levels.
Over this period, the rate of increase of plaque volume was 1.9 times greater in patients with high Lp(a) levels.
Study presenter Nick S. Nurmohamed, MD, PhD candidate, department of vascular medicine, Amsterdam University Medical Centers, also showed that high Lp(a) levels were associated with a 2.1-fold increase in rates of MACE.
He said in an interview that this finding could be related to Lp(a) increasing inflammatory signaling in the plaque, “making it more prone to rupture, and we saw that on the CCTA scans,” where high Lp(a) levels were associated with the presence of more high-risk plaques.
He added that in the absence of drugs that target Lp(a) levels directly, the results underline the need to focus on other means of lipid-lowering, as well as “creating awareness that Lp(a) is associated with plaque formation.”
Dr. Nurmohamed said that “for the moment, we have to treat patients with high Lp(a) with other risk-lowering therapies, such as low-density lipoprotein [LDL] cholesterol–lowering drugs, and the management of other risk factors.”
However, he noted that “there are a couple of Lp(a)-lowering medications in trials,” with results expected in the next 2-3 years.
“Then we will have the means to treat those patients, and with CCTA we can identify the patients with the biggest risk,” Dr. Nurmohamed added.
Plaque burden
Philippe Moulin, MD, PhD, head of endocrinology and professor of human nutrition at Faculté Lyon Est, Claude Bernard Lyon (France) 1 University, said that the association between Lp(a) and plaque burden has been seen previously in the literature in a very similar study but with only 1-year follow-up.
Similarly, registry data have suggested that Lp(a) is associated with worsening plaque progression over time.
“Here, with 10-year follow-up, [the study] is much more interesting,” due to its greater statistical power, he said in an interview. It is also “well-documented” and uses an “appropriate” methodology.
But Dr. Moulin underlined that the number of patients with high Lp(a) levels included in the study is relatively small.
Consequently, the researchers were not able to look at the level and rate of progression of atherosclerosis between different quartiles of Lp(a), “so you have no dose-response analysis.”
It also does not “establish causality,” as it remains an observational study, despite being longitudinal, “well done, and so on.”
Dr. Moulin added that the study nevertheless adds “one more stone” to the construct of the idea of high risk around high Lp(a) levels, and “prepares the ground” for the availability of two drugs to decrease Lp(a) levels, expected in 2026 and 2027.
These are expected to substantially reduce Lp(a) levels and achieve a reduction in cardiovascular risk of around 20%-40%, “which would be interesting,” especially as “we have patients who have Lp(a) levels four times above the upper normal value.”
Crucially, they may already have normal LDL cholesterol levels, meaning that, for some patients, “there is clearly a need for such treatment, as long as it is proven that it will decrease cardiovascular risk.”
For the moment, however, the strategy for managing patients with high Lp(a) remains to increase the dose of statin and to have more stringent targets, although Dr. Moulin pointed out that, “when you give statins, you raise slightly Lp(a) levels.”
Dr. Nurmohamed said in an interview that “we know from largely genetic and observational studies that Lp(a) is causally associated with atherosclerotic cardiovascular disease.”
What is less clear is the exact underlying mechanism, he said, noting that there have been several imaging studies in high and low Lp(a) patients that have yielded conflicting results in terms of the relationship with plaque burden.
To investigate the impact of Lp(a) levels on long-term coronary plaque progression, the team invited patients who had taken part in a previous CCTA study to undergo repeat CCTA, regardless of their underlying symptoms.
In all, 299 patients underwent follow-up imaging a median of 10.2 years after their original scan. Plaque volumes were quantified and adjusted for vessel volumes, and the patients were classified as having high (≥ 70 nmol/L) or low (< 70 nmol/L) Lp(a) levels.
After excluding patients who had undergone coronary artery bypass grafting, the team analyzed 274 patients with a mean age at baseline of 57 years. Of these, 159 (58%) were men. High Lp(a) levels were identified in 87 (32%) patients.
The team found that at baseline, patients with high Lp(a) levels had significantly larger percent atheroma volumes than those with low levels, at 3.92% versus 2.17%, or an absolute difference of 1.75% (P = .013).
The difference between the two groups was even greater at the follow-up, when percent atheroma volumes reached 8.75% in patients with high Lp(a) levels versus 3.90% for those with low levels, or an absolute difference of 4.85% (P = .005).
Similar findings were seen when looking separately at percentage of noncalcified and calcified plaque volumes as well as when analyzing for the presence of low-density plaques.
Multivariate analysis taking into account clinical risk factors, statin use, and CT tube voltage found that high Lp(a) levels were associated with a greater percent atheroma volume at baseline, at an odds ratio versus low Lp(a) of 1.83 (95% confidence interval, 0.12-3.54; P = .037).
High Lp(a) levels were also linked to a larger percent atheroma volume on follow-up imaging, at an odds ratio of 3.25 (95% CI, 0.80-5.71; P = .010), and a significantly greater change in atheroma volume from baseline to follow-up imaging, at an odds ratio of 1.86 (95% CI, 0.59-3.14; P = .005)
Finally, the team showed that, after adjusting for clinical risk factors, high baseline Lp(a) levels were associated with an increased risk of MACE during the follow-up period, at a hazard ratio versus low Lp(a) levels of 2.10 (95% CI, 1.01-4.29, P = .048).
No funding was declared. Dr. Nurmohamed is cofounder of Lipid Tools. Other authors declare relationships with Amgen, Novartis, Esperion, Sanofi-Regeneron, Ackee, Cleerly, GW Heart and Vascular Institute, Siemens Healthineers, and HeartFlow.
A version of this article first appeared on Medscape.com.
MANNHEIM, GERMANY – , an observational imaging study shows.
This could explain the greater risk for major adverse cardiovascular events seen in patients with high Lp(a) levels, suggests the research, presented during the annual European Atherosclerosis Society Congress.
The team performed follow-up coronary CT angiography (CCTA) on almost 275 patients who had undergone imaging approximately 10 years earlier, finding that almost one-third had high Lp(a) levels.
At baseline, per cent plaque volumes were 1.8 times greater in high Lp(a) patients versus those with low levels of the protein. After 10 years, plaque volumes were 3.3 times larger in patients with high Lp(a) levels.
Over this period, the rate of increase of plaque volume was 1.9 times greater in patients with high Lp(a) levels.
Study presenter Nick S. Nurmohamed, MD, PhD candidate, department of vascular medicine, Amsterdam University Medical Centers, also showed that high Lp(a) levels were associated with a 2.1-fold increase in rates of MACE.
He said in an interview that this finding could be related to Lp(a) increasing inflammatory signaling in the plaque, “making it more prone to rupture, and we saw that on the CCTA scans,” where high Lp(a) levels were associated with the presence of more high-risk plaques.
He added that in the absence of drugs that target Lp(a) levels directly, the results underline the need to focus on other means of lipid-lowering, as well as “creating awareness that Lp(a) is associated with plaque formation.”
Dr. Nurmohamed said that “for the moment, we have to treat patients with high Lp(a) with other risk-lowering therapies, such as low-density lipoprotein [LDL] cholesterol–lowering drugs, and the management of other risk factors.”
However, he noted that “there are a couple of Lp(a)-lowering medications in trials,” with results expected in the next 2-3 years.
“Then we will have the means to treat those patients, and with CCTA we can identify the patients with the biggest risk,” Dr. Nurmohamed added.
Plaque burden
Philippe Moulin, MD, PhD, head of endocrinology and professor of human nutrition at Faculté Lyon Est, Claude Bernard Lyon (France) 1 University, said that the association between Lp(a) and plaque burden has been seen previously in the literature in a very similar study but with only 1-year follow-up.
Similarly, registry data have suggested that Lp(a) is associated with worsening plaque progression over time.
“Here, with 10-year follow-up, [the study] is much more interesting,” due to its greater statistical power, he said in an interview. It is also “well-documented” and uses an “appropriate” methodology.
But Dr. Moulin underlined that the number of patients with high Lp(a) levels included in the study is relatively small.
Consequently, the researchers were not able to look at the level and rate of progression of atherosclerosis between different quartiles of Lp(a), “so you have no dose-response analysis.”
It also does not “establish causality,” as it remains an observational study, despite being longitudinal, “well done, and so on.”
Dr. Moulin added that the study nevertheless adds “one more stone” to the construct of the idea of high risk around high Lp(a) levels, and “prepares the ground” for the availability of two drugs to decrease Lp(a) levels, expected in 2026 and 2027.
These are expected to substantially reduce Lp(a) levels and achieve a reduction in cardiovascular risk of around 20%-40%, “which would be interesting,” especially as “we have patients who have Lp(a) levels four times above the upper normal value.”
Crucially, they may already have normal LDL cholesterol levels, meaning that, for some patients, “there is clearly a need for such treatment, as long as it is proven that it will decrease cardiovascular risk.”
For the moment, however, the strategy for managing patients with high Lp(a) remains to increase the dose of statin and to have more stringent targets, although Dr. Moulin pointed out that, “when you give statins, you raise slightly Lp(a) levels.”
Dr. Nurmohamed said in an interview that “we know from largely genetic and observational studies that Lp(a) is causally associated with atherosclerotic cardiovascular disease.”
What is less clear is the exact underlying mechanism, he said, noting that there have been several imaging studies in high and low Lp(a) patients that have yielded conflicting results in terms of the relationship with plaque burden.
To investigate the impact of Lp(a) levels on long-term coronary plaque progression, the team invited patients who had taken part in a previous CCTA study to undergo repeat CCTA, regardless of their underlying symptoms.
In all, 299 patients underwent follow-up imaging a median of 10.2 years after their original scan. Plaque volumes were quantified and adjusted for vessel volumes, and the patients were classified as having high (≥ 70 nmol/L) or low (< 70 nmol/L) Lp(a) levels.
After excluding patients who had undergone coronary artery bypass grafting, the team analyzed 274 patients with a mean age at baseline of 57 years. Of these, 159 (58%) were men. High Lp(a) levels were identified in 87 (32%) patients.
The team found that at baseline, patients with high Lp(a) levels had significantly larger percent atheroma volumes than those with low levels, at 3.92% versus 2.17%, or an absolute difference of 1.75% (P = .013).
The difference between the two groups was even greater at the follow-up, when percent atheroma volumes reached 8.75% in patients with high Lp(a) levels versus 3.90% for those with low levels, or an absolute difference of 4.85% (P = .005).
Similar findings were seen when looking separately at percentage of noncalcified and calcified plaque volumes as well as when analyzing for the presence of low-density plaques.
Multivariate analysis taking into account clinical risk factors, statin use, and CT tube voltage found that high Lp(a) levels were associated with a greater percent atheroma volume at baseline, at an odds ratio versus low Lp(a) of 1.83 (95% confidence interval, 0.12-3.54; P = .037).
High Lp(a) levels were also linked to a larger percent atheroma volume on follow-up imaging, at an odds ratio of 3.25 (95% CI, 0.80-5.71; P = .010), and a significantly greater change in atheroma volume from baseline to follow-up imaging, at an odds ratio of 1.86 (95% CI, 0.59-3.14; P = .005)
Finally, the team showed that, after adjusting for clinical risk factors, high baseline Lp(a) levels were associated with an increased risk of MACE during the follow-up period, at a hazard ratio versus low Lp(a) levels of 2.10 (95% CI, 1.01-4.29, P = .048).
No funding was declared. Dr. Nurmohamed is cofounder of Lipid Tools. Other authors declare relationships with Amgen, Novartis, Esperion, Sanofi-Regeneron, Ackee, Cleerly, GW Heart and Vascular Institute, Siemens Healthineers, and HeartFlow.
A version of this article first appeared on Medscape.com.
AT EAS 2023
Lomitapide shows promise in pediatric homozygous FH
MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.
The research was presented May 23 at the 91st European Atherosclerosis Society Congress.
Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.
It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.
The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.
The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
Early diagnosis ‘imperative’
The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.
“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”
Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.
He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.
However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”
Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”
Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
Life-limiting condition
HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.
Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.
To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.
“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”
Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.
For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.
Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).
This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.
Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.
Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.
He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).
Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.
He said that, despite these figures, the adverse events were “mostly mild or moderate.”
The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”
Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”
The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.
A version of this article first appeared on Medscape.com.
MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.
The research was presented May 23 at the 91st European Atherosclerosis Society Congress.
Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.
It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.
The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.
The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
Early diagnosis ‘imperative’
The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.
“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”
Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.
He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.
However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”
Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”
Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
Life-limiting condition
HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.
Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.
To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.
“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”
Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.
For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.
Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).
This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.
Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.
Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.
He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).
Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.
He said that, despite these figures, the adverse events were “mostly mild or moderate.”
The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”
Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”
The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.
A version of this article first appeared on Medscape.com.
MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.
The research was presented May 23 at the 91st European Atherosclerosis Society Congress.
Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.
It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.
The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.
The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
Early diagnosis ‘imperative’
The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.
“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”
Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.
He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.
However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”
Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”
Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
Life-limiting condition
HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.
Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.
To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.
“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”
Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.
For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.
Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).
This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.
Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.
Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.
He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).
Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.
He said that, despite these figures, the adverse events were “mostly mild or moderate.”
The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”
Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”
The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.
A version of this article first appeared on Medscape.com.
Plant-based diet tied to healthier blood lipid levels
, in a new meta-analysis of 30 trials.
The findings suggest that “plant-based diets have the potential to lessen the atherosclerotic burden from atherogenic lipoproteins and thereby reduce the risk of cardiovascular disease,” write Caroline Amelie Koch, a medical student at the University of Copenhagen, and colleagues. Their findings were published online in the European Heart Journal (2023 May 24. doi: 10.1093/eurheartj/ehad211).
“Vegetarian and vegan diets were associated with a 14% reduction in all artery-clogging lipoproteins as indicated by apoB,” senior author Ruth Frikke-Schmidt, DMSc, PhD, Rigshospitalet, Copenhagen, and professor, University of Copenhagen, said in a press release from her university.
“This corresponds to a third of the effect of taking cholesterol-lowering medications such as statins,” she added, “and would result in a 7% reduction in the risk of cardiovascular disease in someone who maintained a plant-based diet for 5 years.”
“Importantly, we found similar results, across continents, ages, different ranges of body mass index, and among people in different states of health,” Dr. Frikke-Schmidt stressed.
And combining statins with plant-based diets would likely produce a synergistic effect, she speculated.
“If people start eating vegetarian or vegan diets from an early age,” she said, “the potential for reducing the risk of cardiovascular disease caused by blocked arteries is substantial.”
In addition, the researchers conclude: “Shifting to plant-based diets at a populational level will reduce emissions of greenhouse gases considerably – together making these diets efficient means [moving] towards a more sustainable development, while at the same time reducing the growing burden of atherosclerotic cardiovascular disease.”
More support for vegan, vegetarian diets
These new findings “add to the body of evidence supporting favorable effects of healthy vegan and vegetarian dietary patterns on circulating levels of LDL-C and atherogenic lipoproteins, which would be expected to reduce ASCVD risk,” Kevin C. Maki, PhD, and Carol Kirkpatrick, PhD, MPH, write in an accompanying editorial.
“While it is not necessary to entirely omit foods such as meat, poultry, and fish/seafood to follow a recommended dietary pattern, reducing consumption of such foods is a reasonable option for those who prefer to do so,” note Dr. Maki, of Indiana University School of Public Health, Bloomington, and Kirkpatrick, of Idaho State University, Pocatello.
Plant-based diet needs to be ‘well-planned’
Several experts who were not involved in this meta-analysis shed light on the study and its implications in comments to the U.K. Science Media Center.
“Although a vegetarian and vegan diet can be very healthy and beneficial with respect to cardiovascular risk, it is important that it is well planned so that nutrients it can be low in are included, including iron, iodine, vitamin B12, and vitamin D,” said Duane Mellor, PhD, a registered dietitian and senior lecturer, Aston Medical School, Aston University, Birmingham, England.
Some people “may find it easier to follow a Mediterranean-style diet that features plenty of fruit, vegetables, pulses, wholegrains, fish, eggs and low-fat dairy, with only small amounts of meat,” Tracy Parker, senior dietitian at the British Heart Foundation, London, suggested.
“There is considerable evidence that this type of diet can help lower your risk of developing heart and circulatory diseases by improving cholesterol and blood pressure levels, reducing inflammation, and controlling blood glucose levels,” she added.
And Aedin Cassidy, PhD, chair in nutrition & preventative medicine, Queen’s University Belfast (Ireland), noted that “not all plant-based diets are equal. Healthy plant-based diets, characterized by fruits, vegetables, and whole grains improve health, but other plant diets (for example, those including refined carbohydrates, processed foods high in fat/salt, etc.) do not.”
This new study shows that plant-based diets have the potential to improve health by improving blood lipids, “but this is one of many potential mechanisms, including impact on blood pressure, weight maintenance, and blood sugars,” she added.
“This work represents a well-conducted analysis of 30 clinical trials involving over two thousand participants and highlights the value of a vegetarian diet in reducing the risk of heart attack or stroke through reduction in blood cholesterol levels,” said Robert Storey, BM, DM, professor of cardiology, University of Sheffield, U.K.
However, it also demonstrates that the impact of diet on an individual’s cholesterol level is relatively limited, he added.
“This is because people inherit the tendency for their livers to produce too much cholesterol, meaning that high cholesterol is more strongly influenced by our genes than by our diet,” he explained.
This is “why statins are needed to block cholesterol production in people who are at higher risk of or have already suffered from a heart attack, stroke, or other illness related to cholesterol build-up in blood vessels.”
Beneficial effect on ApoB, LDL-C, and total cholesterol
ApoB is the main apolipoprotein in LDL-C (“bad” cholesterol), the researchers note. Previous studies have shown that LDL-C and apoB-containing particles are associated with increased risk of ASCVD.
They aimed to estimate the effect of vegetarian or vegan diets on blood levels of total cholesterol, LDL-C, triglycerides, and apoB in people randomized to a vegetarian or vegan diet versus an omnivorous diet (that is, including meat and dairy).
They identified 30 studies published between 1982 and 2022 and conducted in the United States (18 studies), Sweden (2), Finland (2), South Korea (2), Australia (1), Brazil (1), Czech Republic (1), Italy (1), Iran (1), and New Zealand (1).
The diet interventions lasted from 10 days to 5 years with a mean of 29 weeks (15 studies ≤ 3 months; 12 studies 3-12 months; and three studies > 1 year). Nine studies used a crossover design, and the rest used a parallel design whereby participants followed only one diet.
The studies had 11 to 291 participants (mean, 79 participants) with a mean BMI of 21.5-35.1 kg/m2 and a mean age of 20-67 years. Thirteen studies included participants treated with lipid-lowering therapy at baseline.
The dietary intervention was vegetarian in 15 trials (three lacto-vegetarian and 12 lacto-ovo-vegetarian) and vegan in the other 15 trials.
On average, compared with people eating an omnivore diet, people eating a plant-based diet had a 7% reduction in total cholesterol from baseline (–0.34 mmol/L), a 10% reduction in LDL-C from baseline (–0.30 mmol/L), and a 14% reduction in apoB from baseline (–12.9 mg/dL) (all P < .01).
The effects were similar across age, continent, study duration, health status, intervention diet, intervention program, and study design subgroups.
There was no significant difference in triglyceride levels in patients in the omnivore versus plant-based diet groups.
Such diets could considerably reduce greenhouse gases
Senior author Dr. Frikke-Schmidt noted: “Recent systematic reviews have shown that if the populations of high-income countries shift to plant-based diets, this can reduce net emissions of greenhouse gases by between 35% to 49%.”
“Plant-based diets are key instruments for changing food production to more environmentally sustainable forms, while at the same time reducing the burden of cardiovascular disease” in an aging population, she said.
“We should be eating a varied, plant-rich diet, not too much, and quenching our thirst with water,” she concluded.
The study was funded by the Lundbeck Foundation, the Danish Heart Foundation, and the Leducq Foundation. The authors, editorialists, Ms. Parker, Dr. Cassidy, and Dr. Storey have reported no relevant financial relationships. Dr. Mellor has disclosed that he is a vegetarian.
A version of this article first appeared on Medscape.com.
, in a new meta-analysis of 30 trials.
The findings suggest that “plant-based diets have the potential to lessen the atherosclerotic burden from atherogenic lipoproteins and thereby reduce the risk of cardiovascular disease,” write Caroline Amelie Koch, a medical student at the University of Copenhagen, and colleagues. Their findings were published online in the European Heart Journal (2023 May 24. doi: 10.1093/eurheartj/ehad211).
“Vegetarian and vegan diets were associated with a 14% reduction in all artery-clogging lipoproteins as indicated by apoB,” senior author Ruth Frikke-Schmidt, DMSc, PhD, Rigshospitalet, Copenhagen, and professor, University of Copenhagen, said in a press release from her university.
“This corresponds to a third of the effect of taking cholesterol-lowering medications such as statins,” she added, “and would result in a 7% reduction in the risk of cardiovascular disease in someone who maintained a plant-based diet for 5 years.”
“Importantly, we found similar results, across continents, ages, different ranges of body mass index, and among people in different states of health,” Dr. Frikke-Schmidt stressed.
And combining statins with plant-based diets would likely produce a synergistic effect, she speculated.
“If people start eating vegetarian or vegan diets from an early age,” she said, “the potential for reducing the risk of cardiovascular disease caused by blocked arteries is substantial.”
In addition, the researchers conclude: “Shifting to plant-based diets at a populational level will reduce emissions of greenhouse gases considerably – together making these diets efficient means [moving] towards a more sustainable development, while at the same time reducing the growing burden of atherosclerotic cardiovascular disease.”
More support for vegan, vegetarian diets
These new findings “add to the body of evidence supporting favorable effects of healthy vegan and vegetarian dietary patterns on circulating levels of LDL-C and atherogenic lipoproteins, which would be expected to reduce ASCVD risk,” Kevin C. Maki, PhD, and Carol Kirkpatrick, PhD, MPH, write in an accompanying editorial.
“While it is not necessary to entirely omit foods such as meat, poultry, and fish/seafood to follow a recommended dietary pattern, reducing consumption of such foods is a reasonable option for those who prefer to do so,” note Dr. Maki, of Indiana University School of Public Health, Bloomington, and Kirkpatrick, of Idaho State University, Pocatello.
Plant-based diet needs to be ‘well-planned’
Several experts who were not involved in this meta-analysis shed light on the study and its implications in comments to the U.K. Science Media Center.
“Although a vegetarian and vegan diet can be very healthy and beneficial with respect to cardiovascular risk, it is important that it is well planned so that nutrients it can be low in are included, including iron, iodine, vitamin B12, and vitamin D,” said Duane Mellor, PhD, a registered dietitian and senior lecturer, Aston Medical School, Aston University, Birmingham, England.
Some people “may find it easier to follow a Mediterranean-style diet that features plenty of fruit, vegetables, pulses, wholegrains, fish, eggs and low-fat dairy, with only small amounts of meat,” Tracy Parker, senior dietitian at the British Heart Foundation, London, suggested.
“There is considerable evidence that this type of diet can help lower your risk of developing heart and circulatory diseases by improving cholesterol and blood pressure levels, reducing inflammation, and controlling blood glucose levels,” she added.
And Aedin Cassidy, PhD, chair in nutrition & preventative medicine, Queen’s University Belfast (Ireland), noted that “not all plant-based diets are equal. Healthy plant-based diets, characterized by fruits, vegetables, and whole grains improve health, but other plant diets (for example, those including refined carbohydrates, processed foods high in fat/salt, etc.) do not.”
This new study shows that plant-based diets have the potential to improve health by improving blood lipids, “but this is one of many potential mechanisms, including impact on blood pressure, weight maintenance, and blood sugars,” she added.
“This work represents a well-conducted analysis of 30 clinical trials involving over two thousand participants and highlights the value of a vegetarian diet in reducing the risk of heart attack or stroke through reduction in blood cholesterol levels,” said Robert Storey, BM, DM, professor of cardiology, University of Sheffield, U.K.
However, it also demonstrates that the impact of diet on an individual’s cholesterol level is relatively limited, he added.
“This is because people inherit the tendency for their livers to produce too much cholesterol, meaning that high cholesterol is more strongly influenced by our genes than by our diet,” he explained.
This is “why statins are needed to block cholesterol production in people who are at higher risk of or have already suffered from a heart attack, stroke, or other illness related to cholesterol build-up in blood vessels.”
Beneficial effect on ApoB, LDL-C, and total cholesterol
ApoB is the main apolipoprotein in LDL-C (“bad” cholesterol), the researchers note. Previous studies have shown that LDL-C and apoB-containing particles are associated with increased risk of ASCVD.
They aimed to estimate the effect of vegetarian or vegan diets on blood levels of total cholesterol, LDL-C, triglycerides, and apoB in people randomized to a vegetarian or vegan diet versus an omnivorous diet (that is, including meat and dairy).
They identified 30 studies published between 1982 and 2022 and conducted in the United States (18 studies), Sweden (2), Finland (2), South Korea (2), Australia (1), Brazil (1), Czech Republic (1), Italy (1), Iran (1), and New Zealand (1).
The diet interventions lasted from 10 days to 5 years with a mean of 29 weeks (15 studies ≤ 3 months; 12 studies 3-12 months; and three studies > 1 year). Nine studies used a crossover design, and the rest used a parallel design whereby participants followed only one diet.
The studies had 11 to 291 participants (mean, 79 participants) with a mean BMI of 21.5-35.1 kg/m2 and a mean age of 20-67 years. Thirteen studies included participants treated with lipid-lowering therapy at baseline.
The dietary intervention was vegetarian in 15 trials (three lacto-vegetarian and 12 lacto-ovo-vegetarian) and vegan in the other 15 trials.
On average, compared with people eating an omnivore diet, people eating a plant-based diet had a 7% reduction in total cholesterol from baseline (–0.34 mmol/L), a 10% reduction in LDL-C from baseline (–0.30 mmol/L), and a 14% reduction in apoB from baseline (–12.9 mg/dL) (all P < .01).
The effects were similar across age, continent, study duration, health status, intervention diet, intervention program, and study design subgroups.
There was no significant difference in triglyceride levels in patients in the omnivore versus plant-based diet groups.
Such diets could considerably reduce greenhouse gases
Senior author Dr. Frikke-Schmidt noted: “Recent systematic reviews have shown that if the populations of high-income countries shift to plant-based diets, this can reduce net emissions of greenhouse gases by between 35% to 49%.”
“Plant-based diets are key instruments for changing food production to more environmentally sustainable forms, while at the same time reducing the burden of cardiovascular disease” in an aging population, she said.
“We should be eating a varied, plant-rich diet, not too much, and quenching our thirst with water,” she concluded.
The study was funded by the Lundbeck Foundation, the Danish Heart Foundation, and the Leducq Foundation. The authors, editorialists, Ms. Parker, Dr. Cassidy, and Dr. Storey have reported no relevant financial relationships. Dr. Mellor has disclosed that he is a vegetarian.
A version of this article first appeared on Medscape.com.
, in a new meta-analysis of 30 trials.
The findings suggest that “plant-based diets have the potential to lessen the atherosclerotic burden from atherogenic lipoproteins and thereby reduce the risk of cardiovascular disease,” write Caroline Amelie Koch, a medical student at the University of Copenhagen, and colleagues. Their findings were published online in the European Heart Journal (2023 May 24. doi: 10.1093/eurheartj/ehad211).
“Vegetarian and vegan diets were associated with a 14% reduction in all artery-clogging lipoproteins as indicated by apoB,” senior author Ruth Frikke-Schmidt, DMSc, PhD, Rigshospitalet, Copenhagen, and professor, University of Copenhagen, said in a press release from her university.
“This corresponds to a third of the effect of taking cholesterol-lowering medications such as statins,” she added, “and would result in a 7% reduction in the risk of cardiovascular disease in someone who maintained a plant-based diet for 5 years.”
“Importantly, we found similar results, across continents, ages, different ranges of body mass index, and among people in different states of health,” Dr. Frikke-Schmidt stressed.
And combining statins with plant-based diets would likely produce a synergistic effect, she speculated.
“If people start eating vegetarian or vegan diets from an early age,” she said, “the potential for reducing the risk of cardiovascular disease caused by blocked arteries is substantial.”
In addition, the researchers conclude: “Shifting to plant-based diets at a populational level will reduce emissions of greenhouse gases considerably – together making these diets efficient means [moving] towards a more sustainable development, while at the same time reducing the growing burden of atherosclerotic cardiovascular disease.”
More support for vegan, vegetarian diets
These new findings “add to the body of evidence supporting favorable effects of healthy vegan and vegetarian dietary patterns on circulating levels of LDL-C and atherogenic lipoproteins, which would be expected to reduce ASCVD risk,” Kevin C. Maki, PhD, and Carol Kirkpatrick, PhD, MPH, write in an accompanying editorial.
“While it is not necessary to entirely omit foods such as meat, poultry, and fish/seafood to follow a recommended dietary pattern, reducing consumption of such foods is a reasonable option for those who prefer to do so,” note Dr. Maki, of Indiana University School of Public Health, Bloomington, and Kirkpatrick, of Idaho State University, Pocatello.
Plant-based diet needs to be ‘well-planned’
Several experts who were not involved in this meta-analysis shed light on the study and its implications in comments to the U.K. Science Media Center.
“Although a vegetarian and vegan diet can be very healthy and beneficial with respect to cardiovascular risk, it is important that it is well planned so that nutrients it can be low in are included, including iron, iodine, vitamin B12, and vitamin D,” said Duane Mellor, PhD, a registered dietitian and senior lecturer, Aston Medical School, Aston University, Birmingham, England.
Some people “may find it easier to follow a Mediterranean-style diet that features plenty of fruit, vegetables, pulses, wholegrains, fish, eggs and low-fat dairy, with only small amounts of meat,” Tracy Parker, senior dietitian at the British Heart Foundation, London, suggested.
“There is considerable evidence that this type of diet can help lower your risk of developing heart and circulatory diseases by improving cholesterol and blood pressure levels, reducing inflammation, and controlling blood glucose levels,” she added.
And Aedin Cassidy, PhD, chair in nutrition & preventative medicine, Queen’s University Belfast (Ireland), noted that “not all plant-based diets are equal. Healthy plant-based diets, characterized by fruits, vegetables, and whole grains improve health, but other plant diets (for example, those including refined carbohydrates, processed foods high in fat/salt, etc.) do not.”
This new study shows that plant-based diets have the potential to improve health by improving blood lipids, “but this is one of many potential mechanisms, including impact on blood pressure, weight maintenance, and blood sugars,” she added.
“This work represents a well-conducted analysis of 30 clinical trials involving over two thousand participants and highlights the value of a vegetarian diet in reducing the risk of heart attack or stroke through reduction in blood cholesterol levels,” said Robert Storey, BM, DM, professor of cardiology, University of Sheffield, U.K.
However, it also demonstrates that the impact of diet on an individual’s cholesterol level is relatively limited, he added.
“This is because people inherit the tendency for their livers to produce too much cholesterol, meaning that high cholesterol is more strongly influenced by our genes than by our diet,” he explained.
This is “why statins are needed to block cholesterol production in people who are at higher risk of or have already suffered from a heart attack, stroke, or other illness related to cholesterol build-up in blood vessels.”
Beneficial effect on ApoB, LDL-C, and total cholesterol
ApoB is the main apolipoprotein in LDL-C (“bad” cholesterol), the researchers note. Previous studies have shown that LDL-C and apoB-containing particles are associated with increased risk of ASCVD.
They aimed to estimate the effect of vegetarian or vegan diets on blood levels of total cholesterol, LDL-C, triglycerides, and apoB in people randomized to a vegetarian or vegan diet versus an omnivorous diet (that is, including meat and dairy).
They identified 30 studies published between 1982 and 2022 and conducted in the United States (18 studies), Sweden (2), Finland (2), South Korea (2), Australia (1), Brazil (1), Czech Republic (1), Italy (1), Iran (1), and New Zealand (1).
The diet interventions lasted from 10 days to 5 years with a mean of 29 weeks (15 studies ≤ 3 months; 12 studies 3-12 months; and three studies > 1 year). Nine studies used a crossover design, and the rest used a parallel design whereby participants followed only one diet.
The studies had 11 to 291 participants (mean, 79 participants) with a mean BMI of 21.5-35.1 kg/m2 and a mean age of 20-67 years. Thirteen studies included participants treated with lipid-lowering therapy at baseline.
The dietary intervention was vegetarian in 15 trials (three lacto-vegetarian and 12 lacto-ovo-vegetarian) and vegan in the other 15 trials.
On average, compared with people eating an omnivore diet, people eating a plant-based diet had a 7% reduction in total cholesterol from baseline (–0.34 mmol/L), a 10% reduction in LDL-C from baseline (–0.30 mmol/L), and a 14% reduction in apoB from baseline (–12.9 mg/dL) (all P < .01).
The effects were similar across age, continent, study duration, health status, intervention diet, intervention program, and study design subgroups.
There was no significant difference in triglyceride levels in patients in the omnivore versus plant-based diet groups.
Such diets could considerably reduce greenhouse gases
Senior author Dr. Frikke-Schmidt noted: “Recent systematic reviews have shown that if the populations of high-income countries shift to plant-based diets, this can reduce net emissions of greenhouse gases by between 35% to 49%.”
“Plant-based diets are key instruments for changing food production to more environmentally sustainable forms, while at the same time reducing the burden of cardiovascular disease” in an aging population, she said.
“We should be eating a varied, plant-rich diet, not too much, and quenching our thirst with water,” she concluded.
The study was funded by the Lundbeck Foundation, the Danish Heart Foundation, and the Leducq Foundation. The authors, editorialists, Ms. Parker, Dr. Cassidy, and Dr. Storey have reported no relevant financial relationships. Dr. Mellor has disclosed that he is a vegetarian.
A version of this article first appeared on Medscape.com.
FROM EUROPEAN HEART JOURNAL
Diabetes, cholesterol meds use drops after bariatric surgery
compared with patients with obesity who did not have such an operation. However, these declines didn’t extend to cardiovascular medication use.
“In this study, undergoing bariatric surgery was associated with a substantial and long-lasting reduction in the use of lipid-lowering and antidiabetic medications, compared with no surgery for obesity, while for cardiovascular medications this reduction was only transient,” the authors report in research published in JAMA Surgery.
“The results can aid in informed decision-making when considering bariatric surgery for patients with morbid obesity and inform patients and professionals about the expected long-term effects of medication use for obesity-related comorbidities,” they write.
The study “highlights the benefits of mandated databases that report metabolic bariatric surgery, obesity-related comorbidities, and medications,” writes Paulina Salminen, MD, in an accompanying editorial.
However, key limitations include a lack of weight data, which is important in light of previous studies showing that suboptimal weight loss after bariatric surgery is linked to a higher incidence of type 2 diabetes, dyslipidemia, and hypertension, note Dr. Salminen, of the department of digestive surgery, University Hospital, Turku, Finland, and colleagues.
Swedish, Finnish obesity data probed
When significant weight loss is achieved, bariatric surgery has been well documented to be associated with improvements in a variety of comorbidities, quality of life, and even life expectancy.
Key comorbidities shown to improve with the surgery include hyperlipidemia, cardiovascular disease, and type 2 diabetes.
However, data are lacking on the association between bariatric surgery and the use of medications for those conditions, particularly compared with people with obesity who don’t have bariatric surgery.
To investigate, first author Joonas H. Kauppila, MD, PhD, of Upper Gastrointestinal Surgery, Karolinska University Hospital, Stockholm, and colleagues conducted a population-based cohort study, evaluating data on 26,396 patients who underwent bariatric surgery with gastric bypass or sleeve gastrectomy in Sweden between 2005 and 2020 or Finland between 1995 and 2018.
Overall, 66.4% of patients were women and their median age was 50.
They were compared with five times as many matched controls with obesity who had not had bariatric surgery from the same population databases, representing a total of 131,980 patients who were matched based on age, country, sex, calendar year, and medication use.
In terms of lipid-lowering medication, rates of use after bariatric surgery decreased from 20.3% at baseline to 12.9% after 2 years and bounced back somewhat to 17.6% after 15 years. Comparatively, in the no surgery group, baseline lipid-lowering medication use of 21.0% increased to 44.6% after 15 years, more than twice the rate of usage in the bariatric surgery group in the same period.
Antidiabetic medications were used by 27.7% of patients in the bariatric surgery group at baseline, with a drop to 10.0% after 2 years, followed by an increase to 23.5% after 15 years. In the no surgery group, the rate of antidiabetic medication use steadily increased from 27.7% at baseline to 54.2% after 15 years, which again was nearly double the rate of antidiabetic medication use in the bariatric surgery group at 15 years.
Meanwhile, cardiovascular medications were used by 60.2% of patients receiving bariatric surgery at baseline, with the rate decreasing to 43.2% after 2 years but increasing to 74.6% after 15 years. Among the nonbariatric surgery patients, use of cardiovascular medications increased from 54.4% at baseline to 83.3% after 15 years.
Causes?
As for the cause of the lack of any decline in use of cardiovascular medications versus other medications in the surgery patients, the authors speculate that the effect “may be related to aging and regain of weight over time after bariatric surgery, a phenomenon caused by hormonal, dietary, physical, and behavioral factors.”
“In contrast, as expected, a gradual increase in the use of all three medication groups was observed over time among the patients treated with no surgery for obesity,” they note.
The lower medication use with bariatric surgery can also translate to economic benefits, the authors add.
“Economically, the long-lasting reductions in medication use for hyperlipidemia, cardiovascular morbidity, and diabetes suggest that surgical treatment of morbid obesity may infer savings in medication expenses for patients, health care, and society,” they report.
“Future research may focus on subgroups that are most likely to benefit from bariatric surgery, including resolution and severity of comorbidities,” they continue.
In their editorial, Dr. Salminen and colleagues note that previous research has shown remission of dyslipidemia in up to 70% of patients after bariatric surgery that was independent of weight loss, which appears to support the sustained reduction in lipid-lowering medications following surgery observed in the current study, suggesting some benefits on lipids beyond weight loss.
Other limitations, however, include that the bariatric surgery group in the study was older and had more comorbidities than those in previous bariatric surgery studies.
“Future studies should assess this in a younger cohort with less disease at baseline and differentiation within cardiovascular disease regarding at least hypertension, ischemic heart disease, and heart failure,” the authors conclude.
The authors have reported no relevant financial relationships. Dr. Salminen has reported receiving grants from the Sigrid Jusélius Foundation, Academy of Finland, Government Research Grant Foundation, and the University of Turku (Finland).
A version of this article first appeared on Medscape.com.
compared with patients with obesity who did not have such an operation. However, these declines didn’t extend to cardiovascular medication use.
“In this study, undergoing bariatric surgery was associated with a substantial and long-lasting reduction in the use of lipid-lowering and antidiabetic medications, compared with no surgery for obesity, while for cardiovascular medications this reduction was only transient,” the authors report in research published in JAMA Surgery.
“The results can aid in informed decision-making when considering bariatric surgery for patients with morbid obesity and inform patients and professionals about the expected long-term effects of medication use for obesity-related comorbidities,” they write.
The study “highlights the benefits of mandated databases that report metabolic bariatric surgery, obesity-related comorbidities, and medications,” writes Paulina Salminen, MD, in an accompanying editorial.
However, key limitations include a lack of weight data, which is important in light of previous studies showing that suboptimal weight loss after bariatric surgery is linked to a higher incidence of type 2 diabetes, dyslipidemia, and hypertension, note Dr. Salminen, of the department of digestive surgery, University Hospital, Turku, Finland, and colleagues.
Swedish, Finnish obesity data probed
When significant weight loss is achieved, bariatric surgery has been well documented to be associated with improvements in a variety of comorbidities, quality of life, and even life expectancy.
Key comorbidities shown to improve with the surgery include hyperlipidemia, cardiovascular disease, and type 2 diabetes.
However, data are lacking on the association between bariatric surgery and the use of medications for those conditions, particularly compared with people with obesity who don’t have bariatric surgery.
To investigate, first author Joonas H. Kauppila, MD, PhD, of Upper Gastrointestinal Surgery, Karolinska University Hospital, Stockholm, and colleagues conducted a population-based cohort study, evaluating data on 26,396 patients who underwent bariatric surgery with gastric bypass or sleeve gastrectomy in Sweden between 2005 and 2020 or Finland between 1995 and 2018.
Overall, 66.4% of patients were women and their median age was 50.
They were compared with five times as many matched controls with obesity who had not had bariatric surgery from the same population databases, representing a total of 131,980 patients who were matched based on age, country, sex, calendar year, and medication use.
In terms of lipid-lowering medication, rates of use after bariatric surgery decreased from 20.3% at baseline to 12.9% after 2 years and bounced back somewhat to 17.6% after 15 years. Comparatively, in the no surgery group, baseline lipid-lowering medication use of 21.0% increased to 44.6% after 15 years, more than twice the rate of usage in the bariatric surgery group in the same period.
Antidiabetic medications were used by 27.7% of patients in the bariatric surgery group at baseline, with a drop to 10.0% after 2 years, followed by an increase to 23.5% after 15 years. In the no surgery group, the rate of antidiabetic medication use steadily increased from 27.7% at baseline to 54.2% after 15 years, which again was nearly double the rate of antidiabetic medication use in the bariatric surgery group at 15 years.
Meanwhile, cardiovascular medications were used by 60.2% of patients receiving bariatric surgery at baseline, with the rate decreasing to 43.2% after 2 years but increasing to 74.6% after 15 years. Among the nonbariatric surgery patients, use of cardiovascular medications increased from 54.4% at baseline to 83.3% after 15 years.
Causes?
As for the cause of the lack of any decline in use of cardiovascular medications versus other medications in the surgery patients, the authors speculate that the effect “may be related to aging and regain of weight over time after bariatric surgery, a phenomenon caused by hormonal, dietary, physical, and behavioral factors.”
“In contrast, as expected, a gradual increase in the use of all three medication groups was observed over time among the patients treated with no surgery for obesity,” they note.
The lower medication use with bariatric surgery can also translate to economic benefits, the authors add.
“Economically, the long-lasting reductions in medication use for hyperlipidemia, cardiovascular morbidity, and diabetes suggest that surgical treatment of morbid obesity may infer savings in medication expenses for patients, health care, and society,” they report.
“Future research may focus on subgroups that are most likely to benefit from bariatric surgery, including resolution and severity of comorbidities,” they continue.
In their editorial, Dr. Salminen and colleagues note that previous research has shown remission of dyslipidemia in up to 70% of patients after bariatric surgery that was independent of weight loss, which appears to support the sustained reduction in lipid-lowering medications following surgery observed in the current study, suggesting some benefits on lipids beyond weight loss.
Other limitations, however, include that the bariatric surgery group in the study was older and had more comorbidities than those in previous bariatric surgery studies.
“Future studies should assess this in a younger cohort with less disease at baseline and differentiation within cardiovascular disease regarding at least hypertension, ischemic heart disease, and heart failure,” the authors conclude.
The authors have reported no relevant financial relationships. Dr. Salminen has reported receiving grants from the Sigrid Jusélius Foundation, Academy of Finland, Government Research Grant Foundation, and the University of Turku (Finland).
A version of this article first appeared on Medscape.com.
compared with patients with obesity who did not have such an operation. However, these declines didn’t extend to cardiovascular medication use.
“In this study, undergoing bariatric surgery was associated with a substantial and long-lasting reduction in the use of lipid-lowering and antidiabetic medications, compared with no surgery for obesity, while for cardiovascular medications this reduction was only transient,” the authors report in research published in JAMA Surgery.
“The results can aid in informed decision-making when considering bariatric surgery for patients with morbid obesity and inform patients and professionals about the expected long-term effects of medication use for obesity-related comorbidities,” they write.
The study “highlights the benefits of mandated databases that report metabolic bariatric surgery, obesity-related comorbidities, and medications,” writes Paulina Salminen, MD, in an accompanying editorial.
However, key limitations include a lack of weight data, which is important in light of previous studies showing that suboptimal weight loss after bariatric surgery is linked to a higher incidence of type 2 diabetes, dyslipidemia, and hypertension, note Dr. Salminen, of the department of digestive surgery, University Hospital, Turku, Finland, and colleagues.
Swedish, Finnish obesity data probed
When significant weight loss is achieved, bariatric surgery has been well documented to be associated with improvements in a variety of comorbidities, quality of life, and even life expectancy.
Key comorbidities shown to improve with the surgery include hyperlipidemia, cardiovascular disease, and type 2 diabetes.
However, data are lacking on the association between bariatric surgery and the use of medications for those conditions, particularly compared with people with obesity who don’t have bariatric surgery.
To investigate, first author Joonas H. Kauppila, MD, PhD, of Upper Gastrointestinal Surgery, Karolinska University Hospital, Stockholm, and colleagues conducted a population-based cohort study, evaluating data on 26,396 patients who underwent bariatric surgery with gastric bypass or sleeve gastrectomy in Sweden between 2005 and 2020 or Finland between 1995 and 2018.
Overall, 66.4% of patients were women and their median age was 50.
They were compared with five times as many matched controls with obesity who had not had bariatric surgery from the same population databases, representing a total of 131,980 patients who were matched based on age, country, sex, calendar year, and medication use.
In terms of lipid-lowering medication, rates of use after bariatric surgery decreased from 20.3% at baseline to 12.9% after 2 years and bounced back somewhat to 17.6% after 15 years. Comparatively, in the no surgery group, baseline lipid-lowering medication use of 21.0% increased to 44.6% after 15 years, more than twice the rate of usage in the bariatric surgery group in the same period.
Antidiabetic medications were used by 27.7% of patients in the bariatric surgery group at baseline, with a drop to 10.0% after 2 years, followed by an increase to 23.5% after 15 years. In the no surgery group, the rate of antidiabetic medication use steadily increased from 27.7% at baseline to 54.2% after 15 years, which again was nearly double the rate of antidiabetic medication use in the bariatric surgery group at 15 years.
Meanwhile, cardiovascular medications were used by 60.2% of patients receiving bariatric surgery at baseline, with the rate decreasing to 43.2% after 2 years but increasing to 74.6% after 15 years. Among the nonbariatric surgery patients, use of cardiovascular medications increased from 54.4% at baseline to 83.3% after 15 years.
Causes?
As for the cause of the lack of any decline in use of cardiovascular medications versus other medications in the surgery patients, the authors speculate that the effect “may be related to aging and regain of weight over time after bariatric surgery, a phenomenon caused by hormonal, dietary, physical, and behavioral factors.”
“In contrast, as expected, a gradual increase in the use of all three medication groups was observed over time among the patients treated with no surgery for obesity,” they note.
The lower medication use with bariatric surgery can also translate to economic benefits, the authors add.
“Economically, the long-lasting reductions in medication use for hyperlipidemia, cardiovascular morbidity, and diabetes suggest that surgical treatment of morbid obesity may infer savings in medication expenses for patients, health care, and society,” they report.
“Future research may focus on subgroups that are most likely to benefit from bariatric surgery, including resolution and severity of comorbidities,” they continue.
In their editorial, Dr. Salminen and colleagues note that previous research has shown remission of dyslipidemia in up to 70% of patients after bariatric surgery that was independent of weight loss, which appears to support the sustained reduction in lipid-lowering medications following surgery observed in the current study, suggesting some benefits on lipids beyond weight loss.
Other limitations, however, include that the bariatric surgery group in the study was older and had more comorbidities than those in previous bariatric surgery studies.
“Future studies should assess this in a younger cohort with less disease at baseline and differentiation within cardiovascular disease regarding at least hypertension, ischemic heart disease, and heart failure,” the authors conclude.
The authors have reported no relevant financial relationships. Dr. Salminen has reported receiving grants from the Sigrid Jusélius Foundation, Academy of Finland, Government Research Grant Foundation, and the University of Turku (Finland).
A version of this article first appeared on Medscape.com.
FROM JAMA SURGERY
Half of deaths from homozygous FH occur before age 32 years
MANNHEIM, GERMANY –
The researchers looked at almost 40 patients from the HoFH International Clinical Collaborators (HICC) registry who had died before data entry, finding that they had a mean age of diagnosis of 12 years.
Even those who received treatment had high LDL cholesterol levels, and 70% developed atherosclerotic cardiovascular disease (ASCVD) at a median age of 28 years.
Worryingly, the results showed that the median age at death was 32 years. Results were presented at the annual congress of the European Atherosclerosis Society.
Patients with HoFH “have severe atherosclerotic cardiovascular disease risk,” said study presenter Janneke Mulder, a PhD candidate at the department of internal medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
“Therefore, early diagnosis and initiation of treatments, and also a combination of treatments, is really crucial,” she added.
Call to action
Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, and Secretary of the EAS, described the results as “terrifying.”
He said in an interview that they are a “call to action,” especially given that so few patients in the study received intensive combination lipid-lowering therapy despite having a baseline LDL cholesterol level that was “very, very high.”
Banach underlined that patients who receive triple lipid-lowering therapy with a high-intensity statin, ezetimibe (Nustendi), and a proprotein convertase subtilisin/kexin type 9 inhibitor, could expect, based on current evidence, to see their LDL cholesterol levels reduced by 85% and be on target.
“Obviously, this is kind of academic,” because in the real-world “this 85% is not observed very often,” but it offers a target for steep reductions in cholesterol levels.
“This is something that we should focus on for these patients from the beginning,” said Dr. Banach, either with a stepwise approach “or for experts in pediatric HoFH, “maybe immediately.”
He emphasized that clinicians have everything at hand to “be both effective in the early diagnosis of HoFH, the earlier the better, and obviously to be effective with its treatment.”
“We should do something to prolong the lives of those people,” because the current results are “terrifying,” Dr. Banach added.
Rare genetic condition
Presenting her findings, Ms. Mulder began by highlighting that HoFH is a “rare genetic condition that occurs due to mutations in cholesterol metabolism.”
This, she continued, leads to “severely increased LDL cholesterol levels, and consequently to very premature cardiovascular disease,” with patients potentially experiencing their first cardiovascular event before age 20 years.
Ms. Mulder pointed out that, although there have been case series in the literature on HoFH, they have had “limited numbers” and patients have typically spent decades being treated at the same lipid management clinic.
To broaden the understanding of the clinical characteristics and management of patients dying with HoFH, the team examined data from the HICC registry, which is “the largest contemporary database of homozygous FH patients,” Ms. Mulder said.
It includes 751 patients with HoFH from 88 centers in 38 countries who were alive in 2010 or later. Data entry was between 2016 and 2020. The current analysis focused on 37 patients who had already died by the time they were included on the registry.
Of those, 49% were women, 38% were of White ethnicity, and 43% were from high-income countries.
The median age at diagnosis was 12 years, Ms. Mulder said, explaining that this is similar to that seen in other studies. The majority (86%) underwent genetic testing, and 92% presented with xanthomas.
Ms. Mulder also noted that, at their final clinical evaluation, which was conducted a median age of 18 years after their initial diagnosis, 43% of patients were recorded as current or former smokers.
In terms of their lipid-lowering therapy, 94% were taking a statin, whereas 68% were on ezetimibe, and 23% were undergoing apheresis.
Ms. Mulder said that the median number of lipid-lowering therapies per patient was two, and that “sadly ... 26% of the deceased patients had only one or no treatment.”
Therefore, perhaps unsurprisingly even those patients who were receiving treatment had LDL cholesterol levels that were “too high,” at 9.4 mmol/L versus 15.6 mmol/L among those who were untreated.
There was a high prevalence of ASCVD, at 70% overall, or 41% for aortic stenosis, 30% for myocardial infarction, 30% for angina pectoris, and 22% each for aortic valve replacement and coronary artery bypass grafting. In addition, 19% underwent percutaneous coronary intervention.
The median age of onset for ASCVD was 28 years. Ms. Mulder pointed out, however, that, as data were not available for all patients, “this might be an underestimation.” About 70% of patients experienced recurrent ASCVD.
There was a wide range in the age at which patients with HoFH died, although the median was, “strikingly,” 32 years, Ms. Mulder said. Death was confirmed as stemming from cardiovascular causes in 76% of cases.
During the postpresentation discussion, session chair Antonio J. Vallejo-Vaz, PhD, from the Research Group of Clinical Epidemiology and Vascular Risk, Institute of Biomedicine of Seville (Spain), highlighted that, if 38% of the patients were of White ethnicity, then the remainder must therefore be from other ethnic groups.
“There could be potential issues with accessibility to lipid centers” for these patients, which could affect the findings, noted Dr. Vallejo-Vaz, who is also chief scientist of the EAS Familial Hypercholesterolaemia Studies Collaboration.
Ms. Mulder agreed, replying that their results, though already striking, may be an underestimation because the patients were all from either high or middle-income countries, “so it would be good to have some data on low-income countries.”
She was also asked about two patients who died at a much older age than did the others, at ages 70 years and 86 years, respectively, and whether they had, for example, a protective genetic mutation.
Ms. Mulder said that they do not yet know, but they are planning an extended case series on these and other long-lived patients so that they can be investigated further.
No funding or relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
MANNHEIM, GERMANY –
The researchers looked at almost 40 patients from the HoFH International Clinical Collaborators (HICC) registry who had died before data entry, finding that they had a mean age of diagnosis of 12 years.
Even those who received treatment had high LDL cholesterol levels, and 70% developed atherosclerotic cardiovascular disease (ASCVD) at a median age of 28 years.
Worryingly, the results showed that the median age at death was 32 years. Results were presented at the annual congress of the European Atherosclerosis Society.
Patients with HoFH “have severe atherosclerotic cardiovascular disease risk,” said study presenter Janneke Mulder, a PhD candidate at the department of internal medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
“Therefore, early diagnosis and initiation of treatments, and also a combination of treatments, is really crucial,” she added.
Call to action
Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, and Secretary of the EAS, described the results as “terrifying.”
He said in an interview that they are a “call to action,” especially given that so few patients in the study received intensive combination lipid-lowering therapy despite having a baseline LDL cholesterol level that was “very, very high.”
Banach underlined that patients who receive triple lipid-lowering therapy with a high-intensity statin, ezetimibe (Nustendi), and a proprotein convertase subtilisin/kexin type 9 inhibitor, could expect, based on current evidence, to see their LDL cholesterol levels reduced by 85% and be on target.
“Obviously, this is kind of academic,” because in the real-world “this 85% is not observed very often,” but it offers a target for steep reductions in cholesterol levels.
“This is something that we should focus on for these patients from the beginning,” said Dr. Banach, either with a stepwise approach “or for experts in pediatric HoFH, “maybe immediately.”
He emphasized that clinicians have everything at hand to “be both effective in the early diagnosis of HoFH, the earlier the better, and obviously to be effective with its treatment.”
“We should do something to prolong the lives of those people,” because the current results are “terrifying,” Dr. Banach added.
Rare genetic condition
Presenting her findings, Ms. Mulder began by highlighting that HoFH is a “rare genetic condition that occurs due to mutations in cholesterol metabolism.”
This, she continued, leads to “severely increased LDL cholesterol levels, and consequently to very premature cardiovascular disease,” with patients potentially experiencing their first cardiovascular event before age 20 years.
Ms. Mulder pointed out that, although there have been case series in the literature on HoFH, they have had “limited numbers” and patients have typically spent decades being treated at the same lipid management clinic.
To broaden the understanding of the clinical characteristics and management of patients dying with HoFH, the team examined data from the HICC registry, which is “the largest contemporary database of homozygous FH patients,” Ms. Mulder said.
It includes 751 patients with HoFH from 88 centers in 38 countries who were alive in 2010 or later. Data entry was between 2016 and 2020. The current analysis focused on 37 patients who had already died by the time they were included on the registry.
Of those, 49% were women, 38% were of White ethnicity, and 43% were from high-income countries.
The median age at diagnosis was 12 years, Ms. Mulder said, explaining that this is similar to that seen in other studies. The majority (86%) underwent genetic testing, and 92% presented with xanthomas.
Ms. Mulder also noted that, at their final clinical evaluation, which was conducted a median age of 18 years after their initial diagnosis, 43% of patients were recorded as current or former smokers.
In terms of their lipid-lowering therapy, 94% were taking a statin, whereas 68% were on ezetimibe, and 23% were undergoing apheresis.
Ms. Mulder said that the median number of lipid-lowering therapies per patient was two, and that “sadly ... 26% of the deceased patients had only one or no treatment.”
Therefore, perhaps unsurprisingly even those patients who were receiving treatment had LDL cholesterol levels that were “too high,” at 9.4 mmol/L versus 15.6 mmol/L among those who were untreated.
There was a high prevalence of ASCVD, at 70% overall, or 41% for aortic stenosis, 30% for myocardial infarction, 30% for angina pectoris, and 22% each for aortic valve replacement and coronary artery bypass grafting. In addition, 19% underwent percutaneous coronary intervention.
The median age of onset for ASCVD was 28 years. Ms. Mulder pointed out, however, that, as data were not available for all patients, “this might be an underestimation.” About 70% of patients experienced recurrent ASCVD.
There was a wide range in the age at which patients with HoFH died, although the median was, “strikingly,” 32 years, Ms. Mulder said. Death was confirmed as stemming from cardiovascular causes in 76% of cases.
During the postpresentation discussion, session chair Antonio J. Vallejo-Vaz, PhD, from the Research Group of Clinical Epidemiology and Vascular Risk, Institute of Biomedicine of Seville (Spain), highlighted that, if 38% of the patients were of White ethnicity, then the remainder must therefore be from other ethnic groups.
“There could be potential issues with accessibility to lipid centers” for these patients, which could affect the findings, noted Dr. Vallejo-Vaz, who is also chief scientist of the EAS Familial Hypercholesterolaemia Studies Collaboration.
Ms. Mulder agreed, replying that their results, though already striking, may be an underestimation because the patients were all from either high or middle-income countries, “so it would be good to have some data on low-income countries.”
She was also asked about two patients who died at a much older age than did the others, at ages 70 years and 86 years, respectively, and whether they had, for example, a protective genetic mutation.
Ms. Mulder said that they do not yet know, but they are planning an extended case series on these and other long-lived patients so that they can be investigated further.
No funding or relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
MANNHEIM, GERMANY –
The researchers looked at almost 40 patients from the HoFH International Clinical Collaborators (HICC) registry who had died before data entry, finding that they had a mean age of diagnosis of 12 years.
Even those who received treatment had high LDL cholesterol levels, and 70% developed atherosclerotic cardiovascular disease (ASCVD) at a median age of 28 years.
Worryingly, the results showed that the median age at death was 32 years. Results were presented at the annual congress of the European Atherosclerosis Society.
Patients with HoFH “have severe atherosclerotic cardiovascular disease risk,” said study presenter Janneke Mulder, a PhD candidate at the department of internal medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
“Therefore, early diagnosis and initiation of treatments, and also a combination of treatments, is really crucial,” she added.
Call to action
Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, and Secretary of the EAS, described the results as “terrifying.”
He said in an interview that they are a “call to action,” especially given that so few patients in the study received intensive combination lipid-lowering therapy despite having a baseline LDL cholesterol level that was “very, very high.”
Banach underlined that patients who receive triple lipid-lowering therapy with a high-intensity statin, ezetimibe (Nustendi), and a proprotein convertase subtilisin/kexin type 9 inhibitor, could expect, based on current evidence, to see their LDL cholesterol levels reduced by 85% and be on target.
“Obviously, this is kind of academic,” because in the real-world “this 85% is not observed very often,” but it offers a target for steep reductions in cholesterol levels.
“This is something that we should focus on for these patients from the beginning,” said Dr. Banach, either with a stepwise approach “or for experts in pediatric HoFH, “maybe immediately.”
He emphasized that clinicians have everything at hand to “be both effective in the early diagnosis of HoFH, the earlier the better, and obviously to be effective with its treatment.”
“We should do something to prolong the lives of those people,” because the current results are “terrifying,” Dr. Banach added.
Rare genetic condition
Presenting her findings, Ms. Mulder began by highlighting that HoFH is a “rare genetic condition that occurs due to mutations in cholesterol metabolism.”
This, she continued, leads to “severely increased LDL cholesterol levels, and consequently to very premature cardiovascular disease,” with patients potentially experiencing their first cardiovascular event before age 20 years.
Ms. Mulder pointed out that, although there have been case series in the literature on HoFH, they have had “limited numbers” and patients have typically spent decades being treated at the same lipid management clinic.
To broaden the understanding of the clinical characteristics and management of patients dying with HoFH, the team examined data from the HICC registry, which is “the largest contemporary database of homozygous FH patients,” Ms. Mulder said.
It includes 751 patients with HoFH from 88 centers in 38 countries who were alive in 2010 or later. Data entry was between 2016 and 2020. The current analysis focused on 37 patients who had already died by the time they were included on the registry.
Of those, 49% were women, 38% were of White ethnicity, and 43% were from high-income countries.
The median age at diagnosis was 12 years, Ms. Mulder said, explaining that this is similar to that seen in other studies. The majority (86%) underwent genetic testing, and 92% presented with xanthomas.
Ms. Mulder also noted that, at their final clinical evaluation, which was conducted a median age of 18 years after their initial diagnosis, 43% of patients were recorded as current or former smokers.
In terms of their lipid-lowering therapy, 94% were taking a statin, whereas 68% were on ezetimibe, and 23% were undergoing apheresis.
Ms. Mulder said that the median number of lipid-lowering therapies per patient was two, and that “sadly ... 26% of the deceased patients had only one or no treatment.”
Therefore, perhaps unsurprisingly even those patients who were receiving treatment had LDL cholesterol levels that were “too high,” at 9.4 mmol/L versus 15.6 mmol/L among those who were untreated.
There was a high prevalence of ASCVD, at 70% overall, or 41% for aortic stenosis, 30% for myocardial infarction, 30% for angina pectoris, and 22% each for aortic valve replacement and coronary artery bypass grafting. In addition, 19% underwent percutaneous coronary intervention.
The median age of onset for ASCVD was 28 years. Ms. Mulder pointed out, however, that, as data were not available for all patients, “this might be an underestimation.” About 70% of patients experienced recurrent ASCVD.
There was a wide range in the age at which patients with HoFH died, although the median was, “strikingly,” 32 years, Ms. Mulder said. Death was confirmed as stemming from cardiovascular causes in 76% of cases.
During the postpresentation discussion, session chair Antonio J. Vallejo-Vaz, PhD, from the Research Group of Clinical Epidemiology and Vascular Risk, Institute of Biomedicine of Seville (Spain), highlighted that, if 38% of the patients were of White ethnicity, then the remainder must therefore be from other ethnic groups.
“There could be potential issues with accessibility to lipid centers” for these patients, which could affect the findings, noted Dr. Vallejo-Vaz, who is also chief scientist of the EAS Familial Hypercholesterolaemia Studies Collaboration.
Ms. Mulder agreed, replying that their results, though already striking, may be an underestimation because the patients were all from either high or middle-income countries, “so it would be good to have some data on low-income countries.”
She was also asked about two patients who died at a much older age than did the others, at ages 70 years and 86 years, respectively, and whether they had, for example, a protective genetic mutation.
Ms. Mulder said that they do not yet know, but they are planning an extended case series on these and other long-lived patients so that they can be investigated further.
No funding or relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.