User login
Statin, antihypertensive treatment don’t guarantee healthier lifestyles
When people learn they have enough cardiovascular disease risk to start treatment with a statin or antihypertensive drug, the impact on their healthy-lifestyle choices seems to often be a wash, based on findings from more than 40,000 Finland residents followed for at least 4 years after starting their primary-prevention regimen.
“Patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” wrote Maarit J. Korhonen, PhD, and associates in a report published in the Journal of the American Heart Association.
“Initiation of antihypertensive or statin therapy appears to be associated with lifestyle changes, some positive and others negative,” wrote Dr. Korhonen, a pharmacoepidemiologist at the University of Turku (Finland), and associates. This was the first reported study to assess a large-scale and prospectively followed cohort to look for associations between the use of medicines that prevent cardiovascular disease (CVD) and lifestyle changes. Most previous studies of these associations “have been cross sectional and provide no information on potential lifestyle changes during the time window around the initiation of medication use,” they added.
The new study specifically found that, on average, people who began treatment with at least one CVD-prevention medication for the first time were more likely to gain weight and more likely to become less active during the years following their treatment onset. But at the same time, these patients were also more likely to either quit or cut down on their smoking and alcohol consumption, the researchers found.
Their analysis used data from 41,225 people enrolled in the Finnish Public Sector Study, which prospectively began collecting data on a large number of Finland residents in the 1990s. They specifically focused on 81,772 completed questionnaires – collected at 4-year intervals – from people who completed at least two consecutive rounds of the survey during 2000-2013, and who were also at least 40 years old and free of prevalent CVD at the time of their first survey. The participants averaged nearly 53 years of age at their first survey, and 84% were women.
The researchers subdivided the survey responses into 8,837 (11%) people who began a statin, antihypertensive drug, or both during their participation; 26,914 (33%) already on a statin or antihypertensive drug when they completed their first questionnaire; and 46,021 response sets (56%) from people who never began treatment with either drug class. People who initiated a relevant drug began a median of 1.7 years following completion of their first survey, and a median of 2.4 years before their next survey. During follow-up, about 2% of all participants became newly diagnosed with some form of CVD.
The results showed that, after full adjustment for possible confounders, the mean increase in body mass index was larger among those who initiated a CVD-prevention drug, compared with those who did not. Among participants who were obese at entry, those who started a CVD drug had a statistically significant 37% increased rate of remaining obese, compared with those not starting these drugs. Among those who were not obese at baseline, those who began a CVD prevention drug had a statistically significant 82%% higher rate of becoming obese, compared with those not on a CVD-prevention drug. In addition, average daily energy expenditure, a measure of physical activity, showed a statistically significant decline among those who started a CVD drug, compared with those who did not. In contrast, CVD drug initiators had an average 1.85 gram/week decline in alcohol intake, compared with noninitiators, and those who were current smokers at the first survey and then started a CVD drug had a 26% relative drop in their smoking prevalence, compared with those who did not start a CVD drug, both statistically significant differences.
The findings suggest that “patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” the authors concluded. “This means that expansion of pharmacologic interventions toward populations at low CVD risk may not necessarily lead to expected benefits at the population level.”
The study received no commercial funding. Dr. Korhonen had no disclosures.
SOURCE: Korhonen MJ et al. J Am Heart Assoc. 2020 Feb 5. doi: 10.1161/JAHA.119.014.168.
When people learn they have enough cardiovascular disease risk to start treatment with a statin or antihypertensive drug, the impact on their healthy-lifestyle choices seems to often be a wash, based on findings from more than 40,000 Finland residents followed for at least 4 years after starting their primary-prevention regimen.
“Patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” wrote Maarit J. Korhonen, PhD, and associates in a report published in the Journal of the American Heart Association.
“Initiation of antihypertensive or statin therapy appears to be associated with lifestyle changes, some positive and others negative,” wrote Dr. Korhonen, a pharmacoepidemiologist at the University of Turku (Finland), and associates. This was the first reported study to assess a large-scale and prospectively followed cohort to look for associations between the use of medicines that prevent cardiovascular disease (CVD) and lifestyle changes. Most previous studies of these associations “have been cross sectional and provide no information on potential lifestyle changes during the time window around the initiation of medication use,” they added.
The new study specifically found that, on average, people who began treatment with at least one CVD-prevention medication for the first time were more likely to gain weight and more likely to become less active during the years following their treatment onset. But at the same time, these patients were also more likely to either quit or cut down on their smoking and alcohol consumption, the researchers found.
Their analysis used data from 41,225 people enrolled in the Finnish Public Sector Study, which prospectively began collecting data on a large number of Finland residents in the 1990s. They specifically focused on 81,772 completed questionnaires – collected at 4-year intervals – from people who completed at least two consecutive rounds of the survey during 2000-2013, and who were also at least 40 years old and free of prevalent CVD at the time of their first survey. The participants averaged nearly 53 years of age at their first survey, and 84% were women.
The researchers subdivided the survey responses into 8,837 (11%) people who began a statin, antihypertensive drug, or both during their participation; 26,914 (33%) already on a statin or antihypertensive drug when they completed their first questionnaire; and 46,021 response sets (56%) from people who never began treatment with either drug class. People who initiated a relevant drug began a median of 1.7 years following completion of their first survey, and a median of 2.4 years before their next survey. During follow-up, about 2% of all participants became newly diagnosed with some form of CVD.
The results showed that, after full adjustment for possible confounders, the mean increase in body mass index was larger among those who initiated a CVD-prevention drug, compared with those who did not. Among participants who were obese at entry, those who started a CVD drug had a statistically significant 37% increased rate of remaining obese, compared with those not starting these drugs. Among those who were not obese at baseline, those who began a CVD prevention drug had a statistically significant 82%% higher rate of becoming obese, compared with those not on a CVD-prevention drug. In addition, average daily energy expenditure, a measure of physical activity, showed a statistically significant decline among those who started a CVD drug, compared with those who did not. In contrast, CVD drug initiators had an average 1.85 gram/week decline in alcohol intake, compared with noninitiators, and those who were current smokers at the first survey and then started a CVD drug had a 26% relative drop in their smoking prevalence, compared with those who did not start a CVD drug, both statistically significant differences.
The findings suggest that “patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” the authors concluded. “This means that expansion of pharmacologic interventions toward populations at low CVD risk may not necessarily lead to expected benefits at the population level.”
The study received no commercial funding. Dr. Korhonen had no disclosures.
SOURCE: Korhonen MJ et al. J Am Heart Assoc. 2020 Feb 5. doi: 10.1161/JAHA.119.014.168.
When people learn they have enough cardiovascular disease risk to start treatment with a statin or antihypertensive drug, the impact on their healthy-lifestyle choices seems to often be a wash, based on findings from more than 40,000 Finland residents followed for at least 4 years after starting their primary-prevention regimen.
“Patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” wrote Maarit J. Korhonen, PhD, and associates in a report published in the Journal of the American Heart Association.
“Initiation of antihypertensive or statin therapy appears to be associated with lifestyle changes, some positive and others negative,” wrote Dr. Korhonen, a pharmacoepidemiologist at the University of Turku (Finland), and associates. This was the first reported study to assess a large-scale and prospectively followed cohort to look for associations between the use of medicines that prevent cardiovascular disease (CVD) and lifestyle changes. Most previous studies of these associations “have been cross sectional and provide no information on potential lifestyle changes during the time window around the initiation of medication use,” they added.
The new study specifically found that, on average, people who began treatment with at least one CVD-prevention medication for the first time were more likely to gain weight and more likely to become less active during the years following their treatment onset. But at the same time, these patients were also more likely to either quit or cut down on their smoking and alcohol consumption, the researchers found.
Their analysis used data from 41,225 people enrolled in the Finnish Public Sector Study, which prospectively began collecting data on a large number of Finland residents in the 1990s. They specifically focused on 81,772 completed questionnaires – collected at 4-year intervals – from people who completed at least two consecutive rounds of the survey during 2000-2013, and who were also at least 40 years old and free of prevalent CVD at the time of their first survey. The participants averaged nearly 53 years of age at their first survey, and 84% were women.
The researchers subdivided the survey responses into 8,837 (11%) people who began a statin, antihypertensive drug, or both during their participation; 26,914 (33%) already on a statin or antihypertensive drug when they completed their first questionnaire; and 46,021 response sets (56%) from people who never began treatment with either drug class. People who initiated a relevant drug began a median of 1.7 years following completion of their first survey, and a median of 2.4 years before their next survey. During follow-up, about 2% of all participants became newly diagnosed with some form of CVD.
The results showed that, after full adjustment for possible confounders, the mean increase in body mass index was larger among those who initiated a CVD-prevention drug, compared with those who did not. Among participants who were obese at entry, those who started a CVD drug had a statistically significant 37% increased rate of remaining obese, compared with those not starting these drugs. Among those who were not obese at baseline, those who began a CVD prevention drug had a statistically significant 82%% higher rate of becoming obese, compared with those not on a CVD-prevention drug. In addition, average daily energy expenditure, a measure of physical activity, showed a statistically significant decline among those who started a CVD drug, compared with those who did not. In contrast, CVD drug initiators had an average 1.85 gram/week decline in alcohol intake, compared with noninitiators, and those who were current smokers at the first survey and then started a CVD drug had a 26% relative drop in their smoking prevalence, compared with those who did not start a CVD drug, both statistically significant differences.
The findings suggest that “patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” the authors concluded. “This means that expansion of pharmacologic interventions toward populations at low CVD risk may not necessarily lead to expected benefits at the population level.”
The study received no commercial funding. Dr. Korhonen had no disclosures.
SOURCE: Korhonen MJ et al. J Am Heart Assoc. 2020 Feb 5. doi: 10.1161/JAHA.119.014.168.
FROM THE JOURNAL OF THE AMERICAN HEART ASSOCIATION
New Vascepa indication opens up treatment to millions; “Most significant event since statins”
The newly approved U.S. indication for icosapent ethyl (Vascepa; Amarin) is broadly in line with the entry criteria for the REDUCE-IT trial and includes a large high-risk primary-prevention population, as well as those with established cardiovascular disease (CVD). The drug, thus, could well be used by millions of patients in the United States alone.
The high-dose, purified eicosapentaenoic acid product was approved last week by the Food and Drug Administration for cardiovascular risk reduction among adults already taking maximally tolerated statins with triglyceride levels of 150 mg/dL or higher who have either established CVD or diabetes and two or more additional risk factors for CVD.
The approval is based largely on the REDUCE-IT trial’s finding of a 25% reduction in risk for major adverse cardiovascular events versus placebo. The FDA stated that the approval is the first for an agent with this specific indication.
Noting that it recognizes the need for additional medical treatments for CVD, the FDA says the new approval “will give patients with elevated triglycerides and other important risk factors, including heart disease, stroke, and diabetes, an adjunctive treatment option that can help decrease their risk of cardiovascular events.”
The drug was unanimously recommended for approval by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee last month. But while the committee all agreed on its use in patients with established CVD, which made up 70% of the REDUCE-IT population, they were divided on whether the indication should be extended to the high-risk primary-prevention population, who made up just 30% of patients in the study.
Nonetheless, the FDA has gone for a broad indication based on the whole REDUCE-IT population.
In a conference call following the approval, Steven Ketchum, PhD, chief scientific officer at Amarin, pointed out that the primary-prevention population stipulated in the new approval differed very slightly from the REDUCE-IT enrollment criteria.
The trial specified that patients with diabetes should be older than 50 with one other cardiovascular risk factor, whereas the approved population is for diabetes and two cardiovascular risk factors. But as these two risk factors are not specified, they could include age, cigarette smoking, hypertension or use of an antihypertensive agent, low HDL cholesterol, high C-reactive protein, body mass index above 25 kg/m2, renal dysfunction, retinopathy, albuminuria, or an ankle branchial index below 0.9, Dr. Ketchum said.
“So while the label asks for two other risk factors, one of these could be age; so we believe the label is actually slightly broader than the REDUCE-IT inclusion criteria, and doctors have been left with significant leeway to decide which risk factors to consider on top of diabetes.”
Deepak Bhatt, MD, the lead investigator of REDUCE-IT, described the Vascepa approval as “the most significant event in the field of cardiovascular prevention since the introduction of statins nearly 3 decades ago.”
He commended the FDA on “a very evidence-based, prescriber-friendly, and most importantly, patient-friendly label,” which he said was in line with guidelines from multiple professional societies that have already incorporated the REDUCE-IT findings for secondary prevention and diabetic primary prevention.
Dr. Bhatt, who is a professor of medicine at Brigham and Women’s Hospital and Harvard Medical School, Boston, said the label essentially matches the REDUCE-IT population.
“The entry criteria for REDUCE-IT was fasting triglycerides greater than or equal to 150 mg/dL, with a 10% variance allowed (giving a minimum triglyceride value of 135 mg/dL). In actuality, we ended up with about 10% of the population with triglycerides between 100 and 150 mg/dL, and they had a similar degree of benefit as those with higher levels,” he reported.
“In the label, the 150 mg/dL does not specify fasting, and in fact many practices have moved away from fasting lipid measurements for the sake of patient comfort,” Dr. Bhatt added. “On average, nonfasting levels are about 50 mg/dL higher, so the label essentially mirrors those we studied, with the FDA applying good common sense and not being overly dogmatic about the exact wording of the trial inclusion criteria.”
No price change foreseen
Vascepa is already on the market for patients with very high triglyceride levels, and the company says it is not increasing the current price of about $300 a month, which is “relatively low, compared to other new breakthrough drugs.” However, it says it expects sales to grow from vastly increased volume based on the new indication.
Dr. Bhatt noted that REDUCE-IT cost-effectiveness data presented at the recent American Heart Association scientific sessions found the drug to be cost saving in the majority of cases. “That is something that is quite rare in cost-effectiveness research,” he said.
“Now, the key challenge is to identify and treat appropriate patients,” Dr. Bhatt noted. He says this task will largely fall on cardiologists, endocrinologists, and primary care physicians, though stroke neurologists, nephrologists, and vascular medicine specialists will also have patients for whom the data are relevant.
“I believe the drug will ultimately be widely prescribed, initially by subspecialists, but by primary care physicians also. It is overall very well tolerated, safe, and easy to use,” he said. “Much like statin prescription started in subspecialty practices but then became quite common in primary care, I envision the same happening with icosapent ethyl.”
Lipid expert Roger Blumenthal, MD, who was not involved in the REDUCE-IT trial, also welcomed the new approval for Vascepa.
“The indication is very appropriate; it is great to have another disease-modifying medication in our prevention toolkit,” Dr. Blumenthal, who is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease in Baltimore, said in an interview.
Some still unsure
But not everyone is in full agreement with the broad indication granted.
One expert who has reservations is James de Lemos, MD, professor of medicine at the University of Texas, Dallas, who sat on the FDA advisory committee that assessed the drug last month.
“I would have preferred a narrower label for now, limited to the secondary prevention indication, because I felt that REDUCE-IT did not include sufficient numbers of patients to justify the high-risk primary-prevention indication. We need an adequately powered, randomized, controlled trial to establish the risk/benefit and cost/benefit in primary prevention, and with this broad label, I worry there will be little incentive for the company to pursue this,” Dr. de Lemos commented in an interview.
“This is a slippery slope, and we should not allow broad indications that extend to primary prevention for drugs that were studied in mixed secondary- and primary-prevention patients, with the results driven by the secondary-prevention subset. These two subgroups are fundamentally different populations in whom the pathophysiology and the background treatments are very different,” he added.
However, Dr. de Lemos acknowledged that he would use Vascepa for some high-risk primary-prevention patients in his practice – those with diabetes, high triglycerides, and multiple risk factors. “I just wish we had more data coming so that I could be more certain of the benefit in this group,” he said.
Dr. Bhatt disclosed sitting on advisory boards for Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio, and Regado Biosciences; conducting unfunded research in association with FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda; and receiving research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, and Forest Laboratories. Dr. De Lemos reported receiving grant and consulting income from Roche Diagnostics and Abbott Diagnostics; and consulting for Ortho Clinical Diagnostics. Dr. Blumenthal has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
The newly approved U.S. indication for icosapent ethyl (Vascepa; Amarin) is broadly in line with the entry criteria for the REDUCE-IT trial and includes a large high-risk primary-prevention population, as well as those with established cardiovascular disease (CVD). The drug, thus, could well be used by millions of patients in the United States alone.
The high-dose, purified eicosapentaenoic acid product was approved last week by the Food and Drug Administration for cardiovascular risk reduction among adults already taking maximally tolerated statins with triglyceride levels of 150 mg/dL or higher who have either established CVD or diabetes and two or more additional risk factors for CVD.
The approval is based largely on the REDUCE-IT trial’s finding of a 25% reduction in risk for major adverse cardiovascular events versus placebo. The FDA stated that the approval is the first for an agent with this specific indication.
Noting that it recognizes the need for additional medical treatments for CVD, the FDA says the new approval “will give patients with elevated triglycerides and other important risk factors, including heart disease, stroke, and diabetes, an adjunctive treatment option that can help decrease their risk of cardiovascular events.”
The drug was unanimously recommended for approval by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee last month. But while the committee all agreed on its use in patients with established CVD, which made up 70% of the REDUCE-IT population, they were divided on whether the indication should be extended to the high-risk primary-prevention population, who made up just 30% of patients in the study.
Nonetheless, the FDA has gone for a broad indication based on the whole REDUCE-IT population.
In a conference call following the approval, Steven Ketchum, PhD, chief scientific officer at Amarin, pointed out that the primary-prevention population stipulated in the new approval differed very slightly from the REDUCE-IT enrollment criteria.
The trial specified that patients with diabetes should be older than 50 with one other cardiovascular risk factor, whereas the approved population is for diabetes and two cardiovascular risk factors. But as these two risk factors are not specified, they could include age, cigarette smoking, hypertension or use of an antihypertensive agent, low HDL cholesterol, high C-reactive protein, body mass index above 25 kg/m2, renal dysfunction, retinopathy, albuminuria, or an ankle branchial index below 0.9, Dr. Ketchum said.
“So while the label asks for two other risk factors, one of these could be age; so we believe the label is actually slightly broader than the REDUCE-IT inclusion criteria, and doctors have been left with significant leeway to decide which risk factors to consider on top of diabetes.”
Deepak Bhatt, MD, the lead investigator of REDUCE-IT, described the Vascepa approval as “the most significant event in the field of cardiovascular prevention since the introduction of statins nearly 3 decades ago.”
He commended the FDA on “a very evidence-based, prescriber-friendly, and most importantly, patient-friendly label,” which he said was in line with guidelines from multiple professional societies that have already incorporated the REDUCE-IT findings for secondary prevention and diabetic primary prevention.
Dr. Bhatt, who is a professor of medicine at Brigham and Women’s Hospital and Harvard Medical School, Boston, said the label essentially matches the REDUCE-IT population.
“The entry criteria for REDUCE-IT was fasting triglycerides greater than or equal to 150 mg/dL, with a 10% variance allowed (giving a minimum triglyceride value of 135 mg/dL). In actuality, we ended up with about 10% of the population with triglycerides between 100 and 150 mg/dL, and they had a similar degree of benefit as those with higher levels,” he reported.
“In the label, the 150 mg/dL does not specify fasting, and in fact many practices have moved away from fasting lipid measurements for the sake of patient comfort,” Dr. Bhatt added. “On average, nonfasting levels are about 50 mg/dL higher, so the label essentially mirrors those we studied, with the FDA applying good common sense and not being overly dogmatic about the exact wording of the trial inclusion criteria.”
No price change foreseen
Vascepa is already on the market for patients with very high triglyceride levels, and the company says it is not increasing the current price of about $300 a month, which is “relatively low, compared to other new breakthrough drugs.” However, it says it expects sales to grow from vastly increased volume based on the new indication.
Dr. Bhatt noted that REDUCE-IT cost-effectiveness data presented at the recent American Heart Association scientific sessions found the drug to be cost saving in the majority of cases. “That is something that is quite rare in cost-effectiveness research,” he said.
“Now, the key challenge is to identify and treat appropriate patients,” Dr. Bhatt noted. He says this task will largely fall on cardiologists, endocrinologists, and primary care physicians, though stroke neurologists, nephrologists, and vascular medicine specialists will also have patients for whom the data are relevant.
“I believe the drug will ultimately be widely prescribed, initially by subspecialists, but by primary care physicians also. It is overall very well tolerated, safe, and easy to use,” he said. “Much like statin prescription started in subspecialty practices but then became quite common in primary care, I envision the same happening with icosapent ethyl.”
Lipid expert Roger Blumenthal, MD, who was not involved in the REDUCE-IT trial, also welcomed the new approval for Vascepa.
“The indication is very appropriate; it is great to have another disease-modifying medication in our prevention toolkit,” Dr. Blumenthal, who is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease in Baltimore, said in an interview.
Some still unsure
But not everyone is in full agreement with the broad indication granted.
One expert who has reservations is James de Lemos, MD, professor of medicine at the University of Texas, Dallas, who sat on the FDA advisory committee that assessed the drug last month.
“I would have preferred a narrower label for now, limited to the secondary prevention indication, because I felt that REDUCE-IT did not include sufficient numbers of patients to justify the high-risk primary-prevention indication. We need an adequately powered, randomized, controlled trial to establish the risk/benefit and cost/benefit in primary prevention, and with this broad label, I worry there will be little incentive for the company to pursue this,” Dr. de Lemos commented in an interview.
“This is a slippery slope, and we should not allow broad indications that extend to primary prevention for drugs that were studied in mixed secondary- and primary-prevention patients, with the results driven by the secondary-prevention subset. These two subgroups are fundamentally different populations in whom the pathophysiology and the background treatments are very different,” he added.
However, Dr. de Lemos acknowledged that he would use Vascepa for some high-risk primary-prevention patients in his practice – those with diabetes, high triglycerides, and multiple risk factors. “I just wish we had more data coming so that I could be more certain of the benefit in this group,” he said.
Dr. Bhatt disclosed sitting on advisory boards for Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio, and Regado Biosciences; conducting unfunded research in association with FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda; and receiving research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, and Forest Laboratories. Dr. De Lemos reported receiving grant and consulting income from Roche Diagnostics and Abbott Diagnostics; and consulting for Ortho Clinical Diagnostics. Dr. Blumenthal has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
The newly approved U.S. indication for icosapent ethyl (Vascepa; Amarin) is broadly in line with the entry criteria for the REDUCE-IT trial and includes a large high-risk primary-prevention population, as well as those with established cardiovascular disease (CVD). The drug, thus, could well be used by millions of patients in the United States alone.
The high-dose, purified eicosapentaenoic acid product was approved last week by the Food and Drug Administration for cardiovascular risk reduction among adults already taking maximally tolerated statins with triglyceride levels of 150 mg/dL or higher who have either established CVD or diabetes and two or more additional risk factors for CVD.
The approval is based largely on the REDUCE-IT trial’s finding of a 25% reduction in risk for major adverse cardiovascular events versus placebo. The FDA stated that the approval is the first for an agent with this specific indication.
Noting that it recognizes the need for additional medical treatments for CVD, the FDA says the new approval “will give patients with elevated triglycerides and other important risk factors, including heart disease, stroke, and diabetes, an adjunctive treatment option that can help decrease their risk of cardiovascular events.”
The drug was unanimously recommended for approval by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee last month. But while the committee all agreed on its use in patients with established CVD, which made up 70% of the REDUCE-IT population, they were divided on whether the indication should be extended to the high-risk primary-prevention population, who made up just 30% of patients in the study.
Nonetheless, the FDA has gone for a broad indication based on the whole REDUCE-IT population.
In a conference call following the approval, Steven Ketchum, PhD, chief scientific officer at Amarin, pointed out that the primary-prevention population stipulated in the new approval differed very slightly from the REDUCE-IT enrollment criteria.
The trial specified that patients with diabetes should be older than 50 with one other cardiovascular risk factor, whereas the approved population is for diabetes and two cardiovascular risk factors. But as these two risk factors are not specified, they could include age, cigarette smoking, hypertension or use of an antihypertensive agent, low HDL cholesterol, high C-reactive protein, body mass index above 25 kg/m2, renal dysfunction, retinopathy, albuminuria, or an ankle branchial index below 0.9, Dr. Ketchum said.
“So while the label asks for two other risk factors, one of these could be age; so we believe the label is actually slightly broader than the REDUCE-IT inclusion criteria, and doctors have been left with significant leeway to decide which risk factors to consider on top of diabetes.”
Deepak Bhatt, MD, the lead investigator of REDUCE-IT, described the Vascepa approval as “the most significant event in the field of cardiovascular prevention since the introduction of statins nearly 3 decades ago.”
He commended the FDA on “a very evidence-based, prescriber-friendly, and most importantly, patient-friendly label,” which he said was in line with guidelines from multiple professional societies that have already incorporated the REDUCE-IT findings for secondary prevention and diabetic primary prevention.
Dr. Bhatt, who is a professor of medicine at Brigham and Women’s Hospital and Harvard Medical School, Boston, said the label essentially matches the REDUCE-IT population.
“The entry criteria for REDUCE-IT was fasting triglycerides greater than or equal to 150 mg/dL, with a 10% variance allowed (giving a minimum triglyceride value of 135 mg/dL). In actuality, we ended up with about 10% of the population with triglycerides between 100 and 150 mg/dL, and they had a similar degree of benefit as those with higher levels,” he reported.
“In the label, the 150 mg/dL does not specify fasting, and in fact many practices have moved away from fasting lipid measurements for the sake of patient comfort,” Dr. Bhatt added. “On average, nonfasting levels are about 50 mg/dL higher, so the label essentially mirrors those we studied, with the FDA applying good common sense and not being overly dogmatic about the exact wording of the trial inclusion criteria.”
No price change foreseen
Vascepa is already on the market for patients with very high triglyceride levels, and the company says it is not increasing the current price of about $300 a month, which is “relatively low, compared to other new breakthrough drugs.” However, it says it expects sales to grow from vastly increased volume based on the new indication.
Dr. Bhatt noted that REDUCE-IT cost-effectiveness data presented at the recent American Heart Association scientific sessions found the drug to be cost saving in the majority of cases. “That is something that is quite rare in cost-effectiveness research,” he said.
“Now, the key challenge is to identify and treat appropriate patients,” Dr. Bhatt noted. He says this task will largely fall on cardiologists, endocrinologists, and primary care physicians, though stroke neurologists, nephrologists, and vascular medicine specialists will also have patients for whom the data are relevant.
“I believe the drug will ultimately be widely prescribed, initially by subspecialists, but by primary care physicians also. It is overall very well tolerated, safe, and easy to use,” he said. “Much like statin prescription started in subspecialty practices but then became quite common in primary care, I envision the same happening with icosapent ethyl.”
Lipid expert Roger Blumenthal, MD, who was not involved in the REDUCE-IT trial, also welcomed the new approval for Vascepa.
“The indication is very appropriate; it is great to have another disease-modifying medication in our prevention toolkit,” Dr. Blumenthal, who is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease in Baltimore, said in an interview.
Some still unsure
But not everyone is in full agreement with the broad indication granted.
One expert who has reservations is James de Lemos, MD, professor of medicine at the University of Texas, Dallas, who sat on the FDA advisory committee that assessed the drug last month.
“I would have preferred a narrower label for now, limited to the secondary prevention indication, because I felt that REDUCE-IT did not include sufficient numbers of patients to justify the high-risk primary-prevention indication. We need an adequately powered, randomized, controlled trial to establish the risk/benefit and cost/benefit in primary prevention, and with this broad label, I worry there will be little incentive for the company to pursue this,” Dr. de Lemos commented in an interview.
“This is a slippery slope, and we should not allow broad indications that extend to primary prevention for drugs that were studied in mixed secondary- and primary-prevention patients, with the results driven by the secondary-prevention subset. These two subgroups are fundamentally different populations in whom the pathophysiology and the background treatments are very different,” he added.
However, Dr. de Lemos acknowledged that he would use Vascepa for some high-risk primary-prevention patients in his practice – those with diabetes, high triglycerides, and multiple risk factors. “I just wish we had more data coming so that I could be more certain of the benefit in this group,” he said.
Dr. Bhatt disclosed sitting on advisory boards for Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio, and Regado Biosciences; conducting unfunded research in association with FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda; and receiving research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, and Forest Laboratories. Dr. De Lemos reported receiving grant and consulting income from Roche Diagnostics and Abbott Diagnostics; and consulting for Ortho Clinical Diagnostics. Dr. Blumenthal has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Carbs, fat, and mortality: Types matter more than levels
The health consequences of diet don’t largely depend on whether a person eats a high or low level of carbohydrates or a diet high or low in fat. What’s much more important is where the carbs and fats come from, according to an analysis that related diet and mortality rates in more than 37,000 American adults.
“Unhealthy low carbohydrate diet [LCD] and low-fat diet [LFD] scores were associated with higher total mortality, whereas healthy LCD and LFD scores were associated with lower total mortality,” Zhilei Shan, MD, and associates wrote in an article (JAMA Intern Med. 2020 Jan 21; doi: 10.1001/jamainternmed.2019.6980). The findings “suggest that the association of LCDs and LFDs with mortality may depend on the quality of food sources of macronutrients,” said the researchers, based at the Harvard T.H. Chan School of Public Health in Boston.
The analysis included follow-up of almost 300,000 person-years. It showed that, for every 20-percentile increase in a person’s unhealthy LCD score, their relative rate of total mortality increased by a statistically significant 7%; and for every 20-percentile rise in unhealthy LFD score, the relative, total mortality rate rose by a statistically significant 6%, after adjustment for several demographic and clinical measures and family and personal histories of diabetes, cancer, and heart disease. In contrast, for each 20-percentile increase in healthy LCD score relative, total mortality fell by 9%, and similar increases in healthy LFD score linked with an 11% relative drop in total mortality, also statistically significant associations in these confounder-adjusted analyses.
The findings “extend the previous evidence” for these links, and the data suggest that “the health benefits of an LCD or LFD may depend not only on the types of protein and fat or carbohydrate but also on the quality of carbohydrate or fat remaining in the diet,” the researchers wrote. They cited the documented health problems caused by eating significant amounts of low-quality carbohydrates such as refined grains and added sugars, which provide limited nutrition and introduce a high glycemic load, and can produce high levels of postprandial glucose and insulin, inflammation, insulin resistance, and dyslipidemia.
The foods people ate that produced healthy diet scores and linked with better survival were diets high in plant protein and unsaturated fat, and low in carbohydrates from refined grains, added sugar, starchy vegetables, and similar sources as part of a low carbohydrate diet. The foods that formed a healthy LFD included whole grains, whole fruit, legumes, and nonstarchy vegetables, along with higher intake of plant protein and low levels of saturated fat.
The study used data from 24-hour diet-recall surveys completed by 37,233 American adults collected by the National Health and Nutrition Examination Survey (NHANES) during 1999-2014, and linked the diet scores calculated for these people with U.S. national death records collected by the National Death Index through the end of 2015. The people included averaged about 50 years of age at the time of their dietary interview, and 53% were women. During 297,768 person-years of follow-up, 4,866 total deaths occurred, including 849 from heart disease and 1,068 from cancer. The analyses found no statistically significant links between overall LCD or LFD scores and mortality; the significant links only existed when the researchers further classified the diet scores into healthy and unhealthy subtypes.
The results also showed statistically significant links or strong trends between high or low levels of healthy or unhealthy LCD and LFD scores and cancer deaths. A 20-percentile increase in unhealthy LCD score linked with an 11% relative increase in cancer deaths, while a 20-percentile increase in the healthy LCD score linked with a 10% decrease in cancer deaths. A 20-percentile increase in the healthy LFD score linked with a 15% relative decrease in cancer mortality.
The study received no commercial fundings, and the authors had no commercial disclosures.
SOURCE: Shan Z et al. JAMA Intern Med. 2020 Jan 21; doi: 10.1001/jamainternmed.2019.6980.
This is an important study because the findings reinforce the already established concept that it’s the quality of the fat and carbohydrate a person eats that matters for health, rather than the relative levels of these nutrients. Eating unsaturated fats and unprocessed carbohydrates like whole grains, fruits, and legumes produces the greatest health and survival, while higher levels of saturated fats and processed carbs in the diet produce health problems. That’s much more important than whether a diet is low fat or low carb. This means sticking with the food principles advanced by the AHA diet, the DASH diet, and a Mediterranean diet.
High-fat and low-carb diets are popular because people who follow them lose weight over the short term, but those weight losses are hard to sustain longer term and create an opportunity for unhealthy effects if people eat the wrong fats, carbohydrates, and proteins. Strategies that focus on healthier food choices like the Mediterranean or AHA diets can minimize disease and produce more sustainable weight control.
Robert A. Vogel, MD , is a cardiologist in Denver affiliated with the University of Colorado School of Medicine and the VA Medical Center in Denver. He has been a consultant to the Pritikin Longevity Institute in Doral, Fla. He made these comments in an interview.
This is an important study because the findings reinforce the already established concept that it’s the quality of the fat and carbohydrate a person eats that matters for health, rather than the relative levels of these nutrients. Eating unsaturated fats and unprocessed carbohydrates like whole grains, fruits, and legumes produces the greatest health and survival, while higher levels of saturated fats and processed carbs in the diet produce health problems. That’s much more important than whether a diet is low fat or low carb. This means sticking with the food principles advanced by the AHA diet, the DASH diet, and a Mediterranean diet.
High-fat and low-carb diets are popular because people who follow them lose weight over the short term, but those weight losses are hard to sustain longer term and create an opportunity for unhealthy effects if people eat the wrong fats, carbohydrates, and proteins. Strategies that focus on healthier food choices like the Mediterranean or AHA diets can minimize disease and produce more sustainable weight control.
Robert A. Vogel, MD , is a cardiologist in Denver affiliated with the University of Colorado School of Medicine and the VA Medical Center in Denver. He has been a consultant to the Pritikin Longevity Institute in Doral, Fla. He made these comments in an interview.
This is an important study because the findings reinforce the already established concept that it’s the quality of the fat and carbohydrate a person eats that matters for health, rather than the relative levels of these nutrients. Eating unsaturated fats and unprocessed carbohydrates like whole grains, fruits, and legumes produces the greatest health and survival, while higher levels of saturated fats and processed carbs in the diet produce health problems. That’s much more important than whether a diet is low fat or low carb. This means sticking with the food principles advanced by the AHA diet, the DASH diet, and a Mediterranean diet.
High-fat and low-carb diets are popular because people who follow them lose weight over the short term, but those weight losses are hard to sustain longer term and create an opportunity for unhealthy effects if people eat the wrong fats, carbohydrates, and proteins. Strategies that focus on healthier food choices like the Mediterranean or AHA diets can minimize disease and produce more sustainable weight control.
Robert A. Vogel, MD , is a cardiologist in Denver affiliated with the University of Colorado School of Medicine and the VA Medical Center in Denver. He has been a consultant to the Pritikin Longevity Institute in Doral, Fla. He made these comments in an interview.
The health consequences of diet don’t largely depend on whether a person eats a high or low level of carbohydrates or a diet high or low in fat. What’s much more important is where the carbs and fats come from, according to an analysis that related diet and mortality rates in more than 37,000 American adults.
“Unhealthy low carbohydrate diet [LCD] and low-fat diet [LFD] scores were associated with higher total mortality, whereas healthy LCD and LFD scores were associated with lower total mortality,” Zhilei Shan, MD, and associates wrote in an article (JAMA Intern Med. 2020 Jan 21; doi: 10.1001/jamainternmed.2019.6980). The findings “suggest that the association of LCDs and LFDs with mortality may depend on the quality of food sources of macronutrients,” said the researchers, based at the Harvard T.H. Chan School of Public Health in Boston.
The analysis included follow-up of almost 300,000 person-years. It showed that, for every 20-percentile increase in a person’s unhealthy LCD score, their relative rate of total mortality increased by a statistically significant 7%; and for every 20-percentile rise in unhealthy LFD score, the relative, total mortality rate rose by a statistically significant 6%, after adjustment for several demographic and clinical measures and family and personal histories of diabetes, cancer, and heart disease. In contrast, for each 20-percentile increase in healthy LCD score relative, total mortality fell by 9%, and similar increases in healthy LFD score linked with an 11% relative drop in total mortality, also statistically significant associations in these confounder-adjusted analyses.
The findings “extend the previous evidence” for these links, and the data suggest that “the health benefits of an LCD or LFD may depend not only on the types of protein and fat or carbohydrate but also on the quality of carbohydrate or fat remaining in the diet,” the researchers wrote. They cited the documented health problems caused by eating significant amounts of low-quality carbohydrates such as refined grains and added sugars, which provide limited nutrition and introduce a high glycemic load, and can produce high levels of postprandial glucose and insulin, inflammation, insulin resistance, and dyslipidemia.
The foods people ate that produced healthy diet scores and linked with better survival were diets high in plant protein and unsaturated fat, and low in carbohydrates from refined grains, added sugar, starchy vegetables, and similar sources as part of a low carbohydrate diet. The foods that formed a healthy LFD included whole grains, whole fruit, legumes, and nonstarchy vegetables, along with higher intake of plant protein and low levels of saturated fat.
The study used data from 24-hour diet-recall surveys completed by 37,233 American adults collected by the National Health and Nutrition Examination Survey (NHANES) during 1999-2014, and linked the diet scores calculated for these people with U.S. national death records collected by the National Death Index through the end of 2015. The people included averaged about 50 years of age at the time of their dietary interview, and 53% were women. During 297,768 person-years of follow-up, 4,866 total deaths occurred, including 849 from heart disease and 1,068 from cancer. The analyses found no statistically significant links between overall LCD or LFD scores and mortality; the significant links only existed when the researchers further classified the diet scores into healthy and unhealthy subtypes.
The results also showed statistically significant links or strong trends between high or low levels of healthy or unhealthy LCD and LFD scores and cancer deaths. A 20-percentile increase in unhealthy LCD score linked with an 11% relative increase in cancer deaths, while a 20-percentile increase in the healthy LCD score linked with a 10% decrease in cancer deaths. A 20-percentile increase in the healthy LFD score linked with a 15% relative decrease in cancer mortality.
The study received no commercial fundings, and the authors had no commercial disclosures.
SOURCE: Shan Z et al. JAMA Intern Med. 2020 Jan 21; doi: 10.1001/jamainternmed.2019.6980.
The health consequences of diet don’t largely depend on whether a person eats a high or low level of carbohydrates or a diet high or low in fat. What’s much more important is where the carbs and fats come from, according to an analysis that related diet and mortality rates in more than 37,000 American adults.
“Unhealthy low carbohydrate diet [LCD] and low-fat diet [LFD] scores were associated with higher total mortality, whereas healthy LCD and LFD scores were associated with lower total mortality,” Zhilei Shan, MD, and associates wrote in an article (JAMA Intern Med. 2020 Jan 21; doi: 10.1001/jamainternmed.2019.6980). The findings “suggest that the association of LCDs and LFDs with mortality may depend on the quality of food sources of macronutrients,” said the researchers, based at the Harvard T.H. Chan School of Public Health in Boston.
The analysis included follow-up of almost 300,000 person-years. It showed that, for every 20-percentile increase in a person’s unhealthy LCD score, their relative rate of total mortality increased by a statistically significant 7%; and for every 20-percentile rise in unhealthy LFD score, the relative, total mortality rate rose by a statistically significant 6%, after adjustment for several demographic and clinical measures and family and personal histories of diabetes, cancer, and heart disease. In contrast, for each 20-percentile increase in healthy LCD score relative, total mortality fell by 9%, and similar increases in healthy LFD score linked with an 11% relative drop in total mortality, also statistically significant associations in these confounder-adjusted analyses.
The findings “extend the previous evidence” for these links, and the data suggest that “the health benefits of an LCD or LFD may depend not only on the types of protein and fat or carbohydrate but also on the quality of carbohydrate or fat remaining in the diet,” the researchers wrote. They cited the documented health problems caused by eating significant amounts of low-quality carbohydrates such as refined grains and added sugars, which provide limited nutrition and introduce a high glycemic load, and can produce high levels of postprandial glucose and insulin, inflammation, insulin resistance, and dyslipidemia.
The foods people ate that produced healthy diet scores and linked with better survival were diets high in plant protein and unsaturated fat, and low in carbohydrates from refined grains, added sugar, starchy vegetables, and similar sources as part of a low carbohydrate diet. The foods that formed a healthy LFD included whole grains, whole fruit, legumes, and nonstarchy vegetables, along with higher intake of plant protein and low levels of saturated fat.
The study used data from 24-hour diet-recall surveys completed by 37,233 American adults collected by the National Health and Nutrition Examination Survey (NHANES) during 1999-2014, and linked the diet scores calculated for these people with U.S. national death records collected by the National Death Index through the end of 2015. The people included averaged about 50 years of age at the time of their dietary interview, and 53% were women. During 297,768 person-years of follow-up, 4,866 total deaths occurred, including 849 from heart disease and 1,068 from cancer. The analyses found no statistically significant links between overall LCD or LFD scores and mortality; the significant links only existed when the researchers further classified the diet scores into healthy and unhealthy subtypes.
The results also showed statistically significant links or strong trends between high or low levels of healthy or unhealthy LCD and LFD scores and cancer deaths. A 20-percentile increase in unhealthy LCD score linked with an 11% relative increase in cancer deaths, while a 20-percentile increase in the healthy LCD score linked with a 10% decrease in cancer deaths. A 20-percentile increase in the healthy LFD score linked with a 15% relative decrease in cancer mortality.
The study received no commercial fundings, and the authors had no commercial disclosures.
SOURCE: Shan Z et al. JAMA Intern Med. 2020 Jan 21; doi: 10.1001/jamainternmed.2019.6980.
REPORTING FROM JAMA INTERNAL MEDICINE
Liver fibrosis scores predict CV event risk associated with NAFLD
Patients with nonalcoholic fatty liver disease (NAFLD) in a prospective observational study had a twofold increase in cardiovascular events, .
At median follow-up of 41.4 months representing 3,044.4 person-years of observation in the Progression of Liver Damage and Cardiometabolic Disorders in NAFLD (PLINIO) study, 58 cardiovascular events (CVEs) were reported in 898 consecutive outpatients who were screened for liver steatosis by ultrasound. The annual rate of CVEs among 643 patients with NAFLD was 2.1%, compared with 1.0% among 255 patients without NAFLD, according to Francesco Baratta, MD, of Clinica Medica, Sapienza University of Rome, and colleagues. Their report is in Clinical Gastroenterology and Hepatology.
The difference did not meet a priori thresholds for statistical significance (P = .066), but became significant after exclusion of new-onset atrial fibrillation events (annual CVE rates of 1.9% vs. 0.7%; P = .034), and on multivariate analysis, age, male sex, and NAFLD were found to be independently associated with CVE occurrence (hazard ratios, 1.07, 3.20, and 2.73, respectively), the investigators found.
In NAFLD patients, a NAFLD fibrosis score (NFS) greater than 0.676 was significantly associated with CVEs after adjustment for comorbidities (HR, 2.29), and a Fibrosis-4 (FIB-4) score greater than 2.67, a history of cardiovascular disease, and metabolic syndrome predicted incident CVEs (HRs, 4.57, 2.95, and 2.30, respectively). The findings were similar after exclusion of new-onset atrial fibrillation from the composite endpoint (HRs, 2.42 and 4.00, respectively).
“Furthermore, when we analyzed only patients without CVEs at baseline, we found a similar association between liver fibrosis and CVEs,” the researchers wrote, noting that the adjusted HRs for NFS were 2.50 and 4.28, respectively.
In addition to liver-related complications, patients with NAFLD are known to have an increased CVE risk, and while liver fibrosis severity is used to determine prognosis, not all patients can undergo a liver biopsy to assess fibrosis. Therefore, there is a need to identify and validate noninvasive markers of liver fibrosis, but few data exist with respect to the predictive role of noninvasive scoring on CVEs, they said.
The findings of this study suggest the use of the NFS and FIB-4 score may reduce the need for liver biopsy by identifying NAFLD patients at higher risk of having advanced liver fibrosis. They further suggest that liver fibrosis development in patients with NAFLD “may be the result of a long-term exposure to cardiometabolic risk factors such as diabetes,” and that “the concomitant presence of multiple cardiometabolic conditions may induce a chronic low-grade proinflammatory and pro-oxidant status leading to liver inflammation (i.e., macrophage activation) and collagen deposition.”
The findings may also have clinical implications: “The association between liver fibrosis and cardiovascular risk supports a potential role for statin treatment in patients with NAFLD,” they explained.
The authors reported having no disclosures.
SOURCE: Baratta F et al. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2019.12.026.
Patients with nonalcoholic fatty liver disease (NAFLD) in a prospective observational study had a twofold increase in cardiovascular events, .
At median follow-up of 41.4 months representing 3,044.4 person-years of observation in the Progression of Liver Damage and Cardiometabolic Disorders in NAFLD (PLINIO) study, 58 cardiovascular events (CVEs) were reported in 898 consecutive outpatients who were screened for liver steatosis by ultrasound. The annual rate of CVEs among 643 patients with NAFLD was 2.1%, compared with 1.0% among 255 patients without NAFLD, according to Francesco Baratta, MD, of Clinica Medica, Sapienza University of Rome, and colleagues. Their report is in Clinical Gastroenterology and Hepatology.
The difference did not meet a priori thresholds for statistical significance (P = .066), but became significant after exclusion of new-onset atrial fibrillation events (annual CVE rates of 1.9% vs. 0.7%; P = .034), and on multivariate analysis, age, male sex, and NAFLD were found to be independently associated with CVE occurrence (hazard ratios, 1.07, 3.20, and 2.73, respectively), the investigators found.
In NAFLD patients, a NAFLD fibrosis score (NFS) greater than 0.676 was significantly associated with CVEs after adjustment for comorbidities (HR, 2.29), and a Fibrosis-4 (FIB-4) score greater than 2.67, a history of cardiovascular disease, and metabolic syndrome predicted incident CVEs (HRs, 4.57, 2.95, and 2.30, respectively). The findings were similar after exclusion of new-onset atrial fibrillation from the composite endpoint (HRs, 2.42 and 4.00, respectively).
“Furthermore, when we analyzed only patients without CVEs at baseline, we found a similar association between liver fibrosis and CVEs,” the researchers wrote, noting that the adjusted HRs for NFS were 2.50 and 4.28, respectively.
In addition to liver-related complications, patients with NAFLD are known to have an increased CVE risk, and while liver fibrosis severity is used to determine prognosis, not all patients can undergo a liver biopsy to assess fibrosis. Therefore, there is a need to identify and validate noninvasive markers of liver fibrosis, but few data exist with respect to the predictive role of noninvasive scoring on CVEs, they said.
The findings of this study suggest the use of the NFS and FIB-4 score may reduce the need for liver biopsy by identifying NAFLD patients at higher risk of having advanced liver fibrosis. They further suggest that liver fibrosis development in patients with NAFLD “may be the result of a long-term exposure to cardiometabolic risk factors such as diabetes,” and that “the concomitant presence of multiple cardiometabolic conditions may induce a chronic low-grade proinflammatory and pro-oxidant status leading to liver inflammation (i.e., macrophage activation) and collagen deposition.”
The findings may also have clinical implications: “The association between liver fibrosis and cardiovascular risk supports a potential role for statin treatment in patients with NAFLD,” they explained.
The authors reported having no disclosures.
SOURCE: Baratta F et al. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2019.12.026.
Patients with nonalcoholic fatty liver disease (NAFLD) in a prospective observational study had a twofold increase in cardiovascular events, .
At median follow-up of 41.4 months representing 3,044.4 person-years of observation in the Progression of Liver Damage and Cardiometabolic Disorders in NAFLD (PLINIO) study, 58 cardiovascular events (CVEs) were reported in 898 consecutive outpatients who were screened for liver steatosis by ultrasound. The annual rate of CVEs among 643 patients with NAFLD was 2.1%, compared with 1.0% among 255 patients without NAFLD, according to Francesco Baratta, MD, of Clinica Medica, Sapienza University of Rome, and colleagues. Their report is in Clinical Gastroenterology and Hepatology.
The difference did not meet a priori thresholds for statistical significance (P = .066), but became significant after exclusion of new-onset atrial fibrillation events (annual CVE rates of 1.9% vs. 0.7%; P = .034), and on multivariate analysis, age, male sex, and NAFLD were found to be independently associated with CVE occurrence (hazard ratios, 1.07, 3.20, and 2.73, respectively), the investigators found.
In NAFLD patients, a NAFLD fibrosis score (NFS) greater than 0.676 was significantly associated with CVEs after adjustment for comorbidities (HR, 2.29), and a Fibrosis-4 (FIB-4) score greater than 2.67, a history of cardiovascular disease, and metabolic syndrome predicted incident CVEs (HRs, 4.57, 2.95, and 2.30, respectively). The findings were similar after exclusion of new-onset atrial fibrillation from the composite endpoint (HRs, 2.42 and 4.00, respectively).
“Furthermore, when we analyzed only patients without CVEs at baseline, we found a similar association between liver fibrosis and CVEs,” the researchers wrote, noting that the adjusted HRs for NFS were 2.50 and 4.28, respectively.
In addition to liver-related complications, patients with NAFLD are known to have an increased CVE risk, and while liver fibrosis severity is used to determine prognosis, not all patients can undergo a liver biopsy to assess fibrosis. Therefore, there is a need to identify and validate noninvasive markers of liver fibrosis, but few data exist with respect to the predictive role of noninvasive scoring on CVEs, they said.
The findings of this study suggest the use of the NFS and FIB-4 score may reduce the need for liver biopsy by identifying NAFLD patients at higher risk of having advanced liver fibrosis. They further suggest that liver fibrosis development in patients with NAFLD “may be the result of a long-term exposure to cardiometabolic risk factors such as diabetes,” and that “the concomitant presence of multiple cardiometabolic conditions may induce a chronic low-grade proinflammatory and pro-oxidant status leading to liver inflammation (i.e., macrophage activation) and collagen deposition.”
The findings may also have clinical implications: “The association between liver fibrosis and cardiovascular risk supports a potential role for statin treatment in patients with NAFLD,” they explained.
The authors reported having no disclosures.
SOURCE: Baratta F et al. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2019.12.026.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Framingham: Exercise lessens cardiometabolic risk of poor diet
PHILADELPHIA – Engaging in at least 150 minutes of moderate to vigorous physical activity per week as recommended in national guidelines appears to mitigate the cardiometabolic risks associated with poor diet quality in middle-aged and older adults, according to an analysis of Framingham Heart Study data.
“Our findings suggest adherence to physical activity guidelines may have a protective effect on cardiometabolic health regardless of diet quality,” Joowon Lee, PhD, declared at the American Heart Association scientific sessions.
He presented separate cross-sectional analyses of the risks of metabolic syndrome in 2,379 middle-aged participants in the National Heart, Lung, and Blood Institute–sponsored Framingham (Mass.) Third Generation Study and 1,180 older participants in the Framingham Offspring Study.
The two analyses showed the same thing across a broad age spectrum: The highest prevalence of metabolic syndrome as defined by Adult Treatment Panel III criteria was present among those individuals who got less than 150 minutes of physical activity per week and were also in the lowest tertile in terms of diet quality, while the lowest prevalence of metabolic syndrome occurred in participants in the top tertile for diet quality who engaged in at least 150 minutes per week of moderate to vigorous physical activity in accord with the Department of Health & Human Services 2018 Physical Activity Guidelines for Americans.
In both the middle-aged and older populations, optimal physical activity – that is, at least 150 minutes per week – appeared to override the adverse impact of suboptimal diet quality. Physically active individuals with moderate or even poor diet quality had a significantly lower prevalence of metabolic syndrome than did the reference group constituted by participants with poor diet quality who didn’t exercise for 150 minutes per week.
But the converse didn’t hold true: Individuals with optimal diet quality who didn’t reach the physical activity threshold had no reduction in metabolic syndrome, compared with the reference group, according to Dr. Lee of Boston University.
For example, among the Framingham Offspring Study participants, whose mean age was 69 years at the time of their ninth formal examination in 2014, the prevalence of metabolic syndrome was 59% in those who got less than 150 minutes of moderate to vigorous physical activity weekly as assessed by accelerometer and who were also in the lowest tertile for diet quality as self-reported on the DGAI-2010 (Dietary Guidelines Adherence Index) semiquantitative food frequency questionnaire. The relative risk of metabolic syndrome was reduced by 61% in participants with both optimal physical activity and diet quality, by 49% in those with at least 150 minutes of physical activity but only moderate diet quality, and by 39% in those with optimal exercise and poor diet quality. In contrast, individuals in the top or middle tertiles for diet quality who didn’t meet the physical activity standard had a metabolic syndrome rate that wasn’t significantly lower than the reference group.
Dr. Lee observed that his analyses are best viewed as hypothesis generating. Their cross-sectional format precludes firm conclusions as to causality.
His findings prompted session comoderator Satyam Sarma, MD, of the University of Texas, Dallas, to make one of the most memorable comments heard at AHA 2019: that the Framingham findings suggest it may be possible to outrun a bad diet.
Dr. Lee reported having no financial conflicts regarding his study, supported by Boston University.
SOURCE: Lee J. AHA 2019, Abstract RF244.
PHILADELPHIA – Engaging in at least 150 minutes of moderate to vigorous physical activity per week as recommended in national guidelines appears to mitigate the cardiometabolic risks associated with poor diet quality in middle-aged and older adults, according to an analysis of Framingham Heart Study data.
“Our findings suggest adherence to physical activity guidelines may have a protective effect on cardiometabolic health regardless of diet quality,” Joowon Lee, PhD, declared at the American Heart Association scientific sessions.
He presented separate cross-sectional analyses of the risks of metabolic syndrome in 2,379 middle-aged participants in the National Heart, Lung, and Blood Institute–sponsored Framingham (Mass.) Third Generation Study and 1,180 older participants in the Framingham Offspring Study.
The two analyses showed the same thing across a broad age spectrum: The highest prevalence of metabolic syndrome as defined by Adult Treatment Panel III criteria was present among those individuals who got less than 150 minutes of physical activity per week and were also in the lowest tertile in terms of diet quality, while the lowest prevalence of metabolic syndrome occurred in participants in the top tertile for diet quality who engaged in at least 150 minutes per week of moderate to vigorous physical activity in accord with the Department of Health & Human Services 2018 Physical Activity Guidelines for Americans.
In both the middle-aged and older populations, optimal physical activity – that is, at least 150 minutes per week – appeared to override the adverse impact of suboptimal diet quality. Physically active individuals with moderate or even poor diet quality had a significantly lower prevalence of metabolic syndrome than did the reference group constituted by participants with poor diet quality who didn’t exercise for 150 minutes per week.
But the converse didn’t hold true: Individuals with optimal diet quality who didn’t reach the physical activity threshold had no reduction in metabolic syndrome, compared with the reference group, according to Dr. Lee of Boston University.
For example, among the Framingham Offspring Study participants, whose mean age was 69 years at the time of their ninth formal examination in 2014, the prevalence of metabolic syndrome was 59% in those who got less than 150 minutes of moderate to vigorous physical activity weekly as assessed by accelerometer and who were also in the lowest tertile for diet quality as self-reported on the DGAI-2010 (Dietary Guidelines Adherence Index) semiquantitative food frequency questionnaire. The relative risk of metabolic syndrome was reduced by 61% in participants with both optimal physical activity and diet quality, by 49% in those with at least 150 minutes of physical activity but only moderate diet quality, and by 39% in those with optimal exercise and poor diet quality. In contrast, individuals in the top or middle tertiles for diet quality who didn’t meet the physical activity standard had a metabolic syndrome rate that wasn’t significantly lower than the reference group.
Dr. Lee observed that his analyses are best viewed as hypothesis generating. Their cross-sectional format precludes firm conclusions as to causality.
His findings prompted session comoderator Satyam Sarma, MD, of the University of Texas, Dallas, to make one of the most memorable comments heard at AHA 2019: that the Framingham findings suggest it may be possible to outrun a bad diet.
Dr. Lee reported having no financial conflicts regarding his study, supported by Boston University.
SOURCE: Lee J. AHA 2019, Abstract RF244.
PHILADELPHIA – Engaging in at least 150 minutes of moderate to vigorous physical activity per week as recommended in national guidelines appears to mitigate the cardiometabolic risks associated with poor diet quality in middle-aged and older adults, according to an analysis of Framingham Heart Study data.
“Our findings suggest adherence to physical activity guidelines may have a protective effect on cardiometabolic health regardless of diet quality,” Joowon Lee, PhD, declared at the American Heart Association scientific sessions.
He presented separate cross-sectional analyses of the risks of metabolic syndrome in 2,379 middle-aged participants in the National Heart, Lung, and Blood Institute–sponsored Framingham (Mass.) Third Generation Study and 1,180 older participants in the Framingham Offspring Study.
The two analyses showed the same thing across a broad age spectrum: The highest prevalence of metabolic syndrome as defined by Adult Treatment Panel III criteria was present among those individuals who got less than 150 minutes of physical activity per week and were also in the lowest tertile in terms of diet quality, while the lowest prevalence of metabolic syndrome occurred in participants in the top tertile for diet quality who engaged in at least 150 minutes per week of moderate to vigorous physical activity in accord with the Department of Health & Human Services 2018 Physical Activity Guidelines for Americans.
In both the middle-aged and older populations, optimal physical activity – that is, at least 150 minutes per week – appeared to override the adverse impact of suboptimal diet quality. Physically active individuals with moderate or even poor diet quality had a significantly lower prevalence of metabolic syndrome than did the reference group constituted by participants with poor diet quality who didn’t exercise for 150 minutes per week.
But the converse didn’t hold true: Individuals with optimal diet quality who didn’t reach the physical activity threshold had no reduction in metabolic syndrome, compared with the reference group, according to Dr. Lee of Boston University.
For example, among the Framingham Offspring Study participants, whose mean age was 69 years at the time of their ninth formal examination in 2014, the prevalence of metabolic syndrome was 59% in those who got less than 150 minutes of moderate to vigorous physical activity weekly as assessed by accelerometer and who were also in the lowest tertile for diet quality as self-reported on the DGAI-2010 (Dietary Guidelines Adherence Index) semiquantitative food frequency questionnaire. The relative risk of metabolic syndrome was reduced by 61% in participants with both optimal physical activity and diet quality, by 49% in those with at least 150 minutes of physical activity but only moderate diet quality, and by 39% in those with optimal exercise and poor diet quality. In contrast, individuals in the top or middle tertiles for diet quality who didn’t meet the physical activity standard had a metabolic syndrome rate that wasn’t significantly lower than the reference group.
Dr. Lee observed that his analyses are best viewed as hypothesis generating. Their cross-sectional format precludes firm conclusions as to causality.
His findings prompted session comoderator Satyam Sarma, MD, of the University of Texas, Dallas, to make one of the most memorable comments heard at AHA 2019: that the Framingham findings suggest it may be possible to outrun a bad diet.
Dr. Lee reported having no financial conflicts regarding his study, supported by Boston University.
SOURCE: Lee J. AHA 2019, Abstract RF244.
REPORTING FROM AHA 2019
Nearly 25% of U.S. adults take an obesogenic prescription drug
LAS VEGAS – based on national U.S. data collected during 2013-2016.
The Endocrine Society, the STOP Obesity Alliance, and other medical societies have recommended that clinicians try to minimize use of obesogenic drugs and focus on prescribing agents that are weight neutral or that trigger weight loss when those options are available and appropriate, and the new findings add further evidence that clinicians need to be more mindful of this issue, Craig M. Hales, MD, said at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.
Among the American adults interviewed for the survey, 40% of those on at least one prescription medication were on at least one drug that is considered obesogenic, said Dr. Hales, a medical epidemiologist at the Centers for Disease Control and Prevention in Hyattsville, Md.
According to practice guidelines published by the Endocrine Society, all drugs in the classes of glucocorticoids, beta-blockers, and antihistamines are obesogenic, as well as selected agents in the classes of antidepressant drugs, antipsychotics, antidepressants, antidiabetics, and contraceptives that are progestin only, said Dr. Hales (J Clin Endocrinol Metab. 2015 Feb;100[2]:342-62).
The data he reported came from the National Health and Nutrition Examination Survey (NHANES) run by the CDC during 2013-2016 that included 11,055 adults who were at least 20 years old. The findings showed that 23% of those adults had taken at least one drug that was considered obesogenic during the 30 days preceding the survey date. By comparison, 35% of the same adults had taken any type of prescription drug during the previous 30 days. That meant that overall, 40% of surveyed adults who had recently used any prescription medication had taken an obesogenic drug.
The 23% prevalence of recent obesogenic drug use was fairly stable at that level during several preceding NHANES surveys going back to 2001, suggesting that the increasing use of obesogenic drugs during the period since 2001 was not a factor in the recent increased prevalence of obesity among U.S. residents, added Dr. Hales.
The 2013-2016 analysis also showed a strong link between obesogenic drug use and increasing obesity severity. Among survey participants with a body mass index (BMI) in the normal range (18.5-24 kg/m2), 16% had recent use of an obesogenic drug. This prevalence increased to 22% among those who were overweight (BMI, 25-29 kg/m2), 29% among those with class 1 or 2 obesity (BMI, 30-39 kg/m2), and 33% among those with class 3 obesity (BMI, 40 kg/m2 or greater).
In contrast, recent use of prescription medications that do not contribute to obesity showed no significant relationship with BMI, with rates that ranged from 34% among those with a normal BMI, to 37% among those with class 3 obesity.
As an example of this relationship for a specific obesogenic drug class, the prevalence of beta-blocker use was about 7% among people with a normal BMI, about 10% among those who were overweight, about 14% among people with class 1 or 2 obesity, and about 17% among people with class 3 obesity, a statistically significant link suggesting that the relationship between use of obesogenic drugs and obesity is “bidirectional,” Dr. Hales said, in that increasing obesogenic drug use likely contributes to obesity, while simultaneously, the more obese people become, the more likely they are to take additional prescription drugs, particularly those that are obesogenic.
NHANES is run by the CDC and receives no commercial funding. The authors reported no conflicts of interest.
SOURCE: Hales CM et al. Obesity Week 2019, Abstract T-OR-2037.
LAS VEGAS – based on national U.S. data collected during 2013-2016.
The Endocrine Society, the STOP Obesity Alliance, and other medical societies have recommended that clinicians try to minimize use of obesogenic drugs and focus on prescribing agents that are weight neutral or that trigger weight loss when those options are available and appropriate, and the new findings add further evidence that clinicians need to be more mindful of this issue, Craig M. Hales, MD, said at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.
Among the American adults interviewed for the survey, 40% of those on at least one prescription medication were on at least one drug that is considered obesogenic, said Dr. Hales, a medical epidemiologist at the Centers for Disease Control and Prevention in Hyattsville, Md.
According to practice guidelines published by the Endocrine Society, all drugs in the classes of glucocorticoids, beta-blockers, and antihistamines are obesogenic, as well as selected agents in the classes of antidepressant drugs, antipsychotics, antidepressants, antidiabetics, and contraceptives that are progestin only, said Dr. Hales (J Clin Endocrinol Metab. 2015 Feb;100[2]:342-62).
The data he reported came from the National Health and Nutrition Examination Survey (NHANES) run by the CDC during 2013-2016 that included 11,055 adults who were at least 20 years old. The findings showed that 23% of those adults had taken at least one drug that was considered obesogenic during the 30 days preceding the survey date. By comparison, 35% of the same adults had taken any type of prescription drug during the previous 30 days. That meant that overall, 40% of surveyed adults who had recently used any prescription medication had taken an obesogenic drug.
The 23% prevalence of recent obesogenic drug use was fairly stable at that level during several preceding NHANES surveys going back to 2001, suggesting that the increasing use of obesogenic drugs during the period since 2001 was not a factor in the recent increased prevalence of obesity among U.S. residents, added Dr. Hales.
The 2013-2016 analysis also showed a strong link between obesogenic drug use and increasing obesity severity. Among survey participants with a body mass index (BMI) in the normal range (18.5-24 kg/m2), 16% had recent use of an obesogenic drug. This prevalence increased to 22% among those who were overweight (BMI, 25-29 kg/m2), 29% among those with class 1 or 2 obesity (BMI, 30-39 kg/m2), and 33% among those with class 3 obesity (BMI, 40 kg/m2 or greater).
In contrast, recent use of prescription medications that do not contribute to obesity showed no significant relationship with BMI, with rates that ranged from 34% among those with a normal BMI, to 37% among those with class 3 obesity.
As an example of this relationship for a specific obesogenic drug class, the prevalence of beta-blocker use was about 7% among people with a normal BMI, about 10% among those who were overweight, about 14% among people with class 1 or 2 obesity, and about 17% among people with class 3 obesity, a statistically significant link suggesting that the relationship between use of obesogenic drugs and obesity is “bidirectional,” Dr. Hales said, in that increasing obesogenic drug use likely contributes to obesity, while simultaneously, the more obese people become, the more likely they are to take additional prescription drugs, particularly those that are obesogenic.
NHANES is run by the CDC and receives no commercial funding. The authors reported no conflicts of interest.
SOURCE: Hales CM et al. Obesity Week 2019, Abstract T-OR-2037.
LAS VEGAS – based on national U.S. data collected during 2013-2016.
The Endocrine Society, the STOP Obesity Alliance, and other medical societies have recommended that clinicians try to minimize use of obesogenic drugs and focus on prescribing agents that are weight neutral or that trigger weight loss when those options are available and appropriate, and the new findings add further evidence that clinicians need to be more mindful of this issue, Craig M. Hales, MD, said at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.
Among the American adults interviewed for the survey, 40% of those on at least one prescription medication were on at least one drug that is considered obesogenic, said Dr. Hales, a medical epidemiologist at the Centers for Disease Control and Prevention in Hyattsville, Md.
According to practice guidelines published by the Endocrine Society, all drugs in the classes of glucocorticoids, beta-blockers, and antihistamines are obesogenic, as well as selected agents in the classes of antidepressant drugs, antipsychotics, antidepressants, antidiabetics, and contraceptives that are progestin only, said Dr. Hales (J Clin Endocrinol Metab. 2015 Feb;100[2]:342-62).
The data he reported came from the National Health and Nutrition Examination Survey (NHANES) run by the CDC during 2013-2016 that included 11,055 adults who were at least 20 years old. The findings showed that 23% of those adults had taken at least one drug that was considered obesogenic during the 30 days preceding the survey date. By comparison, 35% of the same adults had taken any type of prescription drug during the previous 30 days. That meant that overall, 40% of surveyed adults who had recently used any prescription medication had taken an obesogenic drug.
The 23% prevalence of recent obesogenic drug use was fairly stable at that level during several preceding NHANES surveys going back to 2001, suggesting that the increasing use of obesogenic drugs during the period since 2001 was not a factor in the recent increased prevalence of obesity among U.S. residents, added Dr. Hales.
The 2013-2016 analysis also showed a strong link between obesogenic drug use and increasing obesity severity. Among survey participants with a body mass index (BMI) in the normal range (18.5-24 kg/m2), 16% had recent use of an obesogenic drug. This prevalence increased to 22% among those who were overweight (BMI, 25-29 kg/m2), 29% among those with class 1 or 2 obesity (BMI, 30-39 kg/m2), and 33% among those with class 3 obesity (BMI, 40 kg/m2 or greater).
In contrast, recent use of prescription medications that do not contribute to obesity showed no significant relationship with BMI, with rates that ranged from 34% among those with a normal BMI, to 37% among those with class 3 obesity.
As an example of this relationship for a specific obesogenic drug class, the prevalence of beta-blocker use was about 7% among people with a normal BMI, about 10% among those who were overweight, about 14% among people with class 1 or 2 obesity, and about 17% among people with class 3 obesity, a statistically significant link suggesting that the relationship between use of obesogenic drugs and obesity is “bidirectional,” Dr. Hales said, in that increasing obesogenic drug use likely contributes to obesity, while simultaneously, the more obese people become, the more likely they are to take additional prescription drugs, particularly those that are obesogenic.
NHANES is run by the CDC and receives no commercial funding. The authors reported no conflicts of interest.
SOURCE: Hales CM et al. Obesity Week 2019, Abstract T-OR-2037.
REPORTING FROM OBESITY WEEK 2019
Icosapent ethyl approved for cardiovascular risk reduction
Icosapent ethyl (Vascepa) has gained an indication from the Food and Drug Administration for reduction of cardiovascular events in patients with high triglycerides who are at high risk for cardiovascular events. 
as an add-on to maximally tolerated statin therapy,” the agency said in an announcement.
The decision, announced on Dec. 13, was based primarily on results of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. It showed that patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (N Engl J Med. 2019 Jan 3;380[1]:11-22).
In a November meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously for approval.
The agency notes that, in clinical trials, icosapent ethyl was linked to an increased risk of atrial fibrillation or atrial flutter requiring hospitalization, especially in patients with a history of either condition. The highly purified form of the ethyl ester of eicosapentaenoic acid was also associated with an increased risk of bleeding events, particularly in those taking blood-thinning drugs that increase the risk of bleeding, such as aspirin, clopidogrel, or warfarin.
The most common side effects reported in the clinical trials for icosapent ethyl were musculoskeletal pain, peripheral edema, atrial fibrillation, and arthralgia.
The complete indication is “as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride levels (at least 150 mg/dL) and established cardiovascular disease or diabetes mellitus and two or more additional risk factors for cardiovascular disease,” according to a statement from Amalin, which markets Vascepa.
The drug was approved in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.
Icosapent ethyl (Vascepa) has gained an indication from the Food and Drug Administration for reduction of cardiovascular events in patients with high triglycerides who are at high risk for cardiovascular events.
as an add-on to maximally tolerated statin therapy,” the agency said in an announcement.
The decision, announced on Dec. 13, was based primarily on results of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. It showed that patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (N Engl J Med. 2019 Jan 3;380[1]:11-22).
In a November meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously for approval.
The agency notes that, in clinical trials, icosapent ethyl was linked to an increased risk of atrial fibrillation or atrial flutter requiring hospitalization, especially in patients with a history of either condition. The highly purified form of the ethyl ester of eicosapentaenoic acid was also associated with an increased risk of bleeding events, particularly in those taking blood-thinning drugs that increase the risk of bleeding, such as aspirin, clopidogrel, or warfarin.
The most common side effects reported in the clinical trials for icosapent ethyl were musculoskeletal pain, peripheral edema, atrial fibrillation, and arthralgia.
The complete indication is “as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride levels (at least 150 mg/dL) and established cardiovascular disease or diabetes mellitus and two or more additional risk factors for cardiovascular disease,” according to a statement from Amalin, which markets Vascepa.
The drug was approved in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.
Icosapent ethyl (Vascepa) has gained an indication from the Food and Drug Administration for reduction of cardiovascular events in patients with high triglycerides who are at high risk for cardiovascular events.
as an add-on to maximally tolerated statin therapy,” the agency said in an announcement.
The decision, announced on Dec. 13, was based primarily on results of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. It showed that patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (N Engl J Med. 2019 Jan 3;380[1]:11-22).
In a November meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously for approval.
The agency notes that, in clinical trials, icosapent ethyl was linked to an increased risk of atrial fibrillation or atrial flutter requiring hospitalization, especially in patients with a history of either condition. The highly purified form of the ethyl ester of eicosapentaenoic acid was also associated with an increased risk of bleeding events, particularly in those taking blood-thinning drugs that increase the risk of bleeding, such as aspirin, clopidogrel, or warfarin.
The most common side effects reported in the clinical trials for icosapent ethyl were musculoskeletal pain, peripheral edema, atrial fibrillation, and arthralgia.
The complete indication is “as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride levels (at least 150 mg/dL) and established cardiovascular disease or diabetes mellitus and two or more additional risk factors for cardiovascular disease,” according to a statement from Amalin, which markets Vascepa.
The drug was approved in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.
Lp(a) molar concentration flags CVD, diabetes risk
Lipoprotein(a) molar concentration, rather than apolipoprotein(a) size, appears to be the factor that drives lipoprotein(a)-based cardiovascular disease, according to research published in the Journal of the American College of Cardiology.
The causal association between lipoprotein(a), or Lp(a), and cardiovascular disease has been previously established, but exactly what attribute of Lp(a) is related to cardiovascular risk is not known, Daniel F. Gudbjartsson, PhD, of deCODE genetics and the University of Iceland in Reykjavik, and colleagues wrote in their study. The researchers set out to determine whether Lp(a) molar concentration or apolipoprotein(a), or apo(a), size affects cardiovascular risk. In addition, Dr. Gudbjartsson and colleagues examined the relationship between Lp(a) and type 2 diabetes. While low levels of Lp(a) have been linked to type 2 diabetes, the researchers sought to examine whether low Lp(a) molar concentration levels were also associated with type 2 diabetes risk.
“With Lp(a)-lowering drugs being developed, it is important to understand which attributes of Lp(a) best capture the cardiovascular risk and the consequences of Lp(a) lowering,” noted Dr. Gudbjartsson and colleagues.
Using Mendelian randomization, the researchers assessed Lp(a) molar concentration and kringle IV type 2 (KIV-2) repeat sequence variants to determine a causal relationship between both variants and disease risk. Lp(a) molar concentration serum samples were measured using particle-enhanced turbidimetric immunoassay, while KIV-2 repeats were genotyped with real-time polymerase chain reaction.
Overall, 143,087 participants from Iceland had their genetic information analyzed; of these, 17,715 participants had coronary artery disease, and 8,734 had type 2 diabetes. Lp(a) molecular concentration was analyzed in 12,137 participants and genetically imputed into 130,950 Icelanders, and KIV-2 repeats were estimated in 22,771 Icelanders and genetically imputed into 120,316 Icelanders.
Dr. Gudbjartsson and colleagues found there was a dose-dependent association between Lp(a) molar concentration and risk of coronary artery disease (CAD), peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. In participants in whom Lp(a) molar concentration was at the 79th percentile (50 units of molarity [nM]), the odds ratio was 1.11, and for those in the 99th percentile (250 nM), there was an odds ratio of 2.01 when compared with participants with a median Lp(a) molar concentration of 14 nM. “Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size,” the researchers said.
Participants who were not at increased risk for CAD included those with few KIV-2 repeats and participants with the splice variant G4925A. “This suggested that risk prediction based on Lp(a) should only depend on molar concentration and that treatment of Lp(a) should focus on lowering the molar concentration in subjects with high Lp(a) levels, regardless of the apo(a) size distribution,” Dr. Gudbjartsson and colleagues wrote.
Among participants with type 2 diabetes examined, the 10% of participants with Lp(a) molar concentrations of less than 3.5 nM were at the highest risk of developing type 2 diabetes.
In an accompanying editorial, Benoit J. Arsenault, PhD, of the Quebec Heart and Lung Institute, said that the findings of an association between Lp(a) concentration and atherosclerotic cardiovascular diseases (ASCVD) from Gudbjartsson et al. are important, particularly if they can be replicated in more diverse populations (doi: 10.1016/j.jacc.2019.06.083). “Investigating the association between Lp(a) levels, apo(a) isoform size, and ASCVD risk in different populations is important because the distribution of Lp(a) levels appears to be different across ethnic groups,” he said.
Despite the link between absolute Lp(a) concentrations and cardiovascular disease, cardiovascular outcome trials will need be conducted, Dr. Arsenault noted.
“In the post-statin and post-genomic era, finding much needed therapeutic targets for residual cardiovascular risk can be compared to a gold-digging expedition. Like a map to the location of the gold, GWAS [genome-wide association studies] and Mendelian randomization studies are consistently pointing us in the direction of Lp(a),” he said. “It is time to coordinate our efforts to dig where the map told us, to see once and for all if we will find the golden target of residual cardiovascular risk that we are hoping for and to give hope to high-risk patients with elevated Lp(a) levels.”
Dr. Gudbjartsson and 19 other authors reported being employees of deCODE genetics, owned by Amgen, which is developing Lp(a)-lowering drugs related to the study findings. The other authors reported no relevant conflict of interest. Dr. Arsenault reported being supported by the Fonds de recherche du Québec: Santé and the Canadian Institutes of Health Research; has received research funding from Pfizer, Merck, and Ionis; and was a former consultant for Pfizer and Novartis.
SOURCE: Gudbjartsson DF et al. J Am Coll Cardiol. 2019. doi: 10.1016/j.jacc.2019.10.019.
Lipoprotein(a) molar concentration, rather than apolipoprotein(a) size, appears to be the factor that drives lipoprotein(a)-based cardiovascular disease, according to research published in the Journal of the American College of Cardiology.
The causal association between lipoprotein(a), or Lp(a), and cardiovascular disease has been previously established, but exactly what attribute of Lp(a) is related to cardiovascular risk is not known, Daniel F. Gudbjartsson, PhD, of deCODE genetics and the University of Iceland in Reykjavik, and colleagues wrote in their study. The researchers set out to determine whether Lp(a) molar concentration or apolipoprotein(a), or apo(a), size affects cardiovascular risk. In addition, Dr. Gudbjartsson and colleagues examined the relationship between Lp(a) and type 2 diabetes. While low levels of Lp(a) have been linked to type 2 diabetes, the researchers sought to examine whether low Lp(a) molar concentration levels were also associated with type 2 diabetes risk.
“With Lp(a)-lowering drugs being developed, it is important to understand which attributes of Lp(a) best capture the cardiovascular risk and the consequences of Lp(a) lowering,” noted Dr. Gudbjartsson and colleagues.
Using Mendelian randomization, the researchers assessed Lp(a) molar concentration and kringle IV type 2 (KIV-2) repeat sequence variants to determine a causal relationship between both variants and disease risk. Lp(a) molar concentration serum samples were measured using particle-enhanced turbidimetric immunoassay, while KIV-2 repeats were genotyped with real-time polymerase chain reaction.
Overall, 143,087 participants from Iceland had their genetic information analyzed; of these, 17,715 participants had coronary artery disease, and 8,734 had type 2 diabetes. Lp(a) molecular concentration was analyzed in 12,137 participants and genetically imputed into 130,950 Icelanders, and KIV-2 repeats were estimated in 22,771 Icelanders and genetically imputed into 120,316 Icelanders.
Dr. Gudbjartsson and colleagues found there was a dose-dependent association between Lp(a) molar concentration and risk of coronary artery disease (CAD), peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. In participants in whom Lp(a) molar concentration was at the 79th percentile (50 units of molarity [nM]), the odds ratio was 1.11, and for those in the 99th percentile (250 nM), there was an odds ratio of 2.01 when compared with participants with a median Lp(a) molar concentration of 14 nM. “Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size,” the researchers said.
Participants who were not at increased risk for CAD included those with few KIV-2 repeats and participants with the splice variant G4925A. “This suggested that risk prediction based on Lp(a) should only depend on molar concentration and that treatment of Lp(a) should focus on lowering the molar concentration in subjects with high Lp(a) levels, regardless of the apo(a) size distribution,” Dr. Gudbjartsson and colleagues wrote.
Among participants with type 2 diabetes examined, the 10% of participants with Lp(a) molar concentrations of less than 3.5 nM were at the highest risk of developing type 2 diabetes.
In an accompanying editorial, Benoit J. Arsenault, PhD, of the Quebec Heart and Lung Institute, said that the findings of an association between Lp(a) concentration and atherosclerotic cardiovascular diseases (ASCVD) from Gudbjartsson et al. are important, particularly if they can be replicated in more diverse populations (doi: 10.1016/j.jacc.2019.06.083). “Investigating the association between Lp(a) levels, apo(a) isoform size, and ASCVD risk in different populations is important because the distribution of Lp(a) levels appears to be different across ethnic groups,” he said.
Despite the link between absolute Lp(a) concentrations and cardiovascular disease, cardiovascular outcome trials will need be conducted, Dr. Arsenault noted.
“In the post-statin and post-genomic era, finding much needed therapeutic targets for residual cardiovascular risk can be compared to a gold-digging expedition. Like a map to the location of the gold, GWAS [genome-wide association studies] and Mendelian randomization studies are consistently pointing us in the direction of Lp(a),” he said. “It is time to coordinate our efforts to dig where the map told us, to see once and for all if we will find the golden target of residual cardiovascular risk that we are hoping for and to give hope to high-risk patients with elevated Lp(a) levels.”
Dr. Gudbjartsson and 19 other authors reported being employees of deCODE genetics, owned by Amgen, which is developing Lp(a)-lowering drugs related to the study findings. The other authors reported no relevant conflict of interest. Dr. Arsenault reported being supported by the Fonds de recherche du Québec: Santé and the Canadian Institutes of Health Research; has received research funding from Pfizer, Merck, and Ionis; and was a former consultant for Pfizer and Novartis.
SOURCE: Gudbjartsson DF et al. J Am Coll Cardiol. 2019. doi: 10.1016/j.jacc.2019.10.019.
Lipoprotein(a) molar concentration, rather than apolipoprotein(a) size, appears to be the factor that drives lipoprotein(a)-based cardiovascular disease, according to research published in the Journal of the American College of Cardiology.
The causal association between lipoprotein(a), or Lp(a), and cardiovascular disease has been previously established, but exactly what attribute of Lp(a) is related to cardiovascular risk is not known, Daniel F. Gudbjartsson, PhD, of deCODE genetics and the University of Iceland in Reykjavik, and colleagues wrote in their study. The researchers set out to determine whether Lp(a) molar concentration or apolipoprotein(a), or apo(a), size affects cardiovascular risk. In addition, Dr. Gudbjartsson and colleagues examined the relationship between Lp(a) and type 2 diabetes. While low levels of Lp(a) have been linked to type 2 diabetes, the researchers sought to examine whether low Lp(a) molar concentration levels were also associated with type 2 diabetes risk.
“With Lp(a)-lowering drugs being developed, it is important to understand which attributes of Lp(a) best capture the cardiovascular risk and the consequences of Lp(a) lowering,” noted Dr. Gudbjartsson and colleagues.
Using Mendelian randomization, the researchers assessed Lp(a) molar concentration and kringle IV type 2 (KIV-2) repeat sequence variants to determine a causal relationship between both variants and disease risk. Lp(a) molar concentration serum samples were measured using particle-enhanced turbidimetric immunoassay, while KIV-2 repeats were genotyped with real-time polymerase chain reaction.
Overall, 143,087 participants from Iceland had their genetic information analyzed; of these, 17,715 participants had coronary artery disease, and 8,734 had type 2 diabetes. Lp(a) molecular concentration was analyzed in 12,137 participants and genetically imputed into 130,950 Icelanders, and KIV-2 repeats were estimated in 22,771 Icelanders and genetically imputed into 120,316 Icelanders.
Dr. Gudbjartsson and colleagues found there was a dose-dependent association between Lp(a) molar concentration and risk of coronary artery disease (CAD), peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. In participants in whom Lp(a) molar concentration was at the 79th percentile (50 units of molarity [nM]), the odds ratio was 1.11, and for those in the 99th percentile (250 nM), there was an odds ratio of 2.01 when compared with participants with a median Lp(a) molar concentration of 14 nM. “Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size,” the researchers said.
Participants who were not at increased risk for CAD included those with few KIV-2 repeats and participants with the splice variant G4925A. “This suggested that risk prediction based on Lp(a) should only depend on molar concentration and that treatment of Lp(a) should focus on lowering the molar concentration in subjects with high Lp(a) levels, regardless of the apo(a) size distribution,” Dr. Gudbjartsson and colleagues wrote.
Among participants with type 2 diabetes examined, the 10% of participants with Lp(a) molar concentrations of less than 3.5 nM were at the highest risk of developing type 2 diabetes.
In an accompanying editorial, Benoit J. Arsenault, PhD, of the Quebec Heart and Lung Institute, said that the findings of an association between Lp(a) concentration and atherosclerotic cardiovascular diseases (ASCVD) from Gudbjartsson et al. are important, particularly if they can be replicated in more diverse populations (doi: 10.1016/j.jacc.2019.06.083). “Investigating the association between Lp(a) levels, apo(a) isoform size, and ASCVD risk in different populations is important because the distribution of Lp(a) levels appears to be different across ethnic groups,” he said.
Despite the link between absolute Lp(a) concentrations and cardiovascular disease, cardiovascular outcome trials will need be conducted, Dr. Arsenault noted.
“In the post-statin and post-genomic era, finding much needed therapeutic targets for residual cardiovascular risk can be compared to a gold-digging expedition. Like a map to the location of the gold, GWAS [genome-wide association studies] and Mendelian randomization studies are consistently pointing us in the direction of Lp(a),” he said. “It is time to coordinate our efforts to dig where the map told us, to see once and for all if we will find the golden target of residual cardiovascular risk that we are hoping for and to give hope to high-risk patients with elevated Lp(a) levels.”
Dr. Gudbjartsson and 19 other authors reported being employees of deCODE genetics, owned by Amgen, which is developing Lp(a)-lowering drugs related to the study findings. The other authors reported no relevant conflict of interest. Dr. Arsenault reported being supported by the Fonds de recherche du Québec: Santé and the Canadian Institutes of Health Research; has received research funding from Pfizer, Merck, and Ionis; and was a former consultant for Pfizer and Novartis.
SOURCE: Gudbjartsson DF et al. J Am Coll Cardiol. 2019. doi: 10.1016/j.jacc.2019.10.019.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Key clinical point:
Major finding: There was a dose-dependent association between Lp(a) molar concentration and risk of coronary artery disease (CAD), peripheral artery disease, aortic valve stenosis, heart failure, and lifespan.
Study details: A case-control study of genetic information from 143,087 Icelandic participants.
Disclosures: Dr. Gudbjartsson and 19 other authors reported being employees of deCODE genetics, owned by Amgen, which is developing Lp(a)-lowering drugs related to the study findings. The other authors reported no relevant conflict of interest. Dr. Arsenault reported being supported by the Fonds de recherche du Québec: Santé and the Canadian Institutes of Health Research; has received research funding from Pfizer, Merck, and Ionis; and was a former consultant for Pfizer and Novartis.
Source: Gudbjartsson DF et al. J Am Coll Cardiol. 2019. doi: 10.1016/j.jacc.2019.10.019.
Effective NASH medications are coming ‘sooner than you think’
SAN ANTONIO – The therapeutic Dark Ages of nonalcoholic steatohepatitis (NASH) are finally drawing to a close.
“NASH-specific therapies are coming soon – sooner than you think,” Naim Alkhouri, MD, predicted at the annual meeting of the American College of Gastroenterology.
And that, he added, has important implications for clinical practice. Physicians are going to need to step up their game with regard to screening and staging patients with nonalcoholic fatty liver disease to identify the right candidates for the coming effective treatments.
The new treatment era in NASH could dawn as soon as the spring of 2020, by which time the Food and Drug Administration is expected to issue a decision on obeticholic acid, an oral FXR agonist for which the agency has granted breakthrough therapy status. Intercept Pharmaceuticals has filed for marketing approval of obeticholic acid for NASH on the strength of the positive 18-month histologic results of the pivotal phase 3 REGENERATE trial, the first-ever successful phase 3 study of a medication for NASH, noted Dr. Alkhouri, a gastroenterologist at the University of Texas, San Antonio, and director of the Metabolic Health Center at the Texas Liver Institute.
At present there are no FDA-approved pharmacotherapies for NASH. The unmet medical need is huge, since NASH is now recognized to be a full-blown, burgeoning epidemic. NASH will soon become the No. 1 indication for liver transplantation in the United States. A full-throttle race is on to find effective therapies targeting the various dimensions of NASH, with more than 70 drugs now in phase 2 studies. These drugs collectively address all four mechanisms of the disease’s development and progression: the metabolic targets, perturbations in the gut-liver axis, liver inflammation, and fibrosis.
Moreover, even as the FDA considers the application for approval of obeticholic acid in NASH, at least four other investigational drugs are in pivotal phase 3 clinical trials. These include elafibranor, aramchol, resmetirom, and cenicriviroc.
Cenicriviroc is a dual CCR 2/5 receptor antagonist that targets the hepatic inflammation and fibrosis dimensions of NASH. It is now being evaluated in the phase 3 AURORA trial on the strength of the earlier positive phase 2b Centaur study, in which patients randomized to cenicriviroc were twice as likely to experience significant improvement in fibrosis as were placebo-treated controls.
Elafibranor, aramchol, and resmetirom employ different mechanisms of action to address the metabolic derangements of NASH. What they share in common is their aim to reduce the influx of free fatty acids from adipose tissue to the liver, and/or to inhibit lipogenesis from carbohydrate building blocks. In so doing, these medications should result in reduced hepatocyte injury and liver inflammation.
Elafibranor is a peroxisome proliferator-activated receptor alpha/delta agonist that achieved significant biopsy-proven reversal of NASH in moderate- or severely affected patients in the phase 2 GOLDEN study. The phase 3 RESOLVE IT trial is underway.
Aramchol is a first-in-class synthetic fatty acid/bile acid conjugate that inhibits stearoyl-CoA desaturate activity. It’s designed to improve insulin resistance and curb accumulation of triglycerides in hepatocytes. In the 52-week, phase 2 ARREST trial, oral aramchol at 600 mg/day was 4.7-fold more likely than was placebo to achieve NASH resolution without worsening of fibrosis. The drug is now in phase 3 in the ARMOR study.
Resmetirom is a selective thyroid hormone receptor–beta agonist. Activation of the beta receptor lowers LDL cholesterol, triglycerides, and liver fat, whereas activation of the alpha receptor has the unwanted effects of promoting bone loss, thyrotoxicosis, and arrhythmias. In phase 2, 75% of patients on high-dose resmetirom achieved at least a 30% reduction in hepatic fat by MRI at week 12, compared with 18% of placebo-treated controls. And 39% of the high-dose resmetirom group showed histologic resolution of NASH on a week-36 liver biopsy, as did a mere 6% of controls. The phase 3 MAESTRO randomized trial is underway.
Obeticholic acid addresses the gut-liver axis abnormalities present in NASH, especially the exuberant bile acid circulation.
Clinical implications of the coming wave of medications
In Dr. Alkhouri’s view, .
“These are the patients with a high chance of progressing to cirrhosis and end-stage liver disease,” the gastroenterologist said.
Patients with earlier-stage nonalcoholic fatty liver disease are best managed via lifestyle changes, with particular emphasis upon 10% weight loss accompanied by exercise. And patients with more advanced disease – NASH with cirrhosis – appear thus far to be beyond the reach of the next-generation therapies.
None of the coming drugs is a cure-all. In the landmark phase 3 REGENERATE trial, for example, the rate of the primary outcome – fibrosis improvement of at least one stage plus no worsening of NASH at 18 months – was 23% in patients randomized to obeticholic acid at 25 mg/day, compared to 12% with placebo.
“These are not like hepatitis C medications, with 97% efficacy, so combination therapy targeting upstream and downstream for NASH is rational,” Dr. Alkhouri observed.
He reported serving on advisory boards for Allergan, Gilead, and Intercept, and receiving research grants from those companies as well as from Galmed, Genfit, and Madrigal.
*This story was updated on 12/5/2019.
SAN ANTONIO – The therapeutic Dark Ages of nonalcoholic steatohepatitis (NASH) are finally drawing to a close.
“NASH-specific therapies are coming soon – sooner than you think,” Naim Alkhouri, MD, predicted at the annual meeting of the American College of Gastroenterology.
And that, he added, has important implications for clinical practice. Physicians are going to need to step up their game with regard to screening and staging patients with nonalcoholic fatty liver disease to identify the right candidates for the coming effective treatments.
The new treatment era in NASH could dawn as soon as the spring of 2020, by which time the Food and Drug Administration is expected to issue a decision on obeticholic acid, an oral FXR agonist for which the agency has granted breakthrough therapy status. Intercept Pharmaceuticals has filed for marketing approval of obeticholic acid for NASH on the strength of the positive 18-month histologic results of the pivotal phase 3 REGENERATE trial, the first-ever successful phase 3 study of a medication for NASH, noted Dr. Alkhouri, a gastroenterologist at the University of Texas, San Antonio, and director of the Metabolic Health Center at the Texas Liver Institute.
At present there are no FDA-approved pharmacotherapies for NASH. The unmet medical need is huge, since NASH is now recognized to be a full-blown, burgeoning epidemic. NASH will soon become the No. 1 indication for liver transplantation in the United States. A full-throttle race is on to find effective therapies targeting the various dimensions of NASH, with more than 70 drugs now in phase 2 studies. These drugs collectively address all four mechanisms of the disease’s development and progression: the metabolic targets, perturbations in the gut-liver axis, liver inflammation, and fibrosis.
Moreover, even as the FDA considers the application for approval of obeticholic acid in NASH, at least four other investigational drugs are in pivotal phase 3 clinical trials. These include elafibranor, aramchol, resmetirom, and cenicriviroc.
Cenicriviroc is a dual CCR 2/5 receptor antagonist that targets the hepatic inflammation and fibrosis dimensions of NASH. It is now being evaluated in the phase 3 AURORA trial on the strength of the earlier positive phase 2b Centaur study, in which patients randomized to cenicriviroc were twice as likely to experience significant improvement in fibrosis as were placebo-treated controls.
Elafibranor, aramchol, and resmetirom employ different mechanisms of action to address the metabolic derangements of NASH. What they share in common is their aim to reduce the influx of free fatty acids from adipose tissue to the liver, and/or to inhibit lipogenesis from carbohydrate building blocks. In so doing, these medications should result in reduced hepatocyte injury and liver inflammation.
Elafibranor is a peroxisome proliferator-activated receptor alpha/delta agonist that achieved significant biopsy-proven reversal of NASH in moderate- or severely affected patients in the phase 2 GOLDEN study. The phase 3 RESOLVE IT trial is underway.
Aramchol is a first-in-class synthetic fatty acid/bile acid conjugate that inhibits stearoyl-CoA desaturate activity. It’s designed to improve insulin resistance and curb accumulation of triglycerides in hepatocytes. In the 52-week, phase 2 ARREST trial, oral aramchol at 600 mg/day was 4.7-fold more likely than was placebo to achieve NASH resolution without worsening of fibrosis. The drug is now in phase 3 in the ARMOR study.
Resmetirom is a selective thyroid hormone receptor–beta agonist. Activation of the beta receptor lowers LDL cholesterol, triglycerides, and liver fat, whereas activation of the alpha receptor has the unwanted effects of promoting bone loss, thyrotoxicosis, and arrhythmias. In phase 2, 75% of patients on high-dose resmetirom achieved at least a 30% reduction in hepatic fat by MRI at week 12, compared with 18% of placebo-treated controls. And 39% of the high-dose resmetirom group showed histologic resolution of NASH on a week-36 liver biopsy, as did a mere 6% of controls. The phase 3 MAESTRO randomized trial is underway.
Obeticholic acid addresses the gut-liver axis abnormalities present in NASH, especially the exuberant bile acid circulation.
Clinical implications of the coming wave of medications
In Dr. Alkhouri’s view, .
“These are the patients with a high chance of progressing to cirrhosis and end-stage liver disease,” the gastroenterologist said.
Patients with earlier-stage nonalcoholic fatty liver disease are best managed via lifestyle changes, with particular emphasis upon 10% weight loss accompanied by exercise. And patients with more advanced disease – NASH with cirrhosis – appear thus far to be beyond the reach of the next-generation therapies.
None of the coming drugs is a cure-all. In the landmark phase 3 REGENERATE trial, for example, the rate of the primary outcome – fibrosis improvement of at least one stage plus no worsening of NASH at 18 months – was 23% in patients randomized to obeticholic acid at 25 mg/day, compared to 12% with placebo.
“These are not like hepatitis C medications, with 97% efficacy, so combination therapy targeting upstream and downstream for NASH is rational,” Dr. Alkhouri observed.
He reported serving on advisory boards for Allergan, Gilead, and Intercept, and receiving research grants from those companies as well as from Galmed, Genfit, and Madrigal.
*This story was updated on 12/5/2019.
SAN ANTONIO – The therapeutic Dark Ages of nonalcoholic steatohepatitis (NASH) are finally drawing to a close.
“NASH-specific therapies are coming soon – sooner than you think,” Naim Alkhouri, MD, predicted at the annual meeting of the American College of Gastroenterology.
And that, he added, has important implications for clinical practice. Physicians are going to need to step up their game with regard to screening and staging patients with nonalcoholic fatty liver disease to identify the right candidates for the coming effective treatments.
The new treatment era in NASH could dawn as soon as the spring of 2020, by which time the Food and Drug Administration is expected to issue a decision on obeticholic acid, an oral FXR agonist for which the agency has granted breakthrough therapy status. Intercept Pharmaceuticals has filed for marketing approval of obeticholic acid for NASH on the strength of the positive 18-month histologic results of the pivotal phase 3 REGENERATE trial, the first-ever successful phase 3 study of a medication for NASH, noted Dr. Alkhouri, a gastroenterologist at the University of Texas, San Antonio, and director of the Metabolic Health Center at the Texas Liver Institute.
At present there are no FDA-approved pharmacotherapies for NASH. The unmet medical need is huge, since NASH is now recognized to be a full-blown, burgeoning epidemic. NASH will soon become the No. 1 indication for liver transplantation in the United States. A full-throttle race is on to find effective therapies targeting the various dimensions of NASH, with more than 70 drugs now in phase 2 studies. These drugs collectively address all four mechanisms of the disease’s development and progression: the metabolic targets, perturbations in the gut-liver axis, liver inflammation, and fibrosis.
Moreover, even as the FDA considers the application for approval of obeticholic acid in NASH, at least four other investigational drugs are in pivotal phase 3 clinical trials. These include elafibranor, aramchol, resmetirom, and cenicriviroc.
Cenicriviroc is a dual CCR 2/5 receptor antagonist that targets the hepatic inflammation and fibrosis dimensions of NASH. It is now being evaluated in the phase 3 AURORA trial on the strength of the earlier positive phase 2b Centaur study, in which patients randomized to cenicriviroc were twice as likely to experience significant improvement in fibrosis as were placebo-treated controls.
Elafibranor, aramchol, and resmetirom employ different mechanisms of action to address the metabolic derangements of NASH. What they share in common is their aim to reduce the influx of free fatty acids from adipose tissue to the liver, and/or to inhibit lipogenesis from carbohydrate building blocks. In so doing, these medications should result in reduced hepatocyte injury and liver inflammation.
Elafibranor is a peroxisome proliferator-activated receptor alpha/delta agonist that achieved significant biopsy-proven reversal of NASH in moderate- or severely affected patients in the phase 2 GOLDEN study. The phase 3 RESOLVE IT trial is underway.
Aramchol is a first-in-class synthetic fatty acid/bile acid conjugate that inhibits stearoyl-CoA desaturate activity. It’s designed to improve insulin resistance and curb accumulation of triglycerides in hepatocytes. In the 52-week, phase 2 ARREST trial, oral aramchol at 600 mg/day was 4.7-fold more likely than was placebo to achieve NASH resolution without worsening of fibrosis. The drug is now in phase 3 in the ARMOR study.
Resmetirom is a selective thyroid hormone receptor–beta agonist. Activation of the beta receptor lowers LDL cholesterol, triglycerides, and liver fat, whereas activation of the alpha receptor has the unwanted effects of promoting bone loss, thyrotoxicosis, and arrhythmias. In phase 2, 75% of patients on high-dose resmetirom achieved at least a 30% reduction in hepatic fat by MRI at week 12, compared with 18% of placebo-treated controls. And 39% of the high-dose resmetirom group showed histologic resolution of NASH on a week-36 liver biopsy, as did a mere 6% of controls. The phase 3 MAESTRO randomized trial is underway.
Obeticholic acid addresses the gut-liver axis abnormalities present in NASH, especially the exuberant bile acid circulation.
Clinical implications of the coming wave of medications
In Dr. Alkhouri’s view, .
“These are the patients with a high chance of progressing to cirrhosis and end-stage liver disease,” the gastroenterologist said.
Patients with earlier-stage nonalcoholic fatty liver disease are best managed via lifestyle changes, with particular emphasis upon 10% weight loss accompanied by exercise. And patients with more advanced disease – NASH with cirrhosis – appear thus far to be beyond the reach of the next-generation therapies.
None of the coming drugs is a cure-all. In the landmark phase 3 REGENERATE trial, for example, the rate of the primary outcome – fibrosis improvement of at least one stage plus no worsening of NASH at 18 months – was 23% in patients randomized to obeticholic acid at 25 mg/day, compared to 12% with placebo.
“These are not like hepatitis C medications, with 97% efficacy, so combination therapy targeting upstream and downstream for NASH is rational,” Dr. Alkhouri observed.
He reported serving on advisory boards for Allergan, Gilead, and Intercept, and receiving research grants from those companies as well as from Galmed, Genfit, and Madrigal.
*This story was updated on 12/5/2019.
REPORTING FROM ACG 2019
Icosapent ethyl cost effective in REDUCE-IT analysis
PHILADELPHIA – The overall costs of icosapent ethyl were less than placebo, and the medication reduced cardiovascular events by 30% at a cost that fits well within acceptable quality-adjusted life-year (QALY) parameters, according to a cost-effectiveness analysis of the REDUCE-IT trial.
Days before the presentation of the analysis at the American Heart Association scientific sessions, a Food and Drug Administration advisory panel unanimously recommended approval of icosapent ethyl (Vascepa) for a new indication for reducing CV event risk. Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid derived from fish oil, received FDA approval in 2012 for treatment of triglyceride levels of at least 500 mg/dL.
“What we found here is that icosapent ethyl is a dominant strategy,” said William S. Weintraub, MD, director of outcomes research at MedStar Heart & Vascular Institute in Washington, in reporting preliminary cost-analysis findings from REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial). “It’s offering better outcomes at a lower cost.”
The dominant strategy was demonstrated by cost savings in 70% of simulations the cost-effectiveness analysis ran, Dr. Weintraub said.
“These are very impressive results,” said session moderator Seth S. Martin, MD, an internist and cardiologist at Johns Hopkins University, Baltimore. “We don’t often see dominant strategies for new drugs. This is very exciting.”
“Almost never,” Dr. Weintraub responded.
REDUCE-IT randomized 8,179 patients with a diagnosis of CVD or with diabetes and other risk factors who had been on statins and had triglycerides of 135-499 mg/dL to either 4 g of icosapent ethyl daily or placebo (N Engl J Med. 2019;380:11-22). Trial results showed the treatment group had an absolute risk reduction of 4.8% and a relative risk reduction of 25% of first CV events and a 30% relative risk reduction for total events, Dr. Weintraub said.
The analysis determined that the QALYs for icosapent ethyl versus those for placebo were 3.34 and 3.27, respectively, during the trial period and 11.61 and 11.35 over a lifetime. The mean costs for the two treatments were $27,576 and $28,205 during the trial period and $235,352 and $236,636 lifetime, respectively, Dr. Weintraub said.
An analysis of cost effectiveness showed that almost all of the estimates fell below the willingness-to-pay (WTP) threshold of $50,000 per QALY gained, Dr. Weintraub said. “In fact, some 70% plus are in what’s called quadrant two; that is, decreased cost and increased efficacy.”
The analysis also calculated the value of icosapent ethyl at three different WTP thresholds: up to $6 a day at a WTP of $50,000, up to $12 a day at $100,000, and up to $18 a day at $150,000. The analysis used the actual net pricing of $4.16 a day, Dr. Weintraub said. “That’s why we showed we have the dominant strategy,” he said.
Further cost-effectiveness analyses of the REDUCE-IT data will focus on subgroups, such as U.S. and non–U.S. patients and people with diabetes. He also emphasized the data he reported were preliminary. “We have a lot more work to do,” Dr. Weintraub said.
Dr. Weintraub reported having financial relationships with Amarin Pharma, which markets Vascepa, and AstraZeneca.
SOURCE: Weintraub WS. AHA 2019, Session FS.AOS.F1.
PHILADELPHIA – The overall costs of icosapent ethyl were less than placebo, and the medication reduced cardiovascular events by 30% at a cost that fits well within acceptable quality-adjusted life-year (QALY) parameters, according to a cost-effectiveness analysis of the REDUCE-IT trial.
Days before the presentation of the analysis at the American Heart Association scientific sessions, a Food and Drug Administration advisory panel unanimously recommended approval of icosapent ethyl (Vascepa) for a new indication for reducing CV event risk. Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid derived from fish oil, received FDA approval in 2012 for treatment of triglyceride levels of at least 500 mg/dL.
“What we found here is that icosapent ethyl is a dominant strategy,” said William S. Weintraub, MD, director of outcomes research at MedStar Heart & Vascular Institute in Washington, in reporting preliminary cost-analysis findings from REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial). “It’s offering better outcomes at a lower cost.”
The dominant strategy was demonstrated by cost savings in 70% of simulations the cost-effectiveness analysis ran, Dr. Weintraub said.
“These are very impressive results,” said session moderator Seth S. Martin, MD, an internist and cardiologist at Johns Hopkins University, Baltimore. “We don’t often see dominant strategies for new drugs. This is very exciting.”
“Almost never,” Dr. Weintraub responded.
REDUCE-IT randomized 8,179 patients with a diagnosis of CVD or with diabetes and other risk factors who had been on statins and had triglycerides of 135-499 mg/dL to either 4 g of icosapent ethyl daily or placebo (N Engl J Med. 2019;380:11-22). Trial results showed the treatment group had an absolute risk reduction of 4.8% and a relative risk reduction of 25% of first CV events and a 30% relative risk reduction for total events, Dr. Weintraub said.
The analysis determined that the QALYs for icosapent ethyl versus those for placebo were 3.34 and 3.27, respectively, during the trial period and 11.61 and 11.35 over a lifetime. The mean costs for the two treatments were $27,576 and $28,205 during the trial period and $235,352 and $236,636 lifetime, respectively, Dr. Weintraub said.
An analysis of cost effectiveness showed that almost all of the estimates fell below the willingness-to-pay (WTP) threshold of $50,000 per QALY gained, Dr. Weintraub said. “In fact, some 70% plus are in what’s called quadrant two; that is, decreased cost and increased efficacy.”
The analysis also calculated the value of icosapent ethyl at three different WTP thresholds: up to $6 a day at a WTP of $50,000, up to $12 a day at $100,000, and up to $18 a day at $150,000. The analysis used the actual net pricing of $4.16 a day, Dr. Weintraub said. “That’s why we showed we have the dominant strategy,” he said.
Further cost-effectiveness analyses of the REDUCE-IT data will focus on subgroups, such as U.S. and non–U.S. patients and people with diabetes. He also emphasized the data he reported were preliminary. “We have a lot more work to do,” Dr. Weintraub said.
Dr. Weintraub reported having financial relationships with Amarin Pharma, which markets Vascepa, and AstraZeneca.
SOURCE: Weintraub WS. AHA 2019, Session FS.AOS.F1.
PHILADELPHIA – The overall costs of icosapent ethyl were less than placebo, and the medication reduced cardiovascular events by 30% at a cost that fits well within acceptable quality-adjusted life-year (QALY) parameters, according to a cost-effectiveness analysis of the REDUCE-IT trial.
Days before the presentation of the analysis at the American Heart Association scientific sessions, a Food and Drug Administration advisory panel unanimously recommended approval of icosapent ethyl (Vascepa) for a new indication for reducing CV event risk. Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid derived from fish oil, received FDA approval in 2012 for treatment of triglyceride levels of at least 500 mg/dL.
“What we found here is that icosapent ethyl is a dominant strategy,” said William S. Weintraub, MD, director of outcomes research at MedStar Heart & Vascular Institute in Washington, in reporting preliminary cost-analysis findings from REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial). “It’s offering better outcomes at a lower cost.”
The dominant strategy was demonstrated by cost savings in 70% of simulations the cost-effectiveness analysis ran, Dr. Weintraub said.
“These are very impressive results,” said session moderator Seth S. Martin, MD, an internist and cardiologist at Johns Hopkins University, Baltimore. “We don’t often see dominant strategies for new drugs. This is very exciting.”
“Almost never,” Dr. Weintraub responded.
REDUCE-IT randomized 8,179 patients with a diagnosis of CVD or with diabetes and other risk factors who had been on statins and had triglycerides of 135-499 mg/dL to either 4 g of icosapent ethyl daily or placebo (N Engl J Med. 2019;380:11-22). Trial results showed the treatment group had an absolute risk reduction of 4.8% and a relative risk reduction of 25% of first CV events and a 30% relative risk reduction for total events, Dr. Weintraub said.
The analysis determined that the QALYs for icosapent ethyl versus those for placebo were 3.34 and 3.27, respectively, during the trial period and 11.61 and 11.35 over a lifetime. The mean costs for the two treatments were $27,576 and $28,205 during the trial period and $235,352 and $236,636 lifetime, respectively, Dr. Weintraub said.
An analysis of cost effectiveness showed that almost all of the estimates fell below the willingness-to-pay (WTP) threshold of $50,000 per QALY gained, Dr. Weintraub said. “In fact, some 70% plus are in what’s called quadrant two; that is, decreased cost and increased efficacy.”
The analysis also calculated the value of icosapent ethyl at three different WTP thresholds: up to $6 a day at a WTP of $50,000, up to $12 a day at $100,000, and up to $18 a day at $150,000. The analysis used the actual net pricing of $4.16 a day, Dr. Weintraub said. “That’s why we showed we have the dominant strategy,” he said.
Further cost-effectiveness analyses of the REDUCE-IT data will focus on subgroups, such as U.S. and non–U.S. patients and people with diabetes. He also emphasized the data he reported were preliminary. “We have a lot more work to do,” Dr. Weintraub said.
Dr. Weintraub reported having financial relationships with Amarin Pharma, which markets Vascepa, and AstraZeneca.
SOURCE: Weintraub WS. AHA 2019, Session FS.AOS.F1.
REPORTING FROM AHA 2019