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Fresh data confirm healthy plant foods link to lower diabetes risk
A scientific analysis of metabolites from plant-based-diets – especially those rich in whole grains, fruits, and vegetables – may in the future yield clues as to how such eating patterns lower the risk of type 2 diabetes, finds a new study of more than 8,000 people.
The research looked at healthy, unhealthy, and overall plant-based diets, but only metabolic profiles for the healthy and overall plant-based diets showed an inverse relationship with type 2 diabetes.
A primarily “unhealthy” plant-based diet was one including mainly refined grains (e.g., white bread and pasta), fruit juices, potatoes, sugar-sweetened beverages, and sweets/desserts.
“Individual metabolites from consumption of polyphenol-rich plant foods like fruits, vegetables, coffee, and legumes are all closely linked to healthy plant-based diet and lower risk of diabetes,” lead author Frank Hu, MD, said in a press release.
Dr. Hu, of the department of nutrition at Harvard T.H. Chan School of Public Health, Boston, and colleagues reported their findings in Diabetologia.
High-throughput profiling of the metabolome
Given that an individual’s metabolic profile reflects their diet, there is a growing trend in nutritional research to use a technique called high-throughput metabolomics to profile biological samples.
The team conducted an analysis of blood plasma samples and dietary intake using food frequency questionnaires of 10,684 participants from three prospective cohorts (Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-Up Study). Participants were predominantly White and middle-aged (mean age 54 years), with a mean body mass index of 25.6 kg/m2.
Metabolite profile scores were generated from the blood samples, taken in the 1980s and 1990s, and matched to any cases of incident type 2 diabetes reported during follow-up, which ended in 2016-2017.
The team looked at three different plant-based diets – by definition, higher in plant foods and lower in animal foods – and further categorized them according to the actual foods consumed, to generate an overall plant diet index (PDI), a healthy PDI, or an unhealthy PDI.
In all, 8,827 participants completed the study, and 270 cases of diabetes were reported.
Multi-metabolite profiles were composed of 55 metabolites for the overall PDI, 93 metabolites for healthy PDI, and 75 metabolites for unhealthy PDI.
The findings are that metabolomics can be harnessed and “the identified metabolic profiles could be used to assess adherence to ... plant-based diets as part of type 2 diabetes prevention ... and provide new insights for future investigation,” the researchers concluded.
One coauthor received research support from the California Walnut Commission and Swiss ReManagement; another reported being a scientific consultant to LayerIV. The other authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A scientific analysis of metabolites from plant-based-diets – especially those rich in whole grains, fruits, and vegetables – may in the future yield clues as to how such eating patterns lower the risk of type 2 diabetes, finds a new study of more than 8,000 people.
The research looked at healthy, unhealthy, and overall plant-based diets, but only metabolic profiles for the healthy and overall plant-based diets showed an inverse relationship with type 2 diabetes.
A primarily “unhealthy” plant-based diet was one including mainly refined grains (e.g., white bread and pasta), fruit juices, potatoes, sugar-sweetened beverages, and sweets/desserts.
“Individual metabolites from consumption of polyphenol-rich plant foods like fruits, vegetables, coffee, and legumes are all closely linked to healthy plant-based diet and lower risk of diabetes,” lead author Frank Hu, MD, said in a press release.
Dr. Hu, of the department of nutrition at Harvard T.H. Chan School of Public Health, Boston, and colleagues reported their findings in Diabetologia.
High-throughput profiling of the metabolome
Given that an individual’s metabolic profile reflects their diet, there is a growing trend in nutritional research to use a technique called high-throughput metabolomics to profile biological samples.
The team conducted an analysis of blood plasma samples and dietary intake using food frequency questionnaires of 10,684 participants from three prospective cohorts (Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-Up Study). Participants were predominantly White and middle-aged (mean age 54 years), with a mean body mass index of 25.6 kg/m2.
Metabolite profile scores were generated from the blood samples, taken in the 1980s and 1990s, and matched to any cases of incident type 2 diabetes reported during follow-up, which ended in 2016-2017.
The team looked at three different plant-based diets – by definition, higher in plant foods and lower in animal foods – and further categorized them according to the actual foods consumed, to generate an overall plant diet index (PDI), a healthy PDI, or an unhealthy PDI.
In all, 8,827 participants completed the study, and 270 cases of diabetes were reported.
Multi-metabolite profiles were composed of 55 metabolites for the overall PDI, 93 metabolites for healthy PDI, and 75 metabolites for unhealthy PDI.
The findings are that metabolomics can be harnessed and “the identified metabolic profiles could be used to assess adherence to ... plant-based diets as part of type 2 diabetes prevention ... and provide new insights for future investigation,” the researchers concluded.
One coauthor received research support from the California Walnut Commission and Swiss ReManagement; another reported being a scientific consultant to LayerIV. The other authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A scientific analysis of metabolites from plant-based-diets – especially those rich in whole grains, fruits, and vegetables – may in the future yield clues as to how such eating patterns lower the risk of type 2 diabetes, finds a new study of more than 8,000 people.
The research looked at healthy, unhealthy, and overall plant-based diets, but only metabolic profiles for the healthy and overall plant-based diets showed an inverse relationship with type 2 diabetes.
A primarily “unhealthy” plant-based diet was one including mainly refined grains (e.g., white bread and pasta), fruit juices, potatoes, sugar-sweetened beverages, and sweets/desserts.
“Individual metabolites from consumption of polyphenol-rich plant foods like fruits, vegetables, coffee, and legumes are all closely linked to healthy plant-based diet and lower risk of diabetes,” lead author Frank Hu, MD, said in a press release.
Dr. Hu, of the department of nutrition at Harvard T.H. Chan School of Public Health, Boston, and colleagues reported their findings in Diabetologia.
High-throughput profiling of the metabolome
Given that an individual’s metabolic profile reflects their diet, there is a growing trend in nutritional research to use a technique called high-throughput metabolomics to profile biological samples.
The team conducted an analysis of blood plasma samples and dietary intake using food frequency questionnaires of 10,684 participants from three prospective cohorts (Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-Up Study). Participants were predominantly White and middle-aged (mean age 54 years), with a mean body mass index of 25.6 kg/m2.
Metabolite profile scores were generated from the blood samples, taken in the 1980s and 1990s, and matched to any cases of incident type 2 diabetes reported during follow-up, which ended in 2016-2017.
The team looked at three different plant-based diets – by definition, higher in plant foods and lower in animal foods – and further categorized them according to the actual foods consumed, to generate an overall plant diet index (PDI), a healthy PDI, or an unhealthy PDI.
In all, 8,827 participants completed the study, and 270 cases of diabetes were reported.
Multi-metabolite profiles were composed of 55 metabolites for the overall PDI, 93 metabolites for healthy PDI, and 75 metabolites for unhealthy PDI.
The findings are that metabolomics can be harnessed and “the identified metabolic profiles could be used to assess adherence to ... plant-based diets as part of type 2 diabetes prevention ... and provide new insights for future investigation,” the researchers concluded.
One coauthor received research support from the California Walnut Commission and Swiss ReManagement; another reported being a scientific consultant to LayerIV. The other authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM DIABETOLOGIA
The best statins to lower non-HDL cholesterol in diabetes?
A network meta-analysis of 42 clinical trials concludes that rosuvastatin, simvastatin, and atorvastatin are the statins most effective at lowering non-high-density-lipoprotein cholesterol (non-HDL-C) in people with diabetes and at risk for cardiovascular disease.
The analysis focused on the efficacy of statin treatment on reducing non-HDL-C, as opposed to reducing low-density-lipoprotein cholesterol (LDL-C), which has traditionally been used as a surrogate to determine cardiovascular disease risk from hypercholesterolemia.
“The National Cholesterol Education Program in the United States recommends that LDL-C values should be used to estimate the risk of cardiovascular disease related to lipoproteins,” lead author Alexander Hodkinson, MD, senior National Institute for Health Research fellow, University of Manchester, England, told this news organization.
“But we believe that non-high-density-lipoprotein cholesterol is more strongly associated with the risk of cardiovascular disease, because non-HDL-C combines all the bad types of cholesterol, which LDL-C misses, so it could be a better tool than LDL-C for assessing CVD risk and effects of treatment. We already knew which of the statins reduce LDL-C, but we wanted to know which ones reduced non-HDL-C; hence the reason for our study,” Dr. Hodkinson said.
The findings were published online in BMJ.
In April 2021, the National Institute for Health and Care Excellence (NICE) in the United Kingdom updated guidelines for adults with diabetes to recommend that non-HDL-C should replace LDL-C as the primary target for reducing the risk for cardiovascular disease with lipid-lowering treatment.
Currently, NICE is alone in its recommendation. Other international guidelines do not have a non-HDL-C target and use LDL-C reduction instead. These include guidelines from the European Society of Cardiology (ESC), the American College of Cardiology (ACC), the American Heart Association (AHA), and the National Lipid Association.
Non–HDL-C is simple to calculate and can easily be done by clinicians by subtracting HDL-C from the total cholesterol level, he added.
This analysis compared the effectiveness of different statins at different intensities in reducing levels of non-HDL-C in 42 randomized controlled trials that included 20,193 adults with diabetes.
Compared with placebo, rosuvastatin, given at moderate- and high-intensity doses, and simvastatin and atorvastatin at high-intensity doses, were the best at lowering levels of non-HDL-C over an average treatment period of 12 weeks.
High-intensity rosuvastatin led to a 2.31 mmol/L reduction in non-HDL-C (95% credible interval, –3.39 to –1.21). Moderate-intensity rosuvastatin led to a 2.27 mmol/L reduction in non-HDL-C (95% credible interval, –3.00 to –1.49).
High-intensity simvastatin led to a 2.26 mmol/L reduction in non-HDL-C (95% credible interval, –2.99 to –1.51).
High-intensity atorvastatin led to a 2.20 mmol/L reduction in non-HDL-C (95% credible interval, –2.69 to –1.70).
Atorvastatin and simvastatin at any intensity and pravastatin at low intensity were also effective in reducing levels of non-HDL-C, the researchers noted.
In 4,670 patients who were at great risk for a major cardiovascular event, atorvastatin at high intensity showed the largest reduction in levels of non-HDL-C (1.98 mmol/L; 95% credible interval, –4.16 to 0.26).
In addition, high-intensity simvastatin and rosuvastatin were the most effective in reducing LDL-C.
High-intensity simvastatin led to a 1.93 mmol/L reduction in LDL-C (95% credible interval, –2.63 to –1.21), and high-intensity rosuvastatin led to a 1.76 mmol/L reduction in LDL-C (95% credible interval, –2.37 to –1.15).
In four studies, significant reductions in nonfatal myocardial infarction were shown for atorvastatin at moderate intensity, compared with placebo (relative risk, 0.57; 95% confidence interval, 0.43-.76). No significant differences were seen for discontinuations, nonfatal stroke, or cardiovascular death.
“We hope our findings will help guide clinicians on statin selection itself, and what types of doses they should be giving patients. These results support using NICE’s new policy guidelines on cholesterol monitoring, using this non-HDL-C measure, which contains all the bad types of cholesterol for patients with diabetes,” Dr. Hodkinson said.
“This study further emphasizes what we have known about the benefit of statin therapy in patients with type 2 diabetes,” Prakash Deedwania, MD, professor of medicine, University of California, San Francisco, told this news organization.
Dr. Deedwania and others have published data on patients with diabetes that showed that treatment with high-intensity atorvastatin was associated with significant reductions in major adverse cardiovascular events.
“Here they use non-HDL cholesterol as a target. The NICE guidelines are the only guidelines looking at non-HDL cholesterol; however, all guidelines suggest an LDL to be less than 70 in all people with diabetes, and for those with recent acute coronary syndromes, the latest evidence suggests the LDL should actually be less than 50,” said Dr. Deedwania, spokesperson for the AHA and ACC.
As far as which measure to use, he believes both are useful. “It’s six of one and half a dozen of the other, in my opinion. The societies have not recommended non-HDL cholesterol and it’s easier to stay with what is readily available for clinicians, and using LDL cholesterol is still okay. The results of this analysis are confirmatory, in that looking at non-HDL cholesterol gives results very similar to what these statins have shown for their effect on LDL cholesterol,” he said.
Non-HDL cholesterol a better marker?
For Robert Rosenson, MD, director of metabolism and lipids at Mount Sinai Health System and professor of medicine and cardiology at the Icahn School of Medicine at Mount Sinai, New York, non-HDL cholesterol is becoming an important marker of risk for several reasons.
“The focus on LDL cholesterol has been due to the causal relationship of LDL with atherosclerotic cardiovascular disease, but in the last few decades, non-HDL has emerged because more people are overweight, have insulin resistance, and have diabetes,” Dr. Rosenson told this news organization. “In those situations, the LDL cholesterol underrepresents the risk of the LDL particles. With insulin resistance, the particles become more triglycerides and less cholesterol, so on a per-particle basis, you need to get more LDL particles to get to a certain LDL cholesterol concentration.”
Non-HDL cholesterol testing does not require fasting, another advantage of using it to monitor cholesterol, he added.
What is often forgotten is that moderate- to high-intensity statins have very good triglyceride-lowering effects, Dr. Rosenson said.
“This article highlights that, by using higher doses, you get more triglyceride-lowering. Hopefully, this will get practitioners to recognize that non-HDL cholesterol is a better predictor of risk in people with diabetes,” he said.
The study was funded by the National Institute for Health Research. Dr. Hodkinson, Dr. Rosenson, and Dr. Deedwania report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A network meta-analysis of 42 clinical trials concludes that rosuvastatin, simvastatin, and atorvastatin are the statins most effective at lowering non-high-density-lipoprotein cholesterol (non-HDL-C) in people with diabetes and at risk for cardiovascular disease.
The analysis focused on the efficacy of statin treatment on reducing non-HDL-C, as opposed to reducing low-density-lipoprotein cholesterol (LDL-C), which has traditionally been used as a surrogate to determine cardiovascular disease risk from hypercholesterolemia.
“The National Cholesterol Education Program in the United States recommends that LDL-C values should be used to estimate the risk of cardiovascular disease related to lipoproteins,” lead author Alexander Hodkinson, MD, senior National Institute for Health Research fellow, University of Manchester, England, told this news organization.
“But we believe that non-high-density-lipoprotein cholesterol is more strongly associated with the risk of cardiovascular disease, because non-HDL-C combines all the bad types of cholesterol, which LDL-C misses, so it could be a better tool than LDL-C for assessing CVD risk and effects of treatment. We already knew which of the statins reduce LDL-C, but we wanted to know which ones reduced non-HDL-C; hence the reason for our study,” Dr. Hodkinson said.
The findings were published online in BMJ.
In April 2021, the National Institute for Health and Care Excellence (NICE) in the United Kingdom updated guidelines for adults with diabetes to recommend that non-HDL-C should replace LDL-C as the primary target for reducing the risk for cardiovascular disease with lipid-lowering treatment.
Currently, NICE is alone in its recommendation. Other international guidelines do not have a non-HDL-C target and use LDL-C reduction instead. These include guidelines from the European Society of Cardiology (ESC), the American College of Cardiology (ACC), the American Heart Association (AHA), and the National Lipid Association.
Non–HDL-C is simple to calculate and can easily be done by clinicians by subtracting HDL-C from the total cholesterol level, he added.
This analysis compared the effectiveness of different statins at different intensities in reducing levels of non-HDL-C in 42 randomized controlled trials that included 20,193 adults with diabetes.
Compared with placebo, rosuvastatin, given at moderate- and high-intensity doses, and simvastatin and atorvastatin at high-intensity doses, were the best at lowering levels of non-HDL-C over an average treatment period of 12 weeks.
High-intensity rosuvastatin led to a 2.31 mmol/L reduction in non-HDL-C (95% credible interval, –3.39 to –1.21). Moderate-intensity rosuvastatin led to a 2.27 mmol/L reduction in non-HDL-C (95% credible interval, –3.00 to –1.49).
High-intensity simvastatin led to a 2.26 mmol/L reduction in non-HDL-C (95% credible interval, –2.99 to –1.51).
High-intensity atorvastatin led to a 2.20 mmol/L reduction in non-HDL-C (95% credible interval, –2.69 to –1.70).
Atorvastatin and simvastatin at any intensity and pravastatin at low intensity were also effective in reducing levels of non-HDL-C, the researchers noted.
In 4,670 patients who were at great risk for a major cardiovascular event, atorvastatin at high intensity showed the largest reduction in levels of non-HDL-C (1.98 mmol/L; 95% credible interval, –4.16 to 0.26).
In addition, high-intensity simvastatin and rosuvastatin were the most effective in reducing LDL-C.
High-intensity simvastatin led to a 1.93 mmol/L reduction in LDL-C (95% credible interval, –2.63 to –1.21), and high-intensity rosuvastatin led to a 1.76 mmol/L reduction in LDL-C (95% credible interval, –2.37 to –1.15).
In four studies, significant reductions in nonfatal myocardial infarction were shown for atorvastatin at moderate intensity, compared with placebo (relative risk, 0.57; 95% confidence interval, 0.43-.76). No significant differences were seen for discontinuations, nonfatal stroke, or cardiovascular death.
“We hope our findings will help guide clinicians on statin selection itself, and what types of doses they should be giving patients. These results support using NICE’s new policy guidelines on cholesterol monitoring, using this non-HDL-C measure, which contains all the bad types of cholesterol for patients with diabetes,” Dr. Hodkinson said.
“This study further emphasizes what we have known about the benefit of statin therapy in patients with type 2 diabetes,” Prakash Deedwania, MD, professor of medicine, University of California, San Francisco, told this news organization.
Dr. Deedwania and others have published data on patients with diabetes that showed that treatment with high-intensity atorvastatin was associated with significant reductions in major adverse cardiovascular events.
“Here they use non-HDL cholesterol as a target. The NICE guidelines are the only guidelines looking at non-HDL cholesterol; however, all guidelines suggest an LDL to be less than 70 in all people with diabetes, and for those with recent acute coronary syndromes, the latest evidence suggests the LDL should actually be less than 50,” said Dr. Deedwania, spokesperson for the AHA and ACC.
As far as which measure to use, he believes both are useful. “It’s six of one and half a dozen of the other, in my opinion. The societies have not recommended non-HDL cholesterol and it’s easier to stay with what is readily available for clinicians, and using LDL cholesterol is still okay. The results of this analysis are confirmatory, in that looking at non-HDL cholesterol gives results very similar to what these statins have shown for their effect on LDL cholesterol,” he said.
Non-HDL cholesterol a better marker?
For Robert Rosenson, MD, director of metabolism and lipids at Mount Sinai Health System and professor of medicine and cardiology at the Icahn School of Medicine at Mount Sinai, New York, non-HDL cholesterol is becoming an important marker of risk for several reasons.
“The focus on LDL cholesterol has been due to the causal relationship of LDL with atherosclerotic cardiovascular disease, but in the last few decades, non-HDL has emerged because more people are overweight, have insulin resistance, and have diabetes,” Dr. Rosenson told this news organization. “In those situations, the LDL cholesterol underrepresents the risk of the LDL particles. With insulin resistance, the particles become more triglycerides and less cholesterol, so on a per-particle basis, you need to get more LDL particles to get to a certain LDL cholesterol concentration.”
Non-HDL cholesterol testing does not require fasting, another advantage of using it to monitor cholesterol, he added.
What is often forgotten is that moderate- to high-intensity statins have very good triglyceride-lowering effects, Dr. Rosenson said.
“This article highlights that, by using higher doses, you get more triglyceride-lowering. Hopefully, this will get practitioners to recognize that non-HDL cholesterol is a better predictor of risk in people with diabetes,” he said.
The study was funded by the National Institute for Health Research. Dr. Hodkinson, Dr. Rosenson, and Dr. Deedwania report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A network meta-analysis of 42 clinical trials concludes that rosuvastatin, simvastatin, and atorvastatin are the statins most effective at lowering non-high-density-lipoprotein cholesterol (non-HDL-C) in people with diabetes and at risk for cardiovascular disease.
The analysis focused on the efficacy of statin treatment on reducing non-HDL-C, as opposed to reducing low-density-lipoprotein cholesterol (LDL-C), which has traditionally been used as a surrogate to determine cardiovascular disease risk from hypercholesterolemia.
“The National Cholesterol Education Program in the United States recommends that LDL-C values should be used to estimate the risk of cardiovascular disease related to lipoproteins,” lead author Alexander Hodkinson, MD, senior National Institute for Health Research fellow, University of Manchester, England, told this news organization.
“But we believe that non-high-density-lipoprotein cholesterol is more strongly associated with the risk of cardiovascular disease, because non-HDL-C combines all the bad types of cholesterol, which LDL-C misses, so it could be a better tool than LDL-C for assessing CVD risk and effects of treatment. We already knew which of the statins reduce LDL-C, but we wanted to know which ones reduced non-HDL-C; hence the reason for our study,” Dr. Hodkinson said.
The findings were published online in BMJ.
In April 2021, the National Institute for Health and Care Excellence (NICE) in the United Kingdom updated guidelines for adults with diabetes to recommend that non-HDL-C should replace LDL-C as the primary target for reducing the risk for cardiovascular disease with lipid-lowering treatment.
Currently, NICE is alone in its recommendation. Other international guidelines do not have a non-HDL-C target and use LDL-C reduction instead. These include guidelines from the European Society of Cardiology (ESC), the American College of Cardiology (ACC), the American Heart Association (AHA), and the National Lipid Association.
Non–HDL-C is simple to calculate and can easily be done by clinicians by subtracting HDL-C from the total cholesterol level, he added.
This analysis compared the effectiveness of different statins at different intensities in reducing levels of non-HDL-C in 42 randomized controlled trials that included 20,193 adults with diabetes.
Compared with placebo, rosuvastatin, given at moderate- and high-intensity doses, and simvastatin and atorvastatin at high-intensity doses, were the best at lowering levels of non-HDL-C over an average treatment period of 12 weeks.
High-intensity rosuvastatin led to a 2.31 mmol/L reduction in non-HDL-C (95% credible interval, –3.39 to –1.21). Moderate-intensity rosuvastatin led to a 2.27 mmol/L reduction in non-HDL-C (95% credible interval, –3.00 to –1.49).
High-intensity simvastatin led to a 2.26 mmol/L reduction in non-HDL-C (95% credible interval, –2.99 to –1.51).
High-intensity atorvastatin led to a 2.20 mmol/L reduction in non-HDL-C (95% credible interval, –2.69 to –1.70).
Atorvastatin and simvastatin at any intensity and pravastatin at low intensity were also effective in reducing levels of non-HDL-C, the researchers noted.
In 4,670 patients who were at great risk for a major cardiovascular event, atorvastatin at high intensity showed the largest reduction in levels of non-HDL-C (1.98 mmol/L; 95% credible interval, –4.16 to 0.26).
In addition, high-intensity simvastatin and rosuvastatin were the most effective in reducing LDL-C.
High-intensity simvastatin led to a 1.93 mmol/L reduction in LDL-C (95% credible interval, –2.63 to –1.21), and high-intensity rosuvastatin led to a 1.76 mmol/L reduction in LDL-C (95% credible interval, –2.37 to –1.15).
In four studies, significant reductions in nonfatal myocardial infarction were shown for atorvastatin at moderate intensity, compared with placebo (relative risk, 0.57; 95% confidence interval, 0.43-.76). No significant differences were seen for discontinuations, nonfatal stroke, or cardiovascular death.
“We hope our findings will help guide clinicians on statin selection itself, and what types of doses they should be giving patients. These results support using NICE’s new policy guidelines on cholesterol monitoring, using this non-HDL-C measure, which contains all the bad types of cholesterol for patients with diabetes,” Dr. Hodkinson said.
“This study further emphasizes what we have known about the benefit of statin therapy in patients with type 2 diabetes,” Prakash Deedwania, MD, professor of medicine, University of California, San Francisco, told this news organization.
Dr. Deedwania and others have published data on patients with diabetes that showed that treatment with high-intensity atorvastatin was associated with significant reductions in major adverse cardiovascular events.
“Here they use non-HDL cholesterol as a target. The NICE guidelines are the only guidelines looking at non-HDL cholesterol; however, all guidelines suggest an LDL to be less than 70 in all people with diabetes, and for those with recent acute coronary syndromes, the latest evidence suggests the LDL should actually be less than 50,” said Dr. Deedwania, spokesperson for the AHA and ACC.
As far as which measure to use, he believes both are useful. “It’s six of one and half a dozen of the other, in my opinion. The societies have not recommended non-HDL cholesterol and it’s easier to stay with what is readily available for clinicians, and using LDL cholesterol is still okay. The results of this analysis are confirmatory, in that looking at non-HDL cholesterol gives results very similar to what these statins have shown for their effect on LDL cholesterol,” he said.
Non-HDL cholesterol a better marker?
For Robert Rosenson, MD, director of metabolism and lipids at Mount Sinai Health System and professor of medicine and cardiology at the Icahn School of Medicine at Mount Sinai, New York, non-HDL cholesterol is becoming an important marker of risk for several reasons.
“The focus on LDL cholesterol has been due to the causal relationship of LDL with atherosclerotic cardiovascular disease, but in the last few decades, non-HDL has emerged because more people are overweight, have insulin resistance, and have diabetes,” Dr. Rosenson told this news organization. “In those situations, the LDL cholesterol underrepresents the risk of the LDL particles. With insulin resistance, the particles become more triglycerides and less cholesterol, so on a per-particle basis, you need to get more LDL particles to get to a certain LDL cholesterol concentration.”
Non-HDL cholesterol testing does not require fasting, another advantage of using it to monitor cholesterol, he added.
What is often forgotten is that moderate- to high-intensity statins have very good triglyceride-lowering effects, Dr. Rosenson said.
“This article highlights that, by using higher doses, you get more triglyceride-lowering. Hopefully, this will get practitioners to recognize that non-HDL cholesterol is a better predictor of risk in people with diabetes,” he said.
The study was funded by the National Institute for Health Research. Dr. Hodkinson, Dr. Rosenson, and Dr. Deedwania report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FFR not better, just different from IVUS for revascularizing intermediate stenoses
In a head-to-head comparison of fractional flow reserve (FFR) and intravenous ultrasound (IVUS) for guiding revascularization during percutaneous intervention (PCI), outcomes were noninferior at 2 years, but the approaches appear to have different strengths, according to results of the FLAVOUR trial.
For the primary composite outcome of death from any cause, myocardial infarction, or revascularization at 24 months, the approaches performed comparatively, but there were substantial differences in the number of revascularization procedures performed, reported Bon-Kwon Koo, MD, at the annual scientific sessions of the American College of Cardiology.
At 24 months, 8.1% of the FFR group and 8.5% of the IVUS group had a primary event. The 0.4% difference was not significantly different and fulfilled the definition of noninferiority (P = .015). When the components of the primary endpoint were compared along with rates of stroke, the rates were also similar and not significantly different.
However, the proportion of patients who received a stent (44.4% vs. 65.3%), the total number of stents per patient (0.6 vs. 0.9), and the total stent length per patient (16.5 vs. 25.2) were significantly lower (all P < .001) in the FFR group.
FLAVOUR (Fractional Flow Reserve And IVUS for Clinical Outcomes in Patients With Intermediate Stenosis) confirmed the investigators’ hypothesis that an FFR-guided strategy for intermediate coronary stenosis is noninferior to IVUS for outcomes. In addition, patient-reported angina outcomes on the Seattle Angina Questionnaire were nearly identical across domains, including angina frequency, physical limitations, and treatment satisfaction.
FFR vs. IVUS differences revealed
However, the more important value of this study might its role in showing how the two approaches differ in ways unrelated to the primary outcome, according to Dr. Koo, chair of cardiology at Seoul (South Korea) National University Hospital, as well as several experts that commented on the results.
Most notably, the fact that FFR-guided PCI provides similar outcomes at 2 years even though it was associated with a substantially reduced rate of revascularizations is telling about its role relative to IVUS.
“These data confirm how a lot of us are already approaching this,” said an ACC-invited expert, Frederick G. Welt, MD, director of the cardiac catheterization at the University of Utah, Salt Lake City. “FFR should be used to decide who should get an intervention, and IVUS should be use to optimize the intervention.”
Dr. Koo explained that FFR is an invasive tool that provides a physiological assessment of the degree to which a stenosis is causing ischemia. IVUS is a tool that permits visualization and measurement of plaque severity and characteristics to better optimize PCI. They can both help guide PCI, but they are not necessarily competing strategies. Often, the information they provide is complementary.
In this multicenter trial conducted at 18 centers in Korea and China, 1,682 candidates with de novo stenoses of intermediate severity, defined as 40%-70%, were randomized to FFR- or IVUS-guided PCI. At 24 months, outcomes could be assessed in 832 of the FFR patients and 836 of the IVUS patients, which represented more than 99% of both groups.
In the study, the indications for stent placement were predefined for the FFR-guided and IVUS-guided approaches. The criteria to define optimal outcomes post PCI were also predefined. For FFR, this included a postprocedure value of at least 0.88. For IVUS, the definition of optimal outcome included a plaque burden of 55% or less at the stent edge and a minimal stent area of at least 5.5 mm2.
The primary outcome for those with optimal versus suboptimal FFR-guided PCI were similar at all time points. For those with an optimal post-PCI result, the event rate was only slightly higher for those with an optimal relative to a suboptimal result (12.3% vs. 11.8%).
Suboptimal IVUS differs from suboptimal FFR
In contrast, the event rates over the course of follow-up were consistently higher among those with a suboptimal relative to an optimal IVUS-guided PCI. At the end of 2 years, the numerically greater rate of events among those with a suboptimal IVUS-guided PCI was not significant (9.8% vs. 8.5%; P = .212), but the gap was larger than that seen with FFR-guided PCI.
FFR-guided and IVUS-guided PCI performed similarly for the primary outcome across numerous stratifications. These included age older or younger than 65 years, male or female sex, presence or absence of multivessel disease, and presence of diabetes. They were also similar for those with acute coronary syndrome (ACS) as an indication for PCI, which accounted for about 30% of patients, relative to those without ACS.
“I would say that at least some interventionalists in the U.S. would be uncomfortable using FFR in ACS patients,” said Dr. Welt, pointing out a potential difference between how these tools are used to guide PCI. Still, because “there are not a lot of data to compare these technologies,” he expressed appreciation for a study looking at these tools side-by-side.
A similar point was made by Ajay Kirtane, MD, director of Cardiac Catheterization Laboratories at New York–Presbyterian/Columbia University Irving Medical Center. With the slightly lower rates of primary events in those treated optimally according to IVUS relative to those treated optimally by FFR (8.5% vs. 12.3%), he suggested IVUS appears better for evaluating the physiology of the stenosis.
Dr. Kirtane pointed out that two-thirds of the lesions were left behind in those guided by FFR versus only about half of the lesions when PCI was guided by IVUS, yet outcomes were similar. He indicated that the data support current practice in which FFR is most commonly used to select PCI patients with intermediate disease for stent placement.
Dr. Koo has financial relationships with Abbott, Boston Scientific, and Philips Volcano. Dr. Welt has financial relationships with Medtronic and Xenter. Dr. Kirtane has financial relationships with Abbott, Amgen, Boston Scientific, Chiesi, Cardiovascular Systems Incorporate, Medtronic, Philips/Spectranetics, Recor Medical, and Regeneron. The study received a research grant from Boston Scientific.
In a head-to-head comparison of fractional flow reserve (FFR) and intravenous ultrasound (IVUS) for guiding revascularization during percutaneous intervention (PCI), outcomes were noninferior at 2 years, but the approaches appear to have different strengths, according to results of the FLAVOUR trial.
For the primary composite outcome of death from any cause, myocardial infarction, or revascularization at 24 months, the approaches performed comparatively, but there were substantial differences in the number of revascularization procedures performed, reported Bon-Kwon Koo, MD, at the annual scientific sessions of the American College of Cardiology.
At 24 months, 8.1% of the FFR group and 8.5% of the IVUS group had a primary event. The 0.4% difference was not significantly different and fulfilled the definition of noninferiority (P = .015). When the components of the primary endpoint were compared along with rates of stroke, the rates were also similar and not significantly different.
However, the proportion of patients who received a stent (44.4% vs. 65.3%), the total number of stents per patient (0.6 vs. 0.9), and the total stent length per patient (16.5 vs. 25.2) were significantly lower (all P < .001) in the FFR group.
FLAVOUR (Fractional Flow Reserve And IVUS for Clinical Outcomes in Patients With Intermediate Stenosis) confirmed the investigators’ hypothesis that an FFR-guided strategy for intermediate coronary stenosis is noninferior to IVUS for outcomes. In addition, patient-reported angina outcomes on the Seattle Angina Questionnaire were nearly identical across domains, including angina frequency, physical limitations, and treatment satisfaction.
FFR vs. IVUS differences revealed
However, the more important value of this study might its role in showing how the two approaches differ in ways unrelated to the primary outcome, according to Dr. Koo, chair of cardiology at Seoul (South Korea) National University Hospital, as well as several experts that commented on the results.
Most notably, the fact that FFR-guided PCI provides similar outcomes at 2 years even though it was associated with a substantially reduced rate of revascularizations is telling about its role relative to IVUS.
“These data confirm how a lot of us are already approaching this,” said an ACC-invited expert, Frederick G. Welt, MD, director of the cardiac catheterization at the University of Utah, Salt Lake City. “FFR should be used to decide who should get an intervention, and IVUS should be use to optimize the intervention.”
Dr. Koo explained that FFR is an invasive tool that provides a physiological assessment of the degree to which a stenosis is causing ischemia. IVUS is a tool that permits visualization and measurement of plaque severity and characteristics to better optimize PCI. They can both help guide PCI, but they are not necessarily competing strategies. Often, the information they provide is complementary.
In this multicenter trial conducted at 18 centers in Korea and China, 1,682 candidates with de novo stenoses of intermediate severity, defined as 40%-70%, were randomized to FFR- or IVUS-guided PCI. At 24 months, outcomes could be assessed in 832 of the FFR patients and 836 of the IVUS patients, which represented more than 99% of both groups.
In the study, the indications for stent placement were predefined for the FFR-guided and IVUS-guided approaches. The criteria to define optimal outcomes post PCI were also predefined. For FFR, this included a postprocedure value of at least 0.88. For IVUS, the definition of optimal outcome included a plaque burden of 55% or less at the stent edge and a minimal stent area of at least 5.5 mm2.
The primary outcome for those with optimal versus suboptimal FFR-guided PCI were similar at all time points. For those with an optimal post-PCI result, the event rate was only slightly higher for those with an optimal relative to a suboptimal result (12.3% vs. 11.8%).
Suboptimal IVUS differs from suboptimal FFR
In contrast, the event rates over the course of follow-up were consistently higher among those with a suboptimal relative to an optimal IVUS-guided PCI. At the end of 2 years, the numerically greater rate of events among those with a suboptimal IVUS-guided PCI was not significant (9.8% vs. 8.5%; P = .212), but the gap was larger than that seen with FFR-guided PCI.
FFR-guided and IVUS-guided PCI performed similarly for the primary outcome across numerous stratifications. These included age older or younger than 65 years, male or female sex, presence or absence of multivessel disease, and presence of diabetes. They were also similar for those with acute coronary syndrome (ACS) as an indication for PCI, which accounted for about 30% of patients, relative to those without ACS.
“I would say that at least some interventionalists in the U.S. would be uncomfortable using FFR in ACS patients,” said Dr. Welt, pointing out a potential difference between how these tools are used to guide PCI. Still, because “there are not a lot of data to compare these technologies,” he expressed appreciation for a study looking at these tools side-by-side.
A similar point was made by Ajay Kirtane, MD, director of Cardiac Catheterization Laboratories at New York–Presbyterian/Columbia University Irving Medical Center. With the slightly lower rates of primary events in those treated optimally according to IVUS relative to those treated optimally by FFR (8.5% vs. 12.3%), he suggested IVUS appears better for evaluating the physiology of the stenosis.
Dr. Kirtane pointed out that two-thirds of the lesions were left behind in those guided by FFR versus only about half of the lesions when PCI was guided by IVUS, yet outcomes were similar. He indicated that the data support current practice in which FFR is most commonly used to select PCI patients with intermediate disease for stent placement.
Dr. Koo has financial relationships with Abbott, Boston Scientific, and Philips Volcano. Dr. Welt has financial relationships with Medtronic and Xenter. Dr. Kirtane has financial relationships with Abbott, Amgen, Boston Scientific, Chiesi, Cardiovascular Systems Incorporate, Medtronic, Philips/Spectranetics, Recor Medical, and Regeneron. The study received a research grant from Boston Scientific.
In a head-to-head comparison of fractional flow reserve (FFR) and intravenous ultrasound (IVUS) for guiding revascularization during percutaneous intervention (PCI), outcomes were noninferior at 2 years, but the approaches appear to have different strengths, according to results of the FLAVOUR trial.
For the primary composite outcome of death from any cause, myocardial infarction, or revascularization at 24 months, the approaches performed comparatively, but there were substantial differences in the number of revascularization procedures performed, reported Bon-Kwon Koo, MD, at the annual scientific sessions of the American College of Cardiology.
At 24 months, 8.1% of the FFR group and 8.5% of the IVUS group had a primary event. The 0.4% difference was not significantly different and fulfilled the definition of noninferiority (P = .015). When the components of the primary endpoint were compared along with rates of stroke, the rates were also similar and not significantly different.
However, the proportion of patients who received a stent (44.4% vs. 65.3%), the total number of stents per patient (0.6 vs. 0.9), and the total stent length per patient (16.5 vs. 25.2) were significantly lower (all P < .001) in the FFR group.
FLAVOUR (Fractional Flow Reserve And IVUS for Clinical Outcomes in Patients With Intermediate Stenosis) confirmed the investigators’ hypothesis that an FFR-guided strategy for intermediate coronary stenosis is noninferior to IVUS for outcomes. In addition, patient-reported angina outcomes on the Seattle Angina Questionnaire were nearly identical across domains, including angina frequency, physical limitations, and treatment satisfaction.
FFR vs. IVUS differences revealed
However, the more important value of this study might its role in showing how the two approaches differ in ways unrelated to the primary outcome, according to Dr. Koo, chair of cardiology at Seoul (South Korea) National University Hospital, as well as several experts that commented on the results.
Most notably, the fact that FFR-guided PCI provides similar outcomes at 2 years even though it was associated with a substantially reduced rate of revascularizations is telling about its role relative to IVUS.
“These data confirm how a lot of us are already approaching this,” said an ACC-invited expert, Frederick G. Welt, MD, director of the cardiac catheterization at the University of Utah, Salt Lake City. “FFR should be used to decide who should get an intervention, and IVUS should be use to optimize the intervention.”
Dr. Koo explained that FFR is an invasive tool that provides a physiological assessment of the degree to which a stenosis is causing ischemia. IVUS is a tool that permits visualization and measurement of plaque severity and characteristics to better optimize PCI. They can both help guide PCI, but they are not necessarily competing strategies. Often, the information they provide is complementary.
In this multicenter trial conducted at 18 centers in Korea and China, 1,682 candidates with de novo stenoses of intermediate severity, defined as 40%-70%, were randomized to FFR- or IVUS-guided PCI. At 24 months, outcomes could be assessed in 832 of the FFR patients and 836 of the IVUS patients, which represented more than 99% of both groups.
In the study, the indications for stent placement were predefined for the FFR-guided and IVUS-guided approaches. The criteria to define optimal outcomes post PCI were also predefined. For FFR, this included a postprocedure value of at least 0.88. For IVUS, the definition of optimal outcome included a plaque burden of 55% or less at the stent edge and a minimal stent area of at least 5.5 mm2.
The primary outcome for those with optimal versus suboptimal FFR-guided PCI were similar at all time points. For those with an optimal post-PCI result, the event rate was only slightly higher for those with an optimal relative to a suboptimal result (12.3% vs. 11.8%).
Suboptimal IVUS differs from suboptimal FFR
In contrast, the event rates over the course of follow-up were consistently higher among those with a suboptimal relative to an optimal IVUS-guided PCI. At the end of 2 years, the numerically greater rate of events among those with a suboptimal IVUS-guided PCI was not significant (9.8% vs. 8.5%; P = .212), but the gap was larger than that seen with FFR-guided PCI.
FFR-guided and IVUS-guided PCI performed similarly for the primary outcome across numerous stratifications. These included age older or younger than 65 years, male or female sex, presence or absence of multivessel disease, and presence of diabetes. They were also similar for those with acute coronary syndrome (ACS) as an indication for PCI, which accounted for about 30% of patients, relative to those without ACS.
“I would say that at least some interventionalists in the U.S. would be uncomfortable using FFR in ACS patients,” said Dr. Welt, pointing out a potential difference between how these tools are used to guide PCI. Still, because “there are not a lot of data to compare these technologies,” he expressed appreciation for a study looking at these tools side-by-side.
A similar point was made by Ajay Kirtane, MD, director of Cardiac Catheterization Laboratories at New York–Presbyterian/Columbia University Irving Medical Center. With the slightly lower rates of primary events in those treated optimally according to IVUS relative to those treated optimally by FFR (8.5% vs. 12.3%), he suggested IVUS appears better for evaluating the physiology of the stenosis.
Dr. Kirtane pointed out that two-thirds of the lesions were left behind in those guided by FFR versus only about half of the lesions when PCI was guided by IVUS, yet outcomes were similar. He indicated that the data support current practice in which FFR is most commonly used to select PCI patients with intermediate disease for stent placement.
Dr. Koo has financial relationships with Abbott, Boston Scientific, and Philips Volcano. Dr. Welt has financial relationships with Medtronic and Xenter. Dr. Kirtane has financial relationships with Abbott, Amgen, Boston Scientific, Chiesi, Cardiovascular Systems Incorporate, Medtronic, Philips/Spectranetics, Recor Medical, and Regeneron. The study received a research grant from Boston Scientific.
FROM ACC 2022
AHA statement addresses CVD risk in NAFLD
At least one in four adults worldwide is thought to have nonalcoholic fatty liver disease, a major risk factor for cardiovascular disease (CVD), which is the leading cause of death in NAFLD, but the condition is widely underdiagnosed, according to a new American Heart Association scientific statement on NAFLD and cardiovascular risks.
The statement, published in Arteriosclerosis, Thrombosis, and Vascular Biology, aims to increase awareness of NAFLD among cardiologists and other clinicians treating vulnerable patients. It pulls together the existing evidence for using imaging to diagnose NAFLD as well as the role of current and emerging treatments for managing the disease.
“NAFLD is common, but most patients are undiagnosed,” statement writing committee chair P. Barton Duell, MD, said in an interview. “The identification of normal liver enzyme levels does not exclude the diagnosis of NAFLD. Early diagnosis and treatment are necessary to improve the health of patients with established NAFLD, as well as preventing the development of NAFLD in patients who are at risk for the condition.”
Dr. Duell is a professor at the Knight Cardiovascular Institute and division of endocrinology, diabetes and clinical nutrition at Oregon Health & Science University, Portland.
This is the AHA’s first scientific statement on NAFLD. In 2021, the association issued a statement on obesity and CVD). Also in 2021, a multiorganization group headed by the American Gastroenterological Association published a “Call to Action” on nonalcoholic steatohepatitis (NASH) , a form of NAFLD that’s characterized by inflammation and scarring of the liver, and typically requires a liver biopsy for diagnosis.
Key take-homes
The AHA statement on NAFLD is sweeping. Among its key take-home messages:
- Calling into question the effectiveness of AST and ALT testing for diagnosing NAFLD and NASH.
- Providing context to the role of insulin resistance – either with or without diabetes – as well as obesity (particularly visceral adiposity), metabolic syndrome, and dyslipidemia in NAFLD.
- Advocating for lifestyle interventions – diet, exercise, weight loss and alcohol avoidance – as the key therapeutic intervention for NAFLD.
- Asserting that glucagonlike peptide–1 receptor agonists may modestly improve NAFLD.
The statement also tackles the differences in terminology different organizations use to describe NAFLD. “The terminology section is important to ensure everyone is using the right terminology in assessing patients, as well as choosing appropriate treatment interventions,” Dr. Duell said.
The statement also explores genetic factors that can predispose people to NAFLD, Dr. Duell pointed out, and it goes into detail about strategies for screening NAFLD and NASH. “It is not possible to diagnose NAFLD without understanding the pros and cons of various screening modalities, as well as the lack of sensitivity of some tests for detection of NAFLD We hope this information will increase success in screening for and early identification of NAFLD.”
Dr. Duell explained the rationale for issuing the statement. “Rates of NAFLD are increasing worldwide in association with rising rates of elevated body mass index and the metabolic syndrome, but the condition is commonly undiagnosed,” he said. “This allows patients to experience progression of disease, leading to hepatic and cardiovascular complications.”
Avoiding NAFLD risk factors along with early diagnosis and treatment “may have the potential to mitigate long-term complications from NAFLD,” Dr. Duell said.
“This is one of first times where we really look at cardiovascular risks associated with NAFLD and pinpoint the risk factors, the imaging tools that can be used for diagnosing fatty liver disease, and ultimately what potential treatments we can consider,” Tiffany M. Powell-Wiley, MD, MPH, author of the AHA statement on obesity and CV risk, said in an interview.
“NAFLD has not been at the forefront of cardiologists’ minds, but this statement highlights the importance of liver fat as a fat depot,” said Dr. Powell-Wiley, chief of the Social Determinants of Obesity and Cardiovascular Risk Laboratory at the National Heart, Lung, and Blood Institute in Bethesda, Md.
“It does provide greater clarity for us as cardiologists, especially when thinking about what is required for diagnosis and ultimately how this relates to cardiovascular disease for people with fatty liver disease,” she said.
Dr. Duell and Dr. Powell-Wiley have no relevant relationships to disclose.
At least one in four adults worldwide is thought to have nonalcoholic fatty liver disease, a major risk factor for cardiovascular disease (CVD), which is the leading cause of death in NAFLD, but the condition is widely underdiagnosed, according to a new American Heart Association scientific statement on NAFLD and cardiovascular risks.
The statement, published in Arteriosclerosis, Thrombosis, and Vascular Biology, aims to increase awareness of NAFLD among cardiologists and other clinicians treating vulnerable patients. It pulls together the existing evidence for using imaging to diagnose NAFLD as well as the role of current and emerging treatments for managing the disease.
“NAFLD is common, but most patients are undiagnosed,” statement writing committee chair P. Barton Duell, MD, said in an interview. “The identification of normal liver enzyme levels does not exclude the diagnosis of NAFLD. Early diagnosis and treatment are necessary to improve the health of patients with established NAFLD, as well as preventing the development of NAFLD in patients who are at risk for the condition.”
Dr. Duell is a professor at the Knight Cardiovascular Institute and division of endocrinology, diabetes and clinical nutrition at Oregon Health & Science University, Portland.
This is the AHA’s first scientific statement on NAFLD. In 2021, the association issued a statement on obesity and CVD). Also in 2021, a multiorganization group headed by the American Gastroenterological Association published a “Call to Action” on nonalcoholic steatohepatitis (NASH) , a form of NAFLD that’s characterized by inflammation and scarring of the liver, and typically requires a liver biopsy for diagnosis.
Key take-homes
The AHA statement on NAFLD is sweeping. Among its key take-home messages:
- Calling into question the effectiveness of AST and ALT testing for diagnosing NAFLD and NASH.
- Providing context to the role of insulin resistance – either with or without diabetes – as well as obesity (particularly visceral adiposity), metabolic syndrome, and dyslipidemia in NAFLD.
- Advocating for lifestyle interventions – diet, exercise, weight loss and alcohol avoidance – as the key therapeutic intervention for NAFLD.
- Asserting that glucagonlike peptide–1 receptor agonists may modestly improve NAFLD.
The statement also tackles the differences in terminology different organizations use to describe NAFLD. “The terminology section is important to ensure everyone is using the right terminology in assessing patients, as well as choosing appropriate treatment interventions,” Dr. Duell said.
The statement also explores genetic factors that can predispose people to NAFLD, Dr. Duell pointed out, and it goes into detail about strategies for screening NAFLD and NASH. “It is not possible to diagnose NAFLD without understanding the pros and cons of various screening modalities, as well as the lack of sensitivity of some tests for detection of NAFLD We hope this information will increase success in screening for and early identification of NAFLD.”
Dr. Duell explained the rationale for issuing the statement. “Rates of NAFLD are increasing worldwide in association with rising rates of elevated body mass index and the metabolic syndrome, but the condition is commonly undiagnosed,” he said. “This allows patients to experience progression of disease, leading to hepatic and cardiovascular complications.”
Avoiding NAFLD risk factors along with early diagnosis and treatment “may have the potential to mitigate long-term complications from NAFLD,” Dr. Duell said.
“This is one of first times where we really look at cardiovascular risks associated with NAFLD and pinpoint the risk factors, the imaging tools that can be used for diagnosing fatty liver disease, and ultimately what potential treatments we can consider,” Tiffany M. Powell-Wiley, MD, MPH, author of the AHA statement on obesity and CV risk, said in an interview.
“NAFLD has not been at the forefront of cardiologists’ minds, but this statement highlights the importance of liver fat as a fat depot,” said Dr. Powell-Wiley, chief of the Social Determinants of Obesity and Cardiovascular Risk Laboratory at the National Heart, Lung, and Blood Institute in Bethesda, Md.
“It does provide greater clarity for us as cardiologists, especially when thinking about what is required for diagnosis and ultimately how this relates to cardiovascular disease for people with fatty liver disease,” she said.
Dr. Duell and Dr. Powell-Wiley have no relevant relationships to disclose.
At least one in four adults worldwide is thought to have nonalcoholic fatty liver disease, a major risk factor for cardiovascular disease (CVD), which is the leading cause of death in NAFLD, but the condition is widely underdiagnosed, according to a new American Heart Association scientific statement on NAFLD and cardiovascular risks.
The statement, published in Arteriosclerosis, Thrombosis, and Vascular Biology, aims to increase awareness of NAFLD among cardiologists and other clinicians treating vulnerable patients. It pulls together the existing evidence for using imaging to diagnose NAFLD as well as the role of current and emerging treatments for managing the disease.
“NAFLD is common, but most patients are undiagnosed,” statement writing committee chair P. Barton Duell, MD, said in an interview. “The identification of normal liver enzyme levels does not exclude the diagnosis of NAFLD. Early diagnosis and treatment are necessary to improve the health of patients with established NAFLD, as well as preventing the development of NAFLD in patients who are at risk for the condition.”
Dr. Duell is a professor at the Knight Cardiovascular Institute and division of endocrinology, diabetes and clinical nutrition at Oregon Health & Science University, Portland.
This is the AHA’s first scientific statement on NAFLD. In 2021, the association issued a statement on obesity and CVD). Also in 2021, a multiorganization group headed by the American Gastroenterological Association published a “Call to Action” on nonalcoholic steatohepatitis (NASH) , a form of NAFLD that’s characterized by inflammation and scarring of the liver, and typically requires a liver biopsy for diagnosis.
Key take-homes
The AHA statement on NAFLD is sweeping. Among its key take-home messages:
- Calling into question the effectiveness of AST and ALT testing for diagnosing NAFLD and NASH.
- Providing context to the role of insulin resistance – either with or without diabetes – as well as obesity (particularly visceral adiposity), metabolic syndrome, and dyslipidemia in NAFLD.
- Advocating for lifestyle interventions – diet, exercise, weight loss and alcohol avoidance – as the key therapeutic intervention for NAFLD.
- Asserting that glucagonlike peptide–1 receptor agonists may modestly improve NAFLD.
The statement also tackles the differences in terminology different organizations use to describe NAFLD. “The terminology section is important to ensure everyone is using the right terminology in assessing patients, as well as choosing appropriate treatment interventions,” Dr. Duell said.
The statement also explores genetic factors that can predispose people to NAFLD, Dr. Duell pointed out, and it goes into detail about strategies for screening NAFLD and NASH. “It is not possible to diagnose NAFLD without understanding the pros and cons of various screening modalities, as well as the lack of sensitivity of some tests for detection of NAFLD We hope this information will increase success in screening for and early identification of NAFLD.”
Dr. Duell explained the rationale for issuing the statement. “Rates of NAFLD are increasing worldwide in association with rising rates of elevated body mass index and the metabolic syndrome, but the condition is commonly undiagnosed,” he said. “This allows patients to experience progression of disease, leading to hepatic and cardiovascular complications.”
Avoiding NAFLD risk factors along with early diagnosis and treatment “may have the potential to mitigate long-term complications from NAFLD,” Dr. Duell said.
“This is one of first times where we really look at cardiovascular risks associated with NAFLD and pinpoint the risk factors, the imaging tools that can be used for diagnosing fatty liver disease, and ultimately what potential treatments we can consider,” Tiffany M. Powell-Wiley, MD, MPH, author of the AHA statement on obesity and CV risk, said in an interview.
“NAFLD has not been at the forefront of cardiologists’ minds, but this statement highlights the importance of liver fat as a fat depot,” said Dr. Powell-Wiley, chief of the Social Determinants of Obesity and Cardiovascular Risk Laboratory at the National Heart, Lung, and Blood Institute in Bethesda, Md.
“It does provide greater clarity for us as cardiologists, especially when thinking about what is required for diagnosis and ultimately how this relates to cardiovascular disease for people with fatty liver disease,” she said.
Dr. Duell and Dr. Powell-Wiley have no relevant relationships to disclose.
FROM ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY
Erectile dysfunction drugs linked to ocular conditions
, researchers say.
Patients in an insurance database who were prescribed sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), or avanafil (Stendra) were almost twice as likely as were patients not prescribed the drugs to have ischemic optic neuropathy, retinal vascular occlusion, or serous retinal detachment.
In 2020, physicians wrote about 20 million monthly prescriptions for PDE5Is in the United States alone, said Mahyar Etminan, PharmD, associate professor of ophthalmology at the University of British Columbia, Vancouver.
“We don’t want to alarm people taking them, but generally speaking, if they experience visual problems or changes in vision, then these drugs may be the culprits, and they should check it out,” he said in an interview.
The study was published in JAMA Ophthalmology.
Previous reports, including postmarketing studies by the drug makers, have documented ocular events. The monographs for sildenafil, tadalafil, vardenafil, and avanafil warn users about ischemic optic neuropathy, the researchers found.
The monographs for sildenafil, tadalafil, and vardenafil list retinal vascular occlusion as a potential adverse event but do not quantify the risk. None of the drug monographs mention serous retinal detachment.
Previous research has associated PDE5Is with compromised perfusion of the optic nerve. Some researchers have speculated that the choroid blood vessels can undergo smooth muscle relaxation through a cyclic guanosine monophosphate pathway that can lead to choroidal congestion.
To get a better handle on the ocular risks of PDE51s, Dr. Etminan and his colleagues analyzed health insurance claim records from the PharMetrics Plus database of 213,033 men who had not experienced any of the three ocular conditions in the year before they became regular users of the medications.
They identified 1,146 patients who had been diagnosed with at least one of the three conditions.
The overall number of conditions diagnosed was small relative to the size of the population, 15.5 cases per 10,000 person-years. “So that’s still relatively rare, but the problem is that these are very heavily used medications,” Dr. Etminan said.
For each man diagnosed with one of the ocular conditions, the researchers matched four control persons who were the same age and could be followed for the same length of time. There was a total of 4,584 control persons.
The researchers compared regular users of PDE5Is (those who had received at least one prescription for a PDE5I every 3 months in the year before the ocular diagnosis) with nonusers (those who had not received a PDE5I prescription during that time).
Patients with the ocular conditions were more likely than were those in the control group to have hypertension, diabetes, cardiovascular disease, or sleep apnea. After controlling for these covariates, the researchers found that the users were overall 85% more likely to be diagnosed with one or more of them (incidence rate ratio [IRR], 1.85).
The researchers also found that the risk was even greater for those patients who were given five or more prescriptions of PDE5Is, compared to those given fewer than five prescriptions, suggesting a dose response.
On the basis of these findings, Dr. Etminan thinks drug companies should add warnings about serous retinal detachment and retinal vascular occlusion to the drug monographs.
Asked to comment, Pfizer, which developed Viagra, referred questions to its spinoff company, Viatris, which did not respond. Eli Lilly, which makes Cialis, also did not respond to a request for comment. Vivus, which makes Stendra, could not be reached by press time.
Bayer, which makes Levitra, declined to provide anyone who could answer questions, but it provided a statement noting that the occurrence of ocular adverse events is already known among PDE5I users and that retinal vascular occlusion and ischemic optic neuropathy are mentioned in the product information.
“For example, non-arteritic anterior ischemic optic neuropathy (NAION) is a very rare condition which occurs with an overall higher risk in the population usually suffering from erectile dysfunction (ED) – that is, elderly men with concomitant diseases such as diabetes, dyslipidemia, and hypertension – compared to the general population,” the statement said.
Because of the retrospective nature of the analysis, Dr. Etminan acknowledged that researchers could not prove that the increased risk of ocular disease was associated with use of the drugs rather than some underlying condition. But in addition to adjusting for known risk factors, they also separately analyzed men without hypertension, diabetes, or coronary artery disease and still found that the risk of the ocular conditions was roughly double for men with PDE5I prescriptions.
Howard Pomeranz, MD, PhD, professor of ophthalmology at Northwell Health in Great Neck, N.Y., who was not involved in this study, said its findings confirmed similar research that he conducted on ischemic optic neuropathy.
He told this news organization that people taking PDE5Is should weigh the risk against the benefit, but added that the calculation might be different for people who use them to treat pulmonary hypertension rather than erectile dysfunction.
Although people taking the drugs should discuss any changes in their vision with their practitioners, he said they should not be concerned about a “bluish type of tint to the vision that may occur transiently for anywhere from a few minutes up to 40 or 45 minutes.”
Drug companies and regulators should consider changing the monographs in light of this new evidence, Dr. Pomeranz said. “Perhaps this data might drive the warning to be perhaps a little bit stronger, now that there’s more data to suggest maybe a bit of a stronger association and not just some chance association between using these drugs and these visual events.”
The study was funded by the University of British Columbia. Dr. Etminan and Dr. Pomeranz have disclosed no relevant financial interests.
A version of this article first appeared on Medscape.com
, researchers say.
Patients in an insurance database who were prescribed sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), or avanafil (Stendra) were almost twice as likely as were patients not prescribed the drugs to have ischemic optic neuropathy, retinal vascular occlusion, or serous retinal detachment.
In 2020, physicians wrote about 20 million monthly prescriptions for PDE5Is in the United States alone, said Mahyar Etminan, PharmD, associate professor of ophthalmology at the University of British Columbia, Vancouver.
“We don’t want to alarm people taking them, but generally speaking, if they experience visual problems or changes in vision, then these drugs may be the culprits, and they should check it out,” he said in an interview.
The study was published in JAMA Ophthalmology.
Previous reports, including postmarketing studies by the drug makers, have documented ocular events. The monographs for sildenafil, tadalafil, vardenafil, and avanafil warn users about ischemic optic neuropathy, the researchers found.
The monographs for sildenafil, tadalafil, and vardenafil list retinal vascular occlusion as a potential adverse event but do not quantify the risk. None of the drug monographs mention serous retinal detachment.
Previous research has associated PDE5Is with compromised perfusion of the optic nerve. Some researchers have speculated that the choroid blood vessels can undergo smooth muscle relaxation through a cyclic guanosine monophosphate pathway that can lead to choroidal congestion.
To get a better handle on the ocular risks of PDE51s, Dr. Etminan and his colleagues analyzed health insurance claim records from the PharMetrics Plus database of 213,033 men who had not experienced any of the three ocular conditions in the year before they became regular users of the medications.
They identified 1,146 patients who had been diagnosed with at least one of the three conditions.
The overall number of conditions diagnosed was small relative to the size of the population, 15.5 cases per 10,000 person-years. “So that’s still relatively rare, but the problem is that these are very heavily used medications,” Dr. Etminan said.
For each man diagnosed with one of the ocular conditions, the researchers matched four control persons who were the same age and could be followed for the same length of time. There was a total of 4,584 control persons.
The researchers compared regular users of PDE5Is (those who had received at least one prescription for a PDE5I every 3 months in the year before the ocular diagnosis) with nonusers (those who had not received a PDE5I prescription during that time).
Patients with the ocular conditions were more likely than were those in the control group to have hypertension, diabetes, cardiovascular disease, or sleep apnea. After controlling for these covariates, the researchers found that the users were overall 85% more likely to be diagnosed with one or more of them (incidence rate ratio [IRR], 1.85).
The researchers also found that the risk was even greater for those patients who were given five or more prescriptions of PDE5Is, compared to those given fewer than five prescriptions, suggesting a dose response.
On the basis of these findings, Dr. Etminan thinks drug companies should add warnings about serous retinal detachment and retinal vascular occlusion to the drug monographs.
Asked to comment, Pfizer, which developed Viagra, referred questions to its spinoff company, Viatris, which did not respond. Eli Lilly, which makes Cialis, also did not respond to a request for comment. Vivus, which makes Stendra, could not be reached by press time.
Bayer, which makes Levitra, declined to provide anyone who could answer questions, but it provided a statement noting that the occurrence of ocular adverse events is already known among PDE5I users and that retinal vascular occlusion and ischemic optic neuropathy are mentioned in the product information.
“For example, non-arteritic anterior ischemic optic neuropathy (NAION) is a very rare condition which occurs with an overall higher risk in the population usually suffering from erectile dysfunction (ED) – that is, elderly men with concomitant diseases such as diabetes, dyslipidemia, and hypertension – compared to the general population,” the statement said.
Because of the retrospective nature of the analysis, Dr. Etminan acknowledged that researchers could not prove that the increased risk of ocular disease was associated with use of the drugs rather than some underlying condition. But in addition to adjusting for known risk factors, they also separately analyzed men without hypertension, diabetes, or coronary artery disease and still found that the risk of the ocular conditions was roughly double for men with PDE5I prescriptions.
Howard Pomeranz, MD, PhD, professor of ophthalmology at Northwell Health in Great Neck, N.Y., who was not involved in this study, said its findings confirmed similar research that he conducted on ischemic optic neuropathy.
He told this news organization that people taking PDE5Is should weigh the risk against the benefit, but added that the calculation might be different for people who use them to treat pulmonary hypertension rather than erectile dysfunction.
Although people taking the drugs should discuss any changes in their vision with their practitioners, he said they should not be concerned about a “bluish type of tint to the vision that may occur transiently for anywhere from a few minutes up to 40 or 45 minutes.”
Drug companies and regulators should consider changing the monographs in light of this new evidence, Dr. Pomeranz said. “Perhaps this data might drive the warning to be perhaps a little bit stronger, now that there’s more data to suggest maybe a bit of a stronger association and not just some chance association between using these drugs and these visual events.”
The study was funded by the University of British Columbia. Dr. Etminan and Dr. Pomeranz have disclosed no relevant financial interests.
A version of this article first appeared on Medscape.com
, researchers say.
Patients in an insurance database who were prescribed sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), or avanafil (Stendra) were almost twice as likely as were patients not prescribed the drugs to have ischemic optic neuropathy, retinal vascular occlusion, or serous retinal detachment.
In 2020, physicians wrote about 20 million monthly prescriptions for PDE5Is in the United States alone, said Mahyar Etminan, PharmD, associate professor of ophthalmology at the University of British Columbia, Vancouver.
“We don’t want to alarm people taking them, but generally speaking, if they experience visual problems or changes in vision, then these drugs may be the culprits, and they should check it out,” he said in an interview.
The study was published in JAMA Ophthalmology.
Previous reports, including postmarketing studies by the drug makers, have documented ocular events. The monographs for sildenafil, tadalafil, vardenafil, and avanafil warn users about ischemic optic neuropathy, the researchers found.
The monographs for sildenafil, tadalafil, and vardenafil list retinal vascular occlusion as a potential adverse event but do not quantify the risk. None of the drug monographs mention serous retinal detachment.
Previous research has associated PDE5Is with compromised perfusion of the optic nerve. Some researchers have speculated that the choroid blood vessels can undergo smooth muscle relaxation through a cyclic guanosine monophosphate pathway that can lead to choroidal congestion.
To get a better handle on the ocular risks of PDE51s, Dr. Etminan and his colleagues analyzed health insurance claim records from the PharMetrics Plus database of 213,033 men who had not experienced any of the three ocular conditions in the year before they became regular users of the medications.
They identified 1,146 patients who had been diagnosed with at least one of the three conditions.
The overall number of conditions diagnosed was small relative to the size of the population, 15.5 cases per 10,000 person-years. “So that’s still relatively rare, but the problem is that these are very heavily used medications,” Dr. Etminan said.
For each man diagnosed with one of the ocular conditions, the researchers matched four control persons who were the same age and could be followed for the same length of time. There was a total of 4,584 control persons.
The researchers compared regular users of PDE5Is (those who had received at least one prescription for a PDE5I every 3 months in the year before the ocular diagnosis) with nonusers (those who had not received a PDE5I prescription during that time).
Patients with the ocular conditions were more likely than were those in the control group to have hypertension, diabetes, cardiovascular disease, or sleep apnea. After controlling for these covariates, the researchers found that the users were overall 85% more likely to be diagnosed with one or more of them (incidence rate ratio [IRR], 1.85).
The researchers also found that the risk was even greater for those patients who were given five or more prescriptions of PDE5Is, compared to those given fewer than five prescriptions, suggesting a dose response.
On the basis of these findings, Dr. Etminan thinks drug companies should add warnings about serous retinal detachment and retinal vascular occlusion to the drug monographs.
Asked to comment, Pfizer, which developed Viagra, referred questions to its spinoff company, Viatris, which did not respond. Eli Lilly, which makes Cialis, also did not respond to a request for comment. Vivus, which makes Stendra, could not be reached by press time.
Bayer, which makes Levitra, declined to provide anyone who could answer questions, but it provided a statement noting that the occurrence of ocular adverse events is already known among PDE5I users and that retinal vascular occlusion and ischemic optic neuropathy are mentioned in the product information.
“For example, non-arteritic anterior ischemic optic neuropathy (NAION) is a very rare condition which occurs with an overall higher risk in the population usually suffering from erectile dysfunction (ED) – that is, elderly men with concomitant diseases such as diabetes, dyslipidemia, and hypertension – compared to the general population,” the statement said.
Because of the retrospective nature of the analysis, Dr. Etminan acknowledged that researchers could not prove that the increased risk of ocular disease was associated with use of the drugs rather than some underlying condition. But in addition to adjusting for known risk factors, they also separately analyzed men without hypertension, diabetes, or coronary artery disease and still found that the risk of the ocular conditions was roughly double for men with PDE5I prescriptions.
Howard Pomeranz, MD, PhD, professor of ophthalmology at Northwell Health in Great Neck, N.Y., who was not involved in this study, said its findings confirmed similar research that he conducted on ischemic optic neuropathy.
He told this news organization that people taking PDE5Is should weigh the risk against the benefit, but added that the calculation might be different for people who use them to treat pulmonary hypertension rather than erectile dysfunction.
Although people taking the drugs should discuss any changes in their vision with their practitioners, he said they should not be concerned about a “bluish type of tint to the vision that may occur transiently for anywhere from a few minutes up to 40 or 45 minutes.”
Drug companies and regulators should consider changing the monographs in light of this new evidence, Dr. Pomeranz said. “Perhaps this data might drive the warning to be perhaps a little bit stronger, now that there’s more data to suggest maybe a bit of a stronger association and not just some chance association between using these drugs and these visual events.”
The study was funded by the University of British Columbia. Dr. Etminan and Dr. Pomeranz have disclosed no relevant financial interests.
A version of this article first appeared on Medscape.com
Novel tool could calculate CVD risk in T2DM
A genetic risk score based on blood pressure has been shown to potentially help determine the increased risk for heart attack or stroke in people with type 2 diabetes, suggesting that glucose control alone won’t be enough to control a person’s genetic risk for other cardiometabolic diseases.
The study analyzed genetic data from 6,335 participants, characterized as a high-risk multiethnic type 2 diabetes population, in the Action to Control Cardiovascular Risk in Diabetes study (ACCORD). Investigators developed a multivariable-adjustable model that found that, with each degree increase in the genetic score, the risk of cardiovascular disease (CVD) events increased 12%. However, the study found no relationship between glycemic control therapy and BP genetic risk score in CVD risk (P < .10).
Researchers at the University of Alabama at Birmingham reported on the risk score in a research letter
“This study highlights that commonly occurring changes in our DNA that cumulatively contribute to a higher risk of BP and hypertension can predispose T2DM [type 2 diabetes mellitus] patients to a higher risk of CVD events,” lead author Pankaj Arora, MD, said in a comment. The genetic risk score used in the study was effective at identifying CVD risks among the study participants even after accounting for conventional CV risk factors, added Dr. Arora, who’s director of the cardiovascular clinical and translational research and cardiovascular genetics clinic programs at UAB. “We recognize that cardiometabolic diseases travel together. Simply controlling the blood glucose level in isolation without considering an individual’s genetic risk for other cardiometabolic diseases may not yield a reduction of CVD risk in T2DM.”
The study used a map of more than 1,000 common genetic variants known to affect BP and compared that with the DNA of study participants to determine their genetic risks. Dr. Arora and colleagues wrote that the “results invigorate the potential implications” of using a BP polygenic risk score to address CVD risks through early intervention with lifestyle modifications such as diet, exercise, smoking cessation, weight management, and BP control in people with high genetic risk.
Gene profiles like the model the UAB researchers developed are still far away from the clinic, Dr. Arora said. “While such gene profiles are being used regularly in cancer management, these gene profiles are not easily available for cardiologists and endocrinologists to order.” He noted that the cardiogenomics clinic at UAB is one of the few centers that provide this kind of gene profiling in the United States. “Studies like this are bringing gene profiling closer to the doorstep of all cardiology and endocrinology clinics.”
The next step for the research is to expand the genetic variants used in the profiles. “We are now trying to develop a gene profile that encompasses more than 1 million common genetic variations and will be more informative,” Dr. Arora said. He added that few randomized clinical trials have shown using a BP genetic risk score in the clinic would improve outcomes of people with T2DM.
Kiran Musunuru, MD, PhD, MPH, director of the genetic and epigenetic origins of disease program at the University of Pennsylvania’s cardiovascular program in Philadelphia, provided context on what the study adds to the understanding of CVD risk in people with T2DM. “We know that patients with type 2 diabetes are at increased risk of cardiovascular disease, some of which is due to coexisting risk factors like abnormal lipids and hypertension,” he said in a comment. “This study shows that genetic predisposition to high blood pressure is one of the drivers of risk in these patients.” Dr. Musunuru is also chair of the writing group for the American Heart Association scientific statement on the use of genetics and genomics in clinical care.
However, he noted that collecting that kind of genetic data is challenging because few companies offer the tests and few centers do routine genetic testing. “As more studies like this one demonstrate the potential benefits of genetic testing, we can expect to see broader adoption by clinicians,” Dr. Musunuru said.
Dr. Arora receives funding from the National Heart, Lung, and Blood Institute and the Doris Duke Charitable Foundation. The ACCORD study received funding from Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis US, and Schering-Plough. Dr. Musunuru has no relevant relationships to disclose.
A genetic risk score based on blood pressure has been shown to potentially help determine the increased risk for heart attack or stroke in people with type 2 diabetes, suggesting that glucose control alone won’t be enough to control a person’s genetic risk for other cardiometabolic diseases.
The study analyzed genetic data from 6,335 participants, characterized as a high-risk multiethnic type 2 diabetes population, in the Action to Control Cardiovascular Risk in Diabetes study (ACCORD). Investigators developed a multivariable-adjustable model that found that, with each degree increase in the genetic score, the risk of cardiovascular disease (CVD) events increased 12%. However, the study found no relationship between glycemic control therapy and BP genetic risk score in CVD risk (P < .10).
Researchers at the University of Alabama at Birmingham reported on the risk score in a research letter
“This study highlights that commonly occurring changes in our DNA that cumulatively contribute to a higher risk of BP and hypertension can predispose T2DM [type 2 diabetes mellitus] patients to a higher risk of CVD events,” lead author Pankaj Arora, MD, said in a comment. The genetic risk score used in the study was effective at identifying CVD risks among the study participants even after accounting for conventional CV risk factors, added Dr. Arora, who’s director of the cardiovascular clinical and translational research and cardiovascular genetics clinic programs at UAB. “We recognize that cardiometabolic diseases travel together. Simply controlling the blood glucose level in isolation without considering an individual’s genetic risk for other cardiometabolic diseases may not yield a reduction of CVD risk in T2DM.”
The study used a map of more than 1,000 common genetic variants known to affect BP and compared that with the DNA of study participants to determine their genetic risks. Dr. Arora and colleagues wrote that the “results invigorate the potential implications” of using a BP polygenic risk score to address CVD risks through early intervention with lifestyle modifications such as diet, exercise, smoking cessation, weight management, and BP control in people with high genetic risk.
Gene profiles like the model the UAB researchers developed are still far away from the clinic, Dr. Arora said. “While such gene profiles are being used regularly in cancer management, these gene profiles are not easily available for cardiologists and endocrinologists to order.” He noted that the cardiogenomics clinic at UAB is one of the few centers that provide this kind of gene profiling in the United States. “Studies like this are bringing gene profiling closer to the doorstep of all cardiology and endocrinology clinics.”
The next step for the research is to expand the genetic variants used in the profiles. “We are now trying to develop a gene profile that encompasses more than 1 million common genetic variations and will be more informative,” Dr. Arora said. He added that few randomized clinical trials have shown using a BP genetic risk score in the clinic would improve outcomes of people with T2DM.
Kiran Musunuru, MD, PhD, MPH, director of the genetic and epigenetic origins of disease program at the University of Pennsylvania’s cardiovascular program in Philadelphia, provided context on what the study adds to the understanding of CVD risk in people with T2DM. “We know that patients with type 2 diabetes are at increased risk of cardiovascular disease, some of which is due to coexisting risk factors like abnormal lipids and hypertension,” he said in a comment. “This study shows that genetic predisposition to high blood pressure is one of the drivers of risk in these patients.” Dr. Musunuru is also chair of the writing group for the American Heart Association scientific statement on the use of genetics and genomics in clinical care.
However, he noted that collecting that kind of genetic data is challenging because few companies offer the tests and few centers do routine genetic testing. “As more studies like this one demonstrate the potential benefits of genetic testing, we can expect to see broader adoption by clinicians,” Dr. Musunuru said.
Dr. Arora receives funding from the National Heart, Lung, and Blood Institute and the Doris Duke Charitable Foundation. The ACCORD study received funding from Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis US, and Schering-Plough. Dr. Musunuru has no relevant relationships to disclose.
A genetic risk score based on blood pressure has been shown to potentially help determine the increased risk for heart attack or stroke in people with type 2 diabetes, suggesting that glucose control alone won’t be enough to control a person’s genetic risk for other cardiometabolic diseases.
The study analyzed genetic data from 6,335 participants, characterized as a high-risk multiethnic type 2 diabetes population, in the Action to Control Cardiovascular Risk in Diabetes study (ACCORD). Investigators developed a multivariable-adjustable model that found that, with each degree increase in the genetic score, the risk of cardiovascular disease (CVD) events increased 12%. However, the study found no relationship between glycemic control therapy and BP genetic risk score in CVD risk (P < .10).
Researchers at the University of Alabama at Birmingham reported on the risk score in a research letter
“This study highlights that commonly occurring changes in our DNA that cumulatively contribute to a higher risk of BP and hypertension can predispose T2DM [type 2 diabetes mellitus] patients to a higher risk of CVD events,” lead author Pankaj Arora, MD, said in a comment. The genetic risk score used in the study was effective at identifying CVD risks among the study participants even after accounting for conventional CV risk factors, added Dr. Arora, who’s director of the cardiovascular clinical and translational research and cardiovascular genetics clinic programs at UAB. “We recognize that cardiometabolic diseases travel together. Simply controlling the blood glucose level in isolation without considering an individual’s genetic risk for other cardiometabolic diseases may not yield a reduction of CVD risk in T2DM.”
The study used a map of more than 1,000 common genetic variants known to affect BP and compared that with the DNA of study participants to determine their genetic risks. Dr. Arora and colleagues wrote that the “results invigorate the potential implications” of using a BP polygenic risk score to address CVD risks through early intervention with lifestyle modifications such as diet, exercise, smoking cessation, weight management, and BP control in people with high genetic risk.
Gene profiles like the model the UAB researchers developed are still far away from the clinic, Dr. Arora said. “While such gene profiles are being used regularly in cancer management, these gene profiles are not easily available for cardiologists and endocrinologists to order.” He noted that the cardiogenomics clinic at UAB is one of the few centers that provide this kind of gene profiling in the United States. “Studies like this are bringing gene profiling closer to the doorstep of all cardiology and endocrinology clinics.”
The next step for the research is to expand the genetic variants used in the profiles. “We are now trying to develop a gene profile that encompasses more than 1 million common genetic variations and will be more informative,” Dr. Arora said. He added that few randomized clinical trials have shown using a BP genetic risk score in the clinic would improve outcomes of people with T2DM.
Kiran Musunuru, MD, PhD, MPH, director of the genetic and epigenetic origins of disease program at the University of Pennsylvania’s cardiovascular program in Philadelphia, provided context on what the study adds to the understanding of CVD risk in people with T2DM. “We know that patients with type 2 diabetes are at increased risk of cardiovascular disease, some of which is due to coexisting risk factors like abnormal lipids and hypertension,” he said in a comment. “This study shows that genetic predisposition to high blood pressure is one of the drivers of risk in these patients.” Dr. Musunuru is also chair of the writing group for the American Heart Association scientific statement on the use of genetics and genomics in clinical care.
However, he noted that collecting that kind of genetic data is challenging because few companies offer the tests and few centers do routine genetic testing. “As more studies like this one demonstrate the potential benefits of genetic testing, we can expect to see broader adoption by clinicians,” Dr. Musunuru said.
Dr. Arora receives funding from the National Heart, Lung, and Blood Institute and the Doris Duke Charitable Foundation. The ACCORD study received funding from Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis US, and Schering-Plough. Dr. Musunuru has no relevant relationships to disclose.
FROM HYPERTENSION
Early PCSK9 inhibition in AMI yields plaque regression
When the PCSK9 inhibitor alirocumab is added to high-intensity statins soon after an acute myocardial infarction (AMI), the reduction in atheroma volume is doubled at 12 months, compared with placebo, while other key signs of plaque stabilization, such as fibrous cap thickness, are also significantly and substantially improved, according to the results of the PACMAN-AMI trial.
The study is consistent with other PCSK9 inhibitor trials, supporting the concept that “we should be seeking very low levels of LDL-C in high-risk patients,” reported Lorenz Räber, MD, PhD, of Bern (Switz.) University Hospital, at the annual scientific sessions of the American College of Cardiology.
The low LCL-C target, the data from PACMAN-AMI suggest, is below 50 mg/dL, but even lower is better. When displayed graphically, the improvements in remodeling characteristics “get very steep” as levels descend below a 50 mg/dL threshold, Dr. Räber reported. This was true regardless of study arm.
In PACMAN-AMI, 300 AMI patients (with either ST-elevation or non-ST-elevaion) were randomized to 150 mg alirocumab or placebo administered by subcutaneous injection within 24 hours after an urgent percutaneous intervention (PCI) and stent placement. All patients received their assigned therapy on top of a high-intensity statin in the form of 20 mg of rosuvastatin daily.
Primary outcome was atheroma volume
The primary endpoint was atheroma volume as determined by intravenous ultrasound (IVUS), but the secondary endpoints of maximum lipid core burden, as determined by near infrared spectroscopy (NIRS), and fibrous cap thickness, as determined by optical coherence tomography (OCT), were also adequately powered, according to Dr. Räber.
The imaging measures taken at baseline were repeated in exactly the same spot after 52 weeks on treatment.
For the primary outcome of atheroma volume, the mean 2.1% reduction among those randomized to alirocumab was more than double the 0.9% reduction in the placebo group (P = .001).
The mean reduction in lipid core volume based on a maximum lipid core burden index was also more than doubled (-79.42 vs. -37.60 maxLCBI4mm; P = .006). The increase in fibrous cap thickness was not quite twofold greater but very close (62.67 vs. 33.19 mcm; P = .001).
From baseline, the relative reductions in LDL-C, which were reached about 4 weeks after starting treatment and maintained over the course of the study, were greater in the group randomized to alirocumab (-84.8% vs. -50.7%). This was expected, but the more important finding was a near linear relationship between reductions of LDL-C and each of these endpoints regardless of treatment, fully explaining the advantage of alirocumab, according to Dr. Räber.
For the addition of alirocumab, “these findings indicate incremental coronary plaque regression, lipid core reduction, and plaque stabilization, and provide a mechanistic rationale in favor of early initiation of very intensive LDL-C lower in the setting of an acute MI,” he said.
The results of the PACMAN-AMI trial were published simultaneously at the time of the ACC presentation.
Results consistent with earlier trials
Alirocumab was well tolerated. Injection site reactions (6.1% vs. 3.3%) and general allergic reactions (3.4% vs. 0%) were more common on alirocumab, but there were no significant differences between the arms of this study for serious adverse events. There were slightly more neurocognitive events (2.0 vs. 0%) and abnormal alanine transferase levels (0.7% vs. 0%) in the alirocumab group.
The data are generally consistent with two previously published trials with another PCSK9 inhibitor, according to Dr. Räber. In the randomized GLAGOV trial published more than 5 years ago, evolocumab also produced about a 1% absolute reduction (P < .001) in plaque volume at the end of 78 weeks of follow-up relative to placebo.
However, that trial was limited to patients with coronary artery disease without a recent cardiovascular event. The more recent HUYGENS trial, which was presented virtually at the 2021 annual meeting of the European Society of Cardiology meeting and has not yet been published, looked at one of the endpoints also evaluated in PACMAN-AMI. In that study of 161 randomized NSTEMI patients, there was also about a doubling of fibrous cap thickness (42.7 vs. 21.5 mcm) for the PCSK9 inhibitor relative to placebo.
Clinical endpoints were not compared in either the PACMAN-AMI or HUYGENS trial.
PACMAN-AMI confirms plaque stabilization
Nevertheless, the message of plaque stabilization is important, according to Anthony N. DeMaria, MD, Founding Director of the Sulpizio Cardiovascular Center at the University of San Diego. Although he acknowledged that a 1% absolute reduction in mean plaque volume might “make you want to yawn,” he argued that this is a misreading of important changes observed in plaque physiology.
“What we have now is evidence that very low lipid levels result in plaque remodeling. The plaques might not get a whole lot smaller, but the changes are important,” he said, noting, for example, that a thicker fibrous cap and increased plaque stability “clearly plays a role in reducing risk of subsequent events.”
“You cannot help but be impressed by the relationship of lipid lowering and the favorable effect on remodeling,” he added.
The data associating PCSK9 inhibitors with protection from cardiovascular events is already extensive, according to Michael J. Blaha, MD, Director of Clinical Research for Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins University, Baltimore, but he called PACMAN-ACS “an extremely relevant study.”
“This provides more evidence of the mechanism of benefit, which I think is extremely important when talking to patients about the goals of therapy,” he said.
PACMAN-AMI provided a very simple take home message for Pamela B. Morris, MD, Director of Preventive Cardiology, Medical University of South Carolina, Charleston.
“This study shows that if you get LCL-C under 50 mg/dL regardless of treatment, there is a favorable remodeling effect,” Dr. Morris said. In AMI patients, the data confirm “go early and go low,” she added. “You should do whatever is necessary [go get to these lower targets].”
Dr. Räber has financial relationships with Abbott, Amgen, AstraZeneca, Boston Scientific, Biotronik, Canon, Heartflow, Medtronic, Occlutech, Regeneron, Sanofi, and Vifor. Dr. Blaha reports financial relationships with Akcea, Amgen, Bayer, Inozyme, Kaleido, Kowa, Medimmune, Novartis, Novo Nordisk, Regeneron, Roche, Sanofi, Siemens, and 89Bio. Dr. DeMaria reports no potential conflicts of interest. Dr. Morris reports a financial relationship with Amgen. The investigator-initiated trial received research grants from Infraredx, Regeneron, and Sanofi.
When the PCSK9 inhibitor alirocumab is added to high-intensity statins soon after an acute myocardial infarction (AMI), the reduction in atheroma volume is doubled at 12 months, compared with placebo, while other key signs of plaque stabilization, such as fibrous cap thickness, are also significantly and substantially improved, according to the results of the PACMAN-AMI trial.
The study is consistent with other PCSK9 inhibitor trials, supporting the concept that “we should be seeking very low levels of LDL-C in high-risk patients,” reported Lorenz Räber, MD, PhD, of Bern (Switz.) University Hospital, at the annual scientific sessions of the American College of Cardiology.
The low LCL-C target, the data from PACMAN-AMI suggest, is below 50 mg/dL, but even lower is better. When displayed graphically, the improvements in remodeling characteristics “get very steep” as levels descend below a 50 mg/dL threshold, Dr. Räber reported. This was true regardless of study arm.
In PACMAN-AMI, 300 AMI patients (with either ST-elevation or non-ST-elevaion) were randomized to 150 mg alirocumab or placebo administered by subcutaneous injection within 24 hours after an urgent percutaneous intervention (PCI) and stent placement. All patients received their assigned therapy on top of a high-intensity statin in the form of 20 mg of rosuvastatin daily.
Primary outcome was atheroma volume
The primary endpoint was atheroma volume as determined by intravenous ultrasound (IVUS), but the secondary endpoints of maximum lipid core burden, as determined by near infrared spectroscopy (NIRS), and fibrous cap thickness, as determined by optical coherence tomography (OCT), were also adequately powered, according to Dr. Räber.
The imaging measures taken at baseline were repeated in exactly the same spot after 52 weeks on treatment.
For the primary outcome of atheroma volume, the mean 2.1% reduction among those randomized to alirocumab was more than double the 0.9% reduction in the placebo group (P = .001).
The mean reduction in lipid core volume based on a maximum lipid core burden index was also more than doubled (-79.42 vs. -37.60 maxLCBI4mm; P = .006). The increase in fibrous cap thickness was not quite twofold greater but very close (62.67 vs. 33.19 mcm; P = .001).
From baseline, the relative reductions in LDL-C, which were reached about 4 weeks after starting treatment and maintained over the course of the study, were greater in the group randomized to alirocumab (-84.8% vs. -50.7%). This was expected, but the more important finding was a near linear relationship between reductions of LDL-C and each of these endpoints regardless of treatment, fully explaining the advantage of alirocumab, according to Dr. Räber.
For the addition of alirocumab, “these findings indicate incremental coronary plaque regression, lipid core reduction, and plaque stabilization, and provide a mechanistic rationale in favor of early initiation of very intensive LDL-C lower in the setting of an acute MI,” he said.
The results of the PACMAN-AMI trial were published simultaneously at the time of the ACC presentation.
Results consistent with earlier trials
Alirocumab was well tolerated. Injection site reactions (6.1% vs. 3.3%) and general allergic reactions (3.4% vs. 0%) were more common on alirocumab, but there were no significant differences between the arms of this study for serious adverse events. There were slightly more neurocognitive events (2.0 vs. 0%) and abnormal alanine transferase levels (0.7% vs. 0%) in the alirocumab group.
The data are generally consistent with two previously published trials with another PCSK9 inhibitor, according to Dr. Räber. In the randomized GLAGOV trial published more than 5 years ago, evolocumab also produced about a 1% absolute reduction (P < .001) in plaque volume at the end of 78 weeks of follow-up relative to placebo.
However, that trial was limited to patients with coronary artery disease without a recent cardiovascular event. The more recent HUYGENS trial, which was presented virtually at the 2021 annual meeting of the European Society of Cardiology meeting and has not yet been published, looked at one of the endpoints also evaluated in PACMAN-AMI. In that study of 161 randomized NSTEMI patients, there was also about a doubling of fibrous cap thickness (42.7 vs. 21.5 mcm) for the PCSK9 inhibitor relative to placebo.
Clinical endpoints were not compared in either the PACMAN-AMI or HUYGENS trial.
PACMAN-AMI confirms plaque stabilization
Nevertheless, the message of plaque stabilization is important, according to Anthony N. DeMaria, MD, Founding Director of the Sulpizio Cardiovascular Center at the University of San Diego. Although he acknowledged that a 1% absolute reduction in mean plaque volume might “make you want to yawn,” he argued that this is a misreading of important changes observed in plaque physiology.
“What we have now is evidence that very low lipid levels result in plaque remodeling. The plaques might not get a whole lot smaller, but the changes are important,” he said, noting, for example, that a thicker fibrous cap and increased plaque stability “clearly plays a role in reducing risk of subsequent events.”
“You cannot help but be impressed by the relationship of lipid lowering and the favorable effect on remodeling,” he added.
The data associating PCSK9 inhibitors with protection from cardiovascular events is already extensive, according to Michael J. Blaha, MD, Director of Clinical Research for Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins University, Baltimore, but he called PACMAN-ACS “an extremely relevant study.”
“This provides more evidence of the mechanism of benefit, which I think is extremely important when talking to patients about the goals of therapy,” he said.
PACMAN-AMI provided a very simple take home message for Pamela B. Morris, MD, Director of Preventive Cardiology, Medical University of South Carolina, Charleston.
“This study shows that if you get LCL-C under 50 mg/dL regardless of treatment, there is a favorable remodeling effect,” Dr. Morris said. In AMI patients, the data confirm “go early and go low,” she added. “You should do whatever is necessary [go get to these lower targets].”
Dr. Räber has financial relationships with Abbott, Amgen, AstraZeneca, Boston Scientific, Biotronik, Canon, Heartflow, Medtronic, Occlutech, Regeneron, Sanofi, and Vifor. Dr. Blaha reports financial relationships with Akcea, Amgen, Bayer, Inozyme, Kaleido, Kowa, Medimmune, Novartis, Novo Nordisk, Regeneron, Roche, Sanofi, Siemens, and 89Bio. Dr. DeMaria reports no potential conflicts of interest. Dr. Morris reports a financial relationship with Amgen. The investigator-initiated trial received research grants from Infraredx, Regeneron, and Sanofi.
When the PCSK9 inhibitor alirocumab is added to high-intensity statins soon after an acute myocardial infarction (AMI), the reduction in atheroma volume is doubled at 12 months, compared with placebo, while other key signs of plaque stabilization, such as fibrous cap thickness, are also significantly and substantially improved, according to the results of the PACMAN-AMI trial.
The study is consistent with other PCSK9 inhibitor trials, supporting the concept that “we should be seeking very low levels of LDL-C in high-risk patients,” reported Lorenz Räber, MD, PhD, of Bern (Switz.) University Hospital, at the annual scientific sessions of the American College of Cardiology.
The low LCL-C target, the data from PACMAN-AMI suggest, is below 50 mg/dL, but even lower is better. When displayed graphically, the improvements in remodeling characteristics “get very steep” as levels descend below a 50 mg/dL threshold, Dr. Räber reported. This was true regardless of study arm.
In PACMAN-AMI, 300 AMI patients (with either ST-elevation or non-ST-elevaion) were randomized to 150 mg alirocumab or placebo administered by subcutaneous injection within 24 hours after an urgent percutaneous intervention (PCI) and stent placement. All patients received their assigned therapy on top of a high-intensity statin in the form of 20 mg of rosuvastatin daily.
Primary outcome was atheroma volume
The primary endpoint was atheroma volume as determined by intravenous ultrasound (IVUS), but the secondary endpoints of maximum lipid core burden, as determined by near infrared spectroscopy (NIRS), and fibrous cap thickness, as determined by optical coherence tomography (OCT), were also adequately powered, according to Dr. Räber.
The imaging measures taken at baseline were repeated in exactly the same spot after 52 weeks on treatment.
For the primary outcome of atheroma volume, the mean 2.1% reduction among those randomized to alirocumab was more than double the 0.9% reduction in the placebo group (P = .001).
The mean reduction in lipid core volume based on a maximum lipid core burden index was also more than doubled (-79.42 vs. -37.60 maxLCBI4mm; P = .006). The increase in fibrous cap thickness was not quite twofold greater but very close (62.67 vs. 33.19 mcm; P = .001).
From baseline, the relative reductions in LDL-C, which were reached about 4 weeks after starting treatment and maintained over the course of the study, were greater in the group randomized to alirocumab (-84.8% vs. -50.7%). This was expected, but the more important finding was a near linear relationship between reductions of LDL-C and each of these endpoints regardless of treatment, fully explaining the advantage of alirocumab, according to Dr. Räber.
For the addition of alirocumab, “these findings indicate incremental coronary plaque regression, lipid core reduction, and plaque stabilization, and provide a mechanistic rationale in favor of early initiation of very intensive LDL-C lower in the setting of an acute MI,” he said.
The results of the PACMAN-AMI trial were published simultaneously at the time of the ACC presentation.
Results consistent with earlier trials
Alirocumab was well tolerated. Injection site reactions (6.1% vs. 3.3%) and general allergic reactions (3.4% vs. 0%) were more common on alirocumab, but there were no significant differences between the arms of this study for serious adverse events. There were slightly more neurocognitive events (2.0 vs. 0%) and abnormal alanine transferase levels (0.7% vs. 0%) in the alirocumab group.
The data are generally consistent with two previously published trials with another PCSK9 inhibitor, according to Dr. Räber. In the randomized GLAGOV trial published more than 5 years ago, evolocumab also produced about a 1% absolute reduction (P < .001) in plaque volume at the end of 78 weeks of follow-up relative to placebo.
However, that trial was limited to patients with coronary artery disease without a recent cardiovascular event. The more recent HUYGENS trial, which was presented virtually at the 2021 annual meeting of the European Society of Cardiology meeting and has not yet been published, looked at one of the endpoints also evaluated in PACMAN-AMI. In that study of 161 randomized NSTEMI patients, there was also about a doubling of fibrous cap thickness (42.7 vs. 21.5 mcm) for the PCSK9 inhibitor relative to placebo.
Clinical endpoints were not compared in either the PACMAN-AMI or HUYGENS trial.
PACMAN-AMI confirms plaque stabilization
Nevertheless, the message of plaque stabilization is important, according to Anthony N. DeMaria, MD, Founding Director of the Sulpizio Cardiovascular Center at the University of San Diego. Although he acknowledged that a 1% absolute reduction in mean plaque volume might “make you want to yawn,” he argued that this is a misreading of important changes observed in plaque physiology.
“What we have now is evidence that very low lipid levels result in plaque remodeling. The plaques might not get a whole lot smaller, but the changes are important,” he said, noting, for example, that a thicker fibrous cap and increased plaque stability “clearly plays a role in reducing risk of subsequent events.”
“You cannot help but be impressed by the relationship of lipid lowering and the favorable effect on remodeling,” he added.
The data associating PCSK9 inhibitors with protection from cardiovascular events is already extensive, according to Michael J. Blaha, MD, Director of Clinical Research for Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins University, Baltimore, but he called PACMAN-ACS “an extremely relevant study.”
“This provides more evidence of the mechanism of benefit, which I think is extremely important when talking to patients about the goals of therapy,” he said.
PACMAN-AMI provided a very simple take home message for Pamela B. Morris, MD, Director of Preventive Cardiology, Medical University of South Carolina, Charleston.
“This study shows that if you get LCL-C under 50 mg/dL regardless of treatment, there is a favorable remodeling effect,” Dr. Morris said. In AMI patients, the data confirm “go early and go low,” she added. “You should do whatever is necessary [go get to these lower targets].”
Dr. Räber has financial relationships with Abbott, Amgen, AstraZeneca, Boston Scientific, Biotronik, Canon, Heartflow, Medtronic, Occlutech, Regeneron, Sanofi, and Vifor. Dr. Blaha reports financial relationships with Akcea, Amgen, Bayer, Inozyme, Kaleido, Kowa, Medimmune, Novartis, Novo Nordisk, Regeneron, Roche, Sanofi, Siemens, and 89Bio. Dr. DeMaria reports no potential conflicts of interest. Dr. Morris reports a financial relationship with Amgen. The investigator-initiated trial received research grants from Infraredx, Regeneron, and Sanofi.
FROM ACC 2022
APOLLO: SLN360 clears first major hurdle, hammering Lp(a)
The short interfering RNA (siRNA) agent SLN360 was well tolerated and lowered lipoprotein(a) by up to 98% in volunteers without cardiovascular disease but with elevated Lp(a) in the small dose-ranging APOLLO trial.
Following a single subcutaneous dose of SLN360 (Silence Therapeutics), there was a dose-dependent reduction in Lp(a) plasma levels by a median of 46%, 86%, 96%, and 98% at about 45-60 days with 30-mg, 100-mg, 300-mg, and 600-mg doses, respectively.
Lp(a) levels at 150 days were 70% and 81% below baseline with the 300-and 600-mg doses.
In addition, for participants receiving the two highest doses, apolipoprotein B (apo B) was reduced was 21% and 24%, respectively, and LDL cholesterol (LDL-C), by 21% and 26%, respectively.
“The development of therapies targeting messenger RNA has made possible significant lowering of lipoprotein(a). Whether these reductions can impact on the incidence of ASCVD [atherosclerotic cardiovascular disease] or prevent progression of aortic stenosis remains to be determined but, we think, that optimism is warranted,” said principal investigator Steven E. Nissen, MD, Cleveland Clinic.
The results were presented in a late-breaking clinical trial session at the annual scientific sessions of the American College of Cardiology and published simultaneously in JAMA.
Elevated Lp(a) is a powerful genetic risk factor for ASCVD and aortic stenosis, which affects some 64 million Americans and 1.4 billion people globally. Although several experimental agents are under investigation, no currently approved drugs selectively lower Lp(a).
SLN360 is designed to lower Lp(a) production by using RNA interference to silence messenger RNA transcribed from the LPA gene in liver cells.
Testing vacuum
Dr. Nissen said in an interview that one of the big takeaways from the study is the need for greater testing of Lp(a). Automatic assays are available in almost every hospital, but two-unit systems (nmol/L and mg/dL) are used and thresholds for accelerated risk vary. The Cleveland Clinic currently tests all patients in its cardiac critical care unit and its prevention clinic.
“Someone comes in with an MI in their 40s and we measure it and it’s 100, 150 [mg/dL], clearly abnormal, and often these patients don’t have a lot of other risk factors,” Dr. Nissen said. “So the explanation very likely for their premature disease is this risk factor. We now have to educate everybody about the importance of getting it tested and finding out about it.”
During a media briefing, ACC 2022 program cochair Pamela B. Morris, MD, Medical University of South Carolina, Charleston, said testing for Lp(a) is not well reimbursed by insurance providers and that her patients will often cancel the test after learning it won’t be reimbursed because they don’t understand it.
“What Dr. Nissen is telling you: It should be measured in everyone at least once, we all believe that, but it hasn’t made it into the major guidelines,” she added. “I think what we’re going to have to do is have the guidelines mandate it and the insurers will follow.”
Guidelines currently list elevated Lp(a) as a “risk-enhancing factor,” which can help with at least recommending LDL-C treatment in patients with borderline risk and a sky-high Lp(a), noted Dr. Nissen. “But we need to go beyond that.”
Safety analyses
The first-in-human APOLLO trial evaluated 32 adults without known ASCVD and an Lp(a) concentration greater than 150 nmol/L (approximately 60 mg/dL) who received one of the four doses of SLN360 or placebo subcutaneously. Participants were monitored in a research unit for the first 24 hours and then followed periodically for up to 150 days. At baseline, their median Lp(a) level was 224 nmol/L, mean apo B level was 85 mg/dL, and mean LDL-C level was 108 mg/dL.
Treatment-emergent adverse events were generally mild, mostly grade 1 injection site reactions (83% at 30 mg, 100% at 100 mg, 67% at 300 mg, and 33% at 600 mg) and headache (33%, 17%, 0%, and 83%).
At the highest dose, C-reactive protein was increased in four patients and neutrophil counts in three. ALT and AST levels were elevated three times above the upper limit of normal in one patient at the lowest dose.
One participant in the lowest-dose group experienced two serious adverse events unrelated to SLN360 at day 45 after receiving a SARS-Co-V-2 vaccine.
Dr. Nissen noted that safety cannot be comprehensively assessed in a trial of this duration or size and that follow-up has been extended to 1 year in the two highest-dose groups.
Enrollment continues in the multiple-ascending dose portion of the study in patients with high Lp(a) and a history of stable ASCVD. A phase 2 study of SLN360 is also planned for the second half of 2022, pending regulatory discussions.
But will it reduce ASCVD events?
Study discussant Vera Bittner, MD, MSPH, University of Alabama at Birmingham, said that the development of Lp(a)-specific lowering agents has been a “holy grail” for years and congratulated the authors on a successful trial demonstrating very robust Lp(a) lowering.
She asked Dr. Nissen about the observation in proprotein convertase subtilisin/kexin type 9 inhibitor trials that absolute Lp(a) lowering is greater at higher baseline levels.
Dr. Nissen said this kind of analysis wasn’t possible because of the small sample size but “because these agents so effectively degrade messenger RNA, it’s very likely we will see robust suppression of plasma levels virtually regardless of the baseline level.”
Dr. Bittner also questioned if “LDL-C declined because of the cholesterol content in the lipoprotein(a) or is there some additional effect on LDL particles themselves?”
“It’s a really terrific question that will ultimately need to be answered,” Dr. Nissen replied. “There’s some controversy about the extent to which suppressing lipoprotein(a) will reduce LDL because the assays for LDL are measuring the LDL that’s in lipoprotein(a) and the LDL that is not. ... I think it’s probably a bystander effect, but it may also contribute to efficacy from a morbidity and mortality point of view, which is why we measured it.”
Dr. Bittner also called out the elevation in C-reactive protein and leukocytosis, which has not been seen in other siRNA studies. Dr. Nissen said the increases in C-reactive protein occurred in the first few days after administration and were gone after a week or so. “I don’t see it as a long-term limitation.”
In an accompanying editorial, Brian Ference, MD, MPhil, MSc, University of Cambridge (England), suggests that because circulating Lp(a) particles can progressively become trapped within the artery wall over time, it’s unlikely that lowering Lp(a) for only a few years starting later in life will eliminate the effect of lifelong exposure to Lp(a) and may only cut cardiovascular event risk by about 10%-15%.
He called for continued safety and efficacy evaluation of SLN360 and olpasiran, a similar siRNA agent in early development, and said further insights into whether large absolute reductions in Lp(a) can reduce the risk for major cardiovascular events will come from cardiovascular trials, such as the ongoing phase 3 Lp(a)HORIZON trial. It follows strong phase 2 results with the antisense agent AKCEA-APO(a)-LRx and has Dr. Nissen pulling double duty as study chair.
The study was funded by Silence Therapeutics. Dr. Nissen reported consulting for many pharmaceutical companies, which are directed to pay any renumeration directly to charity. Dr. Bittner reported consultant fees or honoraria from Pfizer; other from AstraZeneca, DalCor, Esperion, and Sanofi-Aventis; and research/research grants from Amgen and Novartis. Dr. Ference reported financial ties to Merck, Novartis, Amgen, Pfizer, Esperion Therapeutics, and numerous other companies.
A version of this article first appeared on Medscape.com.
The short interfering RNA (siRNA) agent SLN360 was well tolerated and lowered lipoprotein(a) by up to 98% in volunteers without cardiovascular disease but with elevated Lp(a) in the small dose-ranging APOLLO trial.
Following a single subcutaneous dose of SLN360 (Silence Therapeutics), there was a dose-dependent reduction in Lp(a) plasma levels by a median of 46%, 86%, 96%, and 98% at about 45-60 days with 30-mg, 100-mg, 300-mg, and 600-mg doses, respectively.
Lp(a) levels at 150 days were 70% and 81% below baseline with the 300-and 600-mg doses.
In addition, for participants receiving the two highest doses, apolipoprotein B (apo B) was reduced was 21% and 24%, respectively, and LDL cholesterol (LDL-C), by 21% and 26%, respectively.
“The development of therapies targeting messenger RNA has made possible significant lowering of lipoprotein(a). Whether these reductions can impact on the incidence of ASCVD [atherosclerotic cardiovascular disease] or prevent progression of aortic stenosis remains to be determined but, we think, that optimism is warranted,” said principal investigator Steven E. Nissen, MD, Cleveland Clinic.
The results were presented in a late-breaking clinical trial session at the annual scientific sessions of the American College of Cardiology and published simultaneously in JAMA.
Elevated Lp(a) is a powerful genetic risk factor for ASCVD and aortic stenosis, which affects some 64 million Americans and 1.4 billion people globally. Although several experimental agents are under investigation, no currently approved drugs selectively lower Lp(a).
SLN360 is designed to lower Lp(a) production by using RNA interference to silence messenger RNA transcribed from the LPA gene in liver cells.
Testing vacuum
Dr. Nissen said in an interview that one of the big takeaways from the study is the need for greater testing of Lp(a). Automatic assays are available in almost every hospital, but two-unit systems (nmol/L and mg/dL) are used and thresholds for accelerated risk vary. The Cleveland Clinic currently tests all patients in its cardiac critical care unit and its prevention clinic.
“Someone comes in with an MI in their 40s and we measure it and it’s 100, 150 [mg/dL], clearly abnormal, and often these patients don’t have a lot of other risk factors,” Dr. Nissen said. “So the explanation very likely for their premature disease is this risk factor. We now have to educate everybody about the importance of getting it tested and finding out about it.”
During a media briefing, ACC 2022 program cochair Pamela B. Morris, MD, Medical University of South Carolina, Charleston, said testing for Lp(a) is not well reimbursed by insurance providers and that her patients will often cancel the test after learning it won’t be reimbursed because they don’t understand it.
“What Dr. Nissen is telling you: It should be measured in everyone at least once, we all believe that, but it hasn’t made it into the major guidelines,” she added. “I think what we’re going to have to do is have the guidelines mandate it and the insurers will follow.”
Guidelines currently list elevated Lp(a) as a “risk-enhancing factor,” which can help with at least recommending LDL-C treatment in patients with borderline risk and a sky-high Lp(a), noted Dr. Nissen. “But we need to go beyond that.”
Safety analyses
The first-in-human APOLLO trial evaluated 32 adults without known ASCVD and an Lp(a) concentration greater than 150 nmol/L (approximately 60 mg/dL) who received one of the four doses of SLN360 or placebo subcutaneously. Participants were monitored in a research unit for the first 24 hours and then followed periodically for up to 150 days. At baseline, their median Lp(a) level was 224 nmol/L, mean apo B level was 85 mg/dL, and mean LDL-C level was 108 mg/dL.
Treatment-emergent adverse events were generally mild, mostly grade 1 injection site reactions (83% at 30 mg, 100% at 100 mg, 67% at 300 mg, and 33% at 600 mg) and headache (33%, 17%, 0%, and 83%).
At the highest dose, C-reactive protein was increased in four patients and neutrophil counts in three. ALT and AST levels were elevated three times above the upper limit of normal in one patient at the lowest dose.
One participant in the lowest-dose group experienced two serious adverse events unrelated to SLN360 at day 45 after receiving a SARS-Co-V-2 vaccine.
Dr. Nissen noted that safety cannot be comprehensively assessed in a trial of this duration or size and that follow-up has been extended to 1 year in the two highest-dose groups.
Enrollment continues in the multiple-ascending dose portion of the study in patients with high Lp(a) and a history of stable ASCVD. A phase 2 study of SLN360 is also planned for the second half of 2022, pending regulatory discussions.
But will it reduce ASCVD events?
Study discussant Vera Bittner, MD, MSPH, University of Alabama at Birmingham, said that the development of Lp(a)-specific lowering agents has been a “holy grail” for years and congratulated the authors on a successful trial demonstrating very robust Lp(a) lowering.
She asked Dr. Nissen about the observation in proprotein convertase subtilisin/kexin type 9 inhibitor trials that absolute Lp(a) lowering is greater at higher baseline levels.
Dr. Nissen said this kind of analysis wasn’t possible because of the small sample size but “because these agents so effectively degrade messenger RNA, it’s very likely we will see robust suppression of plasma levels virtually regardless of the baseline level.”
Dr. Bittner also questioned if “LDL-C declined because of the cholesterol content in the lipoprotein(a) or is there some additional effect on LDL particles themselves?”
“It’s a really terrific question that will ultimately need to be answered,” Dr. Nissen replied. “There’s some controversy about the extent to which suppressing lipoprotein(a) will reduce LDL because the assays for LDL are measuring the LDL that’s in lipoprotein(a) and the LDL that is not. ... I think it’s probably a bystander effect, but it may also contribute to efficacy from a morbidity and mortality point of view, which is why we measured it.”
Dr. Bittner also called out the elevation in C-reactive protein and leukocytosis, which has not been seen in other siRNA studies. Dr. Nissen said the increases in C-reactive protein occurred in the first few days after administration and were gone after a week or so. “I don’t see it as a long-term limitation.”
In an accompanying editorial, Brian Ference, MD, MPhil, MSc, University of Cambridge (England), suggests that because circulating Lp(a) particles can progressively become trapped within the artery wall over time, it’s unlikely that lowering Lp(a) for only a few years starting later in life will eliminate the effect of lifelong exposure to Lp(a) and may only cut cardiovascular event risk by about 10%-15%.
He called for continued safety and efficacy evaluation of SLN360 and olpasiran, a similar siRNA agent in early development, and said further insights into whether large absolute reductions in Lp(a) can reduce the risk for major cardiovascular events will come from cardiovascular trials, such as the ongoing phase 3 Lp(a)HORIZON trial. It follows strong phase 2 results with the antisense agent AKCEA-APO(a)-LRx and has Dr. Nissen pulling double duty as study chair.
The study was funded by Silence Therapeutics. Dr. Nissen reported consulting for many pharmaceutical companies, which are directed to pay any renumeration directly to charity. Dr. Bittner reported consultant fees or honoraria from Pfizer; other from AstraZeneca, DalCor, Esperion, and Sanofi-Aventis; and research/research grants from Amgen and Novartis. Dr. Ference reported financial ties to Merck, Novartis, Amgen, Pfizer, Esperion Therapeutics, and numerous other companies.
A version of this article first appeared on Medscape.com.
The short interfering RNA (siRNA) agent SLN360 was well tolerated and lowered lipoprotein(a) by up to 98% in volunteers without cardiovascular disease but with elevated Lp(a) in the small dose-ranging APOLLO trial.
Following a single subcutaneous dose of SLN360 (Silence Therapeutics), there was a dose-dependent reduction in Lp(a) plasma levels by a median of 46%, 86%, 96%, and 98% at about 45-60 days with 30-mg, 100-mg, 300-mg, and 600-mg doses, respectively.
Lp(a) levels at 150 days were 70% and 81% below baseline with the 300-and 600-mg doses.
In addition, for participants receiving the two highest doses, apolipoprotein B (apo B) was reduced was 21% and 24%, respectively, and LDL cholesterol (LDL-C), by 21% and 26%, respectively.
“The development of therapies targeting messenger RNA has made possible significant lowering of lipoprotein(a). Whether these reductions can impact on the incidence of ASCVD [atherosclerotic cardiovascular disease] or prevent progression of aortic stenosis remains to be determined but, we think, that optimism is warranted,” said principal investigator Steven E. Nissen, MD, Cleveland Clinic.
The results were presented in a late-breaking clinical trial session at the annual scientific sessions of the American College of Cardiology and published simultaneously in JAMA.
Elevated Lp(a) is a powerful genetic risk factor for ASCVD and aortic stenosis, which affects some 64 million Americans and 1.4 billion people globally. Although several experimental agents are under investigation, no currently approved drugs selectively lower Lp(a).
SLN360 is designed to lower Lp(a) production by using RNA interference to silence messenger RNA transcribed from the LPA gene in liver cells.
Testing vacuum
Dr. Nissen said in an interview that one of the big takeaways from the study is the need for greater testing of Lp(a). Automatic assays are available in almost every hospital, but two-unit systems (nmol/L and mg/dL) are used and thresholds for accelerated risk vary. The Cleveland Clinic currently tests all patients in its cardiac critical care unit and its prevention clinic.
“Someone comes in with an MI in their 40s and we measure it and it’s 100, 150 [mg/dL], clearly abnormal, and often these patients don’t have a lot of other risk factors,” Dr. Nissen said. “So the explanation very likely for their premature disease is this risk factor. We now have to educate everybody about the importance of getting it tested and finding out about it.”
During a media briefing, ACC 2022 program cochair Pamela B. Morris, MD, Medical University of South Carolina, Charleston, said testing for Lp(a) is not well reimbursed by insurance providers and that her patients will often cancel the test after learning it won’t be reimbursed because they don’t understand it.
“What Dr. Nissen is telling you: It should be measured in everyone at least once, we all believe that, but it hasn’t made it into the major guidelines,” she added. “I think what we’re going to have to do is have the guidelines mandate it and the insurers will follow.”
Guidelines currently list elevated Lp(a) as a “risk-enhancing factor,” which can help with at least recommending LDL-C treatment in patients with borderline risk and a sky-high Lp(a), noted Dr. Nissen. “But we need to go beyond that.”
Safety analyses
The first-in-human APOLLO trial evaluated 32 adults without known ASCVD and an Lp(a) concentration greater than 150 nmol/L (approximately 60 mg/dL) who received one of the four doses of SLN360 or placebo subcutaneously. Participants were monitored in a research unit for the first 24 hours and then followed periodically for up to 150 days. At baseline, their median Lp(a) level was 224 nmol/L, mean apo B level was 85 mg/dL, and mean LDL-C level was 108 mg/dL.
Treatment-emergent adverse events were generally mild, mostly grade 1 injection site reactions (83% at 30 mg, 100% at 100 mg, 67% at 300 mg, and 33% at 600 mg) and headache (33%, 17%, 0%, and 83%).
At the highest dose, C-reactive protein was increased in four patients and neutrophil counts in three. ALT and AST levels were elevated three times above the upper limit of normal in one patient at the lowest dose.
One participant in the lowest-dose group experienced two serious adverse events unrelated to SLN360 at day 45 after receiving a SARS-Co-V-2 vaccine.
Dr. Nissen noted that safety cannot be comprehensively assessed in a trial of this duration or size and that follow-up has been extended to 1 year in the two highest-dose groups.
Enrollment continues in the multiple-ascending dose portion of the study in patients with high Lp(a) and a history of stable ASCVD. A phase 2 study of SLN360 is also planned for the second half of 2022, pending regulatory discussions.
But will it reduce ASCVD events?
Study discussant Vera Bittner, MD, MSPH, University of Alabama at Birmingham, said that the development of Lp(a)-specific lowering agents has been a “holy grail” for years and congratulated the authors on a successful trial demonstrating very robust Lp(a) lowering.
She asked Dr. Nissen about the observation in proprotein convertase subtilisin/kexin type 9 inhibitor trials that absolute Lp(a) lowering is greater at higher baseline levels.
Dr. Nissen said this kind of analysis wasn’t possible because of the small sample size but “because these agents so effectively degrade messenger RNA, it’s very likely we will see robust suppression of plasma levels virtually regardless of the baseline level.”
Dr. Bittner also questioned if “LDL-C declined because of the cholesterol content in the lipoprotein(a) or is there some additional effect on LDL particles themselves?”
“It’s a really terrific question that will ultimately need to be answered,” Dr. Nissen replied. “There’s some controversy about the extent to which suppressing lipoprotein(a) will reduce LDL because the assays for LDL are measuring the LDL that’s in lipoprotein(a) and the LDL that is not. ... I think it’s probably a bystander effect, but it may also contribute to efficacy from a morbidity and mortality point of view, which is why we measured it.”
Dr. Bittner also called out the elevation in C-reactive protein and leukocytosis, which has not been seen in other siRNA studies. Dr. Nissen said the increases in C-reactive protein occurred in the first few days after administration and were gone after a week or so. “I don’t see it as a long-term limitation.”
In an accompanying editorial, Brian Ference, MD, MPhil, MSc, University of Cambridge (England), suggests that because circulating Lp(a) particles can progressively become trapped within the artery wall over time, it’s unlikely that lowering Lp(a) for only a few years starting later in life will eliminate the effect of lifelong exposure to Lp(a) and may only cut cardiovascular event risk by about 10%-15%.
He called for continued safety and efficacy evaluation of SLN360 and olpasiran, a similar siRNA agent in early development, and said further insights into whether large absolute reductions in Lp(a) can reduce the risk for major cardiovascular events will come from cardiovascular trials, such as the ongoing phase 3 Lp(a)HORIZON trial. It follows strong phase 2 results with the antisense agent AKCEA-APO(a)-LRx and has Dr. Nissen pulling double duty as study chair.
The study was funded by Silence Therapeutics. Dr. Nissen reported consulting for many pharmaceutical companies, which are directed to pay any renumeration directly to charity. Dr. Bittner reported consultant fees or honoraria from Pfizer; other from AstraZeneca, DalCor, Esperion, and Sanofi-Aventis; and research/research grants from Amgen and Novartis. Dr. Ference reported financial ties to Merck, Novartis, Amgen, Pfizer, Esperion Therapeutics, and numerous other companies.
A version of this article first appeared on Medscape.com.
FROM ACC 2022
Supermarket diet advice improves DASH adherence: SuperWIN
People who received personalized nutrition education in a series of sessions at their regular grocery store significantly improved adherence to a healthy diet, in a new “first-of-its-kind” study in which scientific researchers partnered with a large supermarket company.
In the SuperWIN study, participants were given individualized advice from supermarket-based dietitians using data on their own buying habits recorded on their supermarket loyalty cards. This was associated with an increased adherence to the DASH (Dietary Approaches to Stop Hypertension) diet, which emphasizes vegetables, fruits and whole grains while limiting foods that are high in saturated fat, sugar, and sodium and has been shown to lower blood pressure and LDL cholesterol.
One group of patients also received additional education about healthy eating and meal planning through online technologies, and this group showed even better adherence to the DASH diet.
The study was presented at the annual scientific sessions of the American College of Cardiology by Dylan Steen, MD, adjunct associate professor of medicine at the University of Cincinnati.
“The SuperWIN study provides evidence for the benefit of delivering healthy-eating interventions at modern supermarkets and retail-based clinics,” Dr. Steen said. “It demonstrates the efficacy of dietary interventions harnessing the physical environment of the supermarket, the retail-based dietitians working within the store, and the purchasing data captured on the store’s loyalty cards.”
The study was conducted in partnership with Kroger, the largest supermarket chain in the United States, which also operates a large chain of pharmacies and health clinics.
Dr. Steen said the study was addressing one of the biggest public health problems – unhealthy eating – with an innovative approach. “We need to think about how we can extend the reach of modern health care systems into communities and better deliver services right where people are; meet them where they live,” he said at an ACC press conference.
Commenting on the study at the press conference, Eileen Handberg, PhD, professor of medicine at University of Florida, Gainesville, and immediate past chair of the ACC Cardiovascular Care Team Council, said: “I am amazingly excited about this. There is so much potential here. We have never really taken advantage of the current explosion in retail-based health care before.”
Dr. Handberg suggested the study had major implications for the primary prevention of cardiovascular disease. “Little kids go shopping with their parents, so you have the ability here to change behavior from children on up if you can change the dynamic of the choices they make in the grocery store.”
In his presentation, Dr. Steen noted that, despite many longstanding guidelines on healthy eating, about 75% of Americans still have a poor-quality diet. This trial was conducted to see if a new approach could improve that situation. “If we change the environment in which we deliver dietary education, we can make a difference.”
The SuperWIN trial was conducted in 13 Kroger stores in Ohio and Kentucky. The study enrolled 267 people with at least one cardiovascular risk factor from a primary care network who regularly shopped at one of the study stores. All participants also had to be willing to follow the DASH diet, which was taught at each educational session in the trial.
All participants received one “enhanced” medical nutrition therapy that was guided by the individual’s own dietary intake analytics.
They were then randomly assigned to one of three arms. The control group received no further education. The strategy 1 group received six additional teaching sessions in the supermarket aisles over a 3-month period. Each session was guided by updated individualized purchasing data provided to the dietitian and the participant.
The strategy 2 group received the same six additional teaching sessions as strategy 1, but they also had some additional teaching on healthy eating and meal planning from a variety of online shopping tools, and nutrition and health care apps.
“The supermarket analytics were automatically collected so the dietitians could tell what each person liked to eat, how much of each product they were buying and how much they were spending,” Dr. Steen explained.
COVID hit halfway through the trial, and 20 participants were withdrawn for their own safety as they could no longer visit the stores, but the trial continued with the rest of the participants with enhanced safety precautions. The overall analysis cohort was 247 participants.
The average age of the participants was mid-50s, around 70% were female, and most did not have a history of cardiovascular disease.
Eating habits were assessed by three 24-hour dietary recalls assessed at the start of the study and at 3 and 6 months. The DASH score, which is a measure of adherence to the DASH diet, was calculated from this information. The score can range from 0 to 90, with an increased score showing increased adherence.
In one analysis, the researchers compared the DASH scores from the two intervention groups together with the control group, and in a second analysis they compared the scores in the strategy 2 group with those in the strategy 1 group.
Before the pandemic there was “near 100%” attendance for the six visits over the 3-month study period, which Dr. Steen said he thought was “remarkable.” During the pandemic, attendance came down to around 80%.
Results showed that the DASH score increased in all three groups at 3 months, with stepwise increases corresponding to the intensity of the intervention. DASH scores increased by 5.8 points in the control group, by 8.6 points in the strategy 1 group, and by 12.4 points in the strategy 2 group.
DASH scores significantly differed between the two intervention groups and the control group (P = .02). “This shows that purchasing data–guided in-store tours do increase the efficacy of dietary education,” Dr. Steen said.
The difference in scores between the strategy 1 and strategy 2 groups was also significant (P = .01). “This shows online enhancements increase adherence to the DASH diet even further,” Dr. Steen commented
By 6 months, the scores had dropped off a little but were still increased from baseline: by 4.4 points in the control group, 6.6 points in the strategy 1 group, and 8.4 points in the strategy 2 group. “There was again a stepwise increase as the intervention intensified, but there was no longer a significant difference between the interventions and control,” Dr. Steen noted.
Secondary endpoints included blood pressure and body mass index. Systolic blood pressure decreased slightly in all three groups: by 2.8 mm Hg in the control group, 6.6 mm Hg in the strategy 1 group, and 5.7 mm Hg in the strategy 2 group. Body mass index was reduced by 0.2, 0.4 and 0.8, respectively, but the between-group differences were not significant.
Dr. Steen said this is the first study of its kind to date in which scientific researchers collaborated with a large supermarket chain. He explained they also involved a primary care network so that health care utilization information will be available.
“We can the integrate retail-based health care information with traditional health care information. And we can start to look at downstream health care utilization and cost outcomes as well, which will be important as we start to think how to evolve the health care system,” he commented. “The hope is that we can get more scientists working with more retailers to really drive the evidence to shape the evolution of our health care system.”
Challenges ahead
Dr. Handberg pointed out there would be challenges in reaching the underserved population who do not shop at the major supermarkets. “We need to figure out how to get partnerships across the whole spectrum of grocery stores.”
She also noted that 3 months (the duration of the study intervention) was not much time to change the eating habits of a family. “Interventions may have to be a bit more intensive to get the change in blood pressure and weight that we would want to see.”
Dr Handberg hoped the major grocery store companies will see the opportunities in this approach. “Changing behavior is very complicated, and the key will be how to make people stick with the changes. But grocery stores are smart. They have got us going to their pharmacies, so getting us to see a dietitian is not that much of a stretch.”
Moderator of the ACC late-breaker session at which the study was presented, Pamela Morris, MD, from the Medical University of South Carolina, Charleston, who is also ACC annual scientific session chair, asked whether the approach could be sustained.
“I am thinking back to the barber shop study of blood pressure treatment and to my knowledge those PharmDs are no longer in those barbershops, taking blood pressures, counseling patients, and prescribing antihypertensives. So is Kroger maintaining a long-term commitment to providing this education, or how can this be financed over the long term?” she asked.
Dr. Steen replied that he believed sustainability to be one of the key strengths of this model. “Retail-based health care is exploding in the U.S. The number of retail outlets offering a comprehensive list of services is going up all the time. These programs exist regardless of whether this trial was conducted or not.”
But Dr. Steen stressed that having an evidence base will be critically important.
“Validation is an enormous part of this evolution in retail-based health care – not only to figure out what works but also to engage payors and others in the process of supporting these interventions. I think the sustainability is there – it is sort of baked into the model – but research will be a huge part of cementing this in and helping us to understand what we should do.”
The study was funded by Kroger. Dr. Steen is a consultant for Sanofi and CEO and cofounder of High Enroll.
A version of this article first appeared on Medscape.com.
People who received personalized nutrition education in a series of sessions at their regular grocery store significantly improved adherence to a healthy diet, in a new “first-of-its-kind” study in which scientific researchers partnered with a large supermarket company.
In the SuperWIN study, participants were given individualized advice from supermarket-based dietitians using data on their own buying habits recorded on their supermarket loyalty cards. This was associated with an increased adherence to the DASH (Dietary Approaches to Stop Hypertension) diet, which emphasizes vegetables, fruits and whole grains while limiting foods that are high in saturated fat, sugar, and sodium and has been shown to lower blood pressure and LDL cholesterol.
One group of patients also received additional education about healthy eating and meal planning through online technologies, and this group showed even better adherence to the DASH diet.
The study was presented at the annual scientific sessions of the American College of Cardiology by Dylan Steen, MD, adjunct associate professor of medicine at the University of Cincinnati.
“The SuperWIN study provides evidence for the benefit of delivering healthy-eating interventions at modern supermarkets and retail-based clinics,” Dr. Steen said. “It demonstrates the efficacy of dietary interventions harnessing the physical environment of the supermarket, the retail-based dietitians working within the store, and the purchasing data captured on the store’s loyalty cards.”
The study was conducted in partnership with Kroger, the largest supermarket chain in the United States, which also operates a large chain of pharmacies and health clinics.
Dr. Steen said the study was addressing one of the biggest public health problems – unhealthy eating – with an innovative approach. “We need to think about how we can extend the reach of modern health care systems into communities and better deliver services right where people are; meet them where they live,” he said at an ACC press conference.
Commenting on the study at the press conference, Eileen Handberg, PhD, professor of medicine at University of Florida, Gainesville, and immediate past chair of the ACC Cardiovascular Care Team Council, said: “I am amazingly excited about this. There is so much potential here. We have never really taken advantage of the current explosion in retail-based health care before.”
Dr. Handberg suggested the study had major implications for the primary prevention of cardiovascular disease. “Little kids go shopping with their parents, so you have the ability here to change behavior from children on up if you can change the dynamic of the choices they make in the grocery store.”
In his presentation, Dr. Steen noted that, despite many longstanding guidelines on healthy eating, about 75% of Americans still have a poor-quality diet. This trial was conducted to see if a new approach could improve that situation. “If we change the environment in which we deliver dietary education, we can make a difference.”
The SuperWIN trial was conducted in 13 Kroger stores in Ohio and Kentucky. The study enrolled 267 people with at least one cardiovascular risk factor from a primary care network who regularly shopped at one of the study stores. All participants also had to be willing to follow the DASH diet, which was taught at each educational session in the trial.
All participants received one “enhanced” medical nutrition therapy that was guided by the individual’s own dietary intake analytics.
They were then randomly assigned to one of three arms. The control group received no further education. The strategy 1 group received six additional teaching sessions in the supermarket aisles over a 3-month period. Each session was guided by updated individualized purchasing data provided to the dietitian and the participant.
The strategy 2 group received the same six additional teaching sessions as strategy 1, but they also had some additional teaching on healthy eating and meal planning from a variety of online shopping tools, and nutrition and health care apps.
“The supermarket analytics were automatically collected so the dietitians could tell what each person liked to eat, how much of each product they were buying and how much they were spending,” Dr. Steen explained.
COVID hit halfway through the trial, and 20 participants were withdrawn for their own safety as they could no longer visit the stores, but the trial continued with the rest of the participants with enhanced safety precautions. The overall analysis cohort was 247 participants.
The average age of the participants was mid-50s, around 70% were female, and most did not have a history of cardiovascular disease.
Eating habits were assessed by three 24-hour dietary recalls assessed at the start of the study and at 3 and 6 months. The DASH score, which is a measure of adherence to the DASH diet, was calculated from this information. The score can range from 0 to 90, with an increased score showing increased adherence.
In one analysis, the researchers compared the DASH scores from the two intervention groups together with the control group, and in a second analysis they compared the scores in the strategy 2 group with those in the strategy 1 group.
Before the pandemic there was “near 100%” attendance for the six visits over the 3-month study period, which Dr. Steen said he thought was “remarkable.” During the pandemic, attendance came down to around 80%.
Results showed that the DASH score increased in all three groups at 3 months, with stepwise increases corresponding to the intensity of the intervention. DASH scores increased by 5.8 points in the control group, by 8.6 points in the strategy 1 group, and by 12.4 points in the strategy 2 group.
DASH scores significantly differed between the two intervention groups and the control group (P = .02). “This shows that purchasing data–guided in-store tours do increase the efficacy of dietary education,” Dr. Steen said.
The difference in scores between the strategy 1 and strategy 2 groups was also significant (P = .01). “This shows online enhancements increase adherence to the DASH diet even further,” Dr. Steen commented
By 6 months, the scores had dropped off a little but were still increased from baseline: by 4.4 points in the control group, 6.6 points in the strategy 1 group, and 8.4 points in the strategy 2 group. “There was again a stepwise increase as the intervention intensified, but there was no longer a significant difference between the interventions and control,” Dr. Steen noted.
Secondary endpoints included blood pressure and body mass index. Systolic blood pressure decreased slightly in all three groups: by 2.8 mm Hg in the control group, 6.6 mm Hg in the strategy 1 group, and 5.7 mm Hg in the strategy 2 group. Body mass index was reduced by 0.2, 0.4 and 0.8, respectively, but the between-group differences were not significant.
Dr. Steen said this is the first study of its kind to date in which scientific researchers collaborated with a large supermarket chain. He explained they also involved a primary care network so that health care utilization information will be available.
“We can the integrate retail-based health care information with traditional health care information. And we can start to look at downstream health care utilization and cost outcomes as well, which will be important as we start to think how to evolve the health care system,” he commented. “The hope is that we can get more scientists working with more retailers to really drive the evidence to shape the evolution of our health care system.”
Challenges ahead
Dr. Handberg pointed out there would be challenges in reaching the underserved population who do not shop at the major supermarkets. “We need to figure out how to get partnerships across the whole spectrum of grocery stores.”
She also noted that 3 months (the duration of the study intervention) was not much time to change the eating habits of a family. “Interventions may have to be a bit more intensive to get the change in blood pressure and weight that we would want to see.”
Dr Handberg hoped the major grocery store companies will see the opportunities in this approach. “Changing behavior is very complicated, and the key will be how to make people stick with the changes. But grocery stores are smart. They have got us going to their pharmacies, so getting us to see a dietitian is not that much of a stretch.”
Moderator of the ACC late-breaker session at which the study was presented, Pamela Morris, MD, from the Medical University of South Carolina, Charleston, who is also ACC annual scientific session chair, asked whether the approach could be sustained.
“I am thinking back to the barber shop study of blood pressure treatment and to my knowledge those PharmDs are no longer in those barbershops, taking blood pressures, counseling patients, and prescribing antihypertensives. So is Kroger maintaining a long-term commitment to providing this education, or how can this be financed over the long term?” she asked.
Dr. Steen replied that he believed sustainability to be one of the key strengths of this model. “Retail-based health care is exploding in the U.S. The number of retail outlets offering a comprehensive list of services is going up all the time. These programs exist regardless of whether this trial was conducted or not.”
But Dr. Steen stressed that having an evidence base will be critically important.
“Validation is an enormous part of this evolution in retail-based health care – not only to figure out what works but also to engage payors and others in the process of supporting these interventions. I think the sustainability is there – it is sort of baked into the model – but research will be a huge part of cementing this in and helping us to understand what we should do.”
The study was funded by Kroger. Dr. Steen is a consultant for Sanofi and CEO and cofounder of High Enroll.
A version of this article first appeared on Medscape.com.
People who received personalized nutrition education in a series of sessions at their regular grocery store significantly improved adherence to a healthy diet, in a new “first-of-its-kind” study in which scientific researchers partnered with a large supermarket company.
In the SuperWIN study, participants were given individualized advice from supermarket-based dietitians using data on their own buying habits recorded on their supermarket loyalty cards. This was associated with an increased adherence to the DASH (Dietary Approaches to Stop Hypertension) diet, which emphasizes vegetables, fruits and whole grains while limiting foods that are high in saturated fat, sugar, and sodium and has been shown to lower blood pressure and LDL cholesterol.
One group of patients also received additional education about healthy eating and meal planning through online technologies, and this group showed even better adherence to the DASH diet.
The study was presented at the annual scientific sessions of the American College of Cardiology by Dylan Steen, MD, adjunct associate professor of medicine at the University of Cincinnati.
“The SuperWIN study provides evidence for the benefit of delivering healthy-eating interventions at modern supermarkets and retail-based clinics,” Dr. Steen said. “It demonstrates the efficacy of dietary interventions harnessing the physical environment of the supermarket, the retail-based dietitians working within the store, and the purchasing data captured on the store’s loyalty cards.”
The study was conducted in partnership with Kroger, the largest supermarket chain in the United States, which also operates a large chain of pharmacies and health clinics.
Dr. Steen said the study was addressing one of the biggest public health problems – unhealthy eating – with an innovative approach. “We need to think about how we can extend the reach of modern health care systems into communities and better deliver services right where people are; meet them where they live,” he said at an ACC press conference.
Commenting on the study at the press conference, Eileen Handberg, PhD, professor of medicine at University of Florida, Gainesville, and immediate past chair of the ACC Cardiovascular Care Team Council, said: “I am amazingly excited about this. There is so much potential here. We have never really taken advantage of the current explosion in retail-based health care before.”
Dr. Handberg suggested the study had major implications for the primary prevention of cardiovascular disease. “Little kids go shopping with their parents, so you have the ability here to change behavior from children on up if you can change the dynamic of the choices they make in the grocery store.”
In his presentation, Dr. Steen noted that, despite many longstanding guidelines on healthy eating, about 75% of Americans still have a poor-quality diet. This trial was conducted to see if a new approach could improve that situation. “If we change the environment in which we deliver dietary education, we can make a difference.”
The SuperWIN trial was conducted in 13 Kroger stores in Ohio and Kentucky. The study enrolled 267 people with at least one cardiovascular risk factor from a primary care network who regularly shopped at one of the study stores. All participants also had to be willing to follow the DASH diet, which was taught at each educational session in the trial.
All participants received one “enhanced” medical nutrition therapy that was guided by the individual’s own dietary intake analytics.
They were then randomly assigned to one of three arms. The control group received no further education. The strategy 1 group received six additional teaching sessions in the supermarket aisles over a 3-month period. Each session was guided by updated individualized purchasing data provided to the dietitian and the participant.
The strategy 2 group received the same six additional teaching sessions as strategy 1, but they also had some additional teaching on healthy eating and meal planning from a variety of online shopping tools, and nutrition and health care apps.
“The supermarket analytics were automatically collected so the dietitians could tell what each person liked to eat, how much of each product they were buying and how much they were spending,” Dr. Steen explained.
COVID hit halfway through the trial, and 20 participants were withdrawn for their own safety as they could no longer visit the stores, but the trial continued with the rest of the participants with enhanced safety precautions. The overall analysis cohort was 247 participants.
The average age of the participants was mid-50s, around 70% were female, and most did not have a history of cardiovascular disease.
Eating habits were assessed by three 24-hour dietary recalls assessed at the start of the study and at 3 and 6 months. The DASH score, which is a measure of adherence to the DASH diet, was calculated from this information. The score can range from 0 to 90, with an increased score showing increased adherence.
In one analysis, the researchers compared the DASH scores from the two intervention groups together with the control group, and in a second analysis they compared the scores in the strategy 2 group with those in the strategy 1 group.
Before the pandemic there was “near 100%” attendance for the six visits over the 3-month study period, which Dr. Steen said he thought was “remarkable.” During the pandemic, attendance came down to around 80%.
Results showed that the DASH score increased in all three groups at 3 months, with stepwise increases corresponding to the intensity of the intervention. DASH scores increased by 5.8 points in the control group, by 8.6 points in the strategy 1 group, and by 12.4 points in the strategy 2 group.
DASH scores significantly differed between the two intervention groups and the control group (P = .02). “This shows that purchasing data–guided in-store tours do increase the efficacy of dietary education,” Dr. Steen said.
The difference in scores between the strategy 1 and strategy 2 groups was also significant (P = .01). “This shows online enhancements increase adherence to the DASH diet even further,” Dr. Steen commented
By 6 months, the scores had dropped off a little but were still increased from baseline: by 4.4 points in the control group, 6.6 points in the strategy 1 group, and 8.4 points in the strategy 2 group. “There was again a stepwise increase as the intervention intensified, but there was no longer a significant difference between the interventions and control,” Dr. Steen noted.
Secondary endpoints included blood pressure and body mass index. Systolic blood pressure decreased slightly in all three groups: by 2.8 mm Hg in the control group, 6.6 mm Hg in the strategy 1 group, and 5.7 mm Hg in the strategy 2 group. Body mass index was reduced by 0.2, 0.4 and 0.8, respectively, but the between-group differences were not significant.
Dr. Steen said this is the first study of its kind to date in which scientific researchers collaborated with a large supermarket chain. He explained they also involved a primary care network so that health care utilization information will be available.
“We can the integrate retail-based health care information with traditional health care information. And we can start to look at downstream health care utilization and cost outcomes as well, which will be important as we start to think how to evolve the health care system,” he commented. “The hope is that we can get more scientists working with more retailers to really drive the evidence to shape the evolution of our health care system.”
Challenges ahead
Dr. Handberg pointed out there would be challenges in reaching the underserved population who do not shop at the major supermarkets. “We need to figure out how to get partnerships across the whole spectrum of grocery stores.”
She also noted that 3 months (the duration of the study intervention) was not much time to change the eating habits of a family. “Interventions may have to be a bit more intensive to get the change in blood pressure and weight that we would want to see.”
Dr Handberg hoped the major grocery store companies will see the opportunities in this approach. “Changing behavior is very complicated, and the key will be how to make people stick with the changes. But grocery stores are smart. They have got us going to their pharmacies, so getting us to see a dietitian is not that much of a stretch.”
Moderator of the ACC late-breaker session at which the study was presented, Pamela Morris, MD, from the Medical University of South Carolina, Charleston, who is also ACC annual scientific session chair, asked whether the approach could be sustained.
“I am thinking back to the barber shop study of blood pressure treatment and to my knowledge those PharmDs are no longer in those barbershops, taking blood pressures, counseling patients, and prescribing antihypertensives. So is Kroger maintaining a long-term commitment to providing this education, or how can this be financed over the long term?” she asked.
Dr. Steen replied that he believed sustainability to be one of the key strengths of this model. “Retail-based health care is exploding in the U.S. The number of retail outlets offering a comprehensive list of services is going up all the time. These programs exist regardless of whether this trial was conducted or not.”
But Dr. Steen stressed that having an evidence base will be critically important.
“Validation is an enormous part of this evolution in retail-based health care – not only to figure out what works but also to engage payors and others in the process of supporting these interventions. I think the sustainability is there – it is sort of baked into the model – but research will be a huge part of cementing this in and helping us to understand what we should do.”
The study was funded by Kroger. Dr. Steen is a consultant for Sanofi and CEO and cofounder of High Enroll.
A version of this article first appeared on Medscape.com.
FROM ACC 2022
Novel cholesterol drug disappoints: TRANSLATE-TIMI 70
An investigational drug targeting a novel cholesterol pathway has shown disappointing results in the TRANSLATE-TIMI 70 phase 2b study.
Vupanorsen is an antisense oligonucleotide targeting hepatic angiopoietin-like protein 3 (ANGPTL3), a protein that inhibits enzymes involved in the metabolism of triglyceride and cholesterol. Inhibition of ANGPTL3 is one of several novel targets for lowering triglycerides and non-HDL cholesterol.
Results of the TRANSLATE-TIMI 70 study were presented at the annual scientific sessions of the American College of Cardiology by Brian Bergmark, MD, a cardiologist at Brigham and Women’s Hospital, Boston. They were also simultaneously published online in Circulation.
“While vupanorsen significantly reduced triglycerides and non-HDL cholesterol, the reduction in non-HDL cholesterol of 22%-27% was not to a degree that was clinically meaningful for cardiovascular risk reduction, and there were also some potentially important safety issues,” Dr. Bergmark said in an interview.
Pfizer has announced that, after reviewing the results of this study, it is discontinuing development of vupanorsen and will return rights to Ionis, from which it licensed the investigational therapy in 2019.
In response to a question at an ACC press conference on whether there could be any future for the drug, Dr. Bergmark said that “the degree of lipid lowering was not as much as what had been suggested was potentially possible by acting on this pathway, and then there are the additional safety concerns. So, for the specific question of what we were looking at – cardiovascular risk reduction by impacting non-HDL cholesterol and apo [apolipoprotein] B – the modest efficacy paired with the safety concerns does not look favorable for future development of this drug.”
But he added: “Whether some other person or company wants to think about triglyceride lowering and try to find a dose that is a bit safer, that is not for me to say.”
In his ACC presentation, Dr. Bergmark explained that ANGPTL3 is a protein secreted by the liver that inhibits lipases, including lipoprotein lipase. Loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids and a monoclonal antibody targeting ANGPTL3, evinacumab (Evkeeza, Regeneron), is approved as an intravenous infusion for the treatment of familial hypercholesterolemia. Vupanorsen is a second-generation antisense oligonucleotide targeting hepatic ANGPTL3 messenger RNA with a potential role for cardiovascular risk reduction.
A previous phase 2a study of vupanorsen in patients with hypertriglyceridemia, hepatic steatosis, and type 2 diabetes mellitus showed significant reductions in triglycerides at all doses studied, as well as reductions in non-HDL cholesterol at the highest doses (80 mg per month given by subcutaneous injection).
Dr. Bergmark noted that, because a potential cardiovascular benefit of vupanorsen would best be reflected by its effects on non-HDL cholesterol, the current TRANSLATE-TIMI 70 trial was designed to assess the effect of escalating doses of vupanorsen on non-HDL cholesterol levels in statin-treated adults with hyperlipidemia.
For the study, 286 adults with non-HDL cholesterol levels of 100 mg/dL or greater (median, 132 mg/dL) and triglyceride levels of 150-500 mg/dL (median, 216 mg/dL) who were receiving statin therapy were randomly assigned to placebo or one of seven vupanorsen dose regimens (80, 120, or 160 mg every 4 weeks or 60, 80, 120, or 160 mg every 2 weeks). All doses were given by subcutaneous injection.
The study population was said to reflect “a typical cohort intended for cardiovascular risk reduction, with type 2 diabetes in approximately one-half of patients and prevalent atherosclerotic cardiovascular disease in a substantial portion,” the researchers wrote in the published report.
The primary endpoint was placebo-adjusted percentage change from baseline in non-HDL cholesterol at 24 weeks. Secondary endpoints included placebo-adjusted percentage changes from baseline in triglycerides, LDL cholesterol, apo B, and ANGPTL3.
Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL cholesterol ranging from 22.0% in the group receiving 60 mg every 2 weeks to 27.7% in the group receiving 80 mg every 2 weeks, but there did not appear to be a dose response.
Regarding additional lipid endpoints, vupanorsen reduced triglyceride levels in a dose-dependent manner, ranging from 41.3% in the group receiving 120 mg every 4 weeks to 56.8% in the group receiving 160 mg every 2 weeks.
The effects of vupanorsen on LDL cholesterol and apo B were more modest and without a clear dose response. Vupanorsen also lowered HDL cholesterol levels at all doses studied, and there was no significant change in high-sensitivity C-reactive protein at any dose.
Liver enzymes and hepatic fat increases of concern
In terms of safety, vupanorsen treatment was linked to liver enzyme elevations; more than three-times elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively). Injection site reactions were also an issue, including recall reactions at sites of previous injections when subsequent injections were given. In addition, there was a dose-related increase (up to 76%) in hepatic fat fraction.
In the Circulation paper, the researchers say it is unclear whether the increases in hepatic fat fraction and liver enzymes reflect a metabolic effect of vupanorsen specifically or an off-target effect resulting from hepatic targeting of ANGPTL3. “Regardless, these are medically meaningful findings with important safety ramifications,” they wrote.
They pointed out that, whereas the reduction in ANGPTL3 levels increased with total monthly dose of vupanorsen, there was no clear dose-response reduction in LDL cholesterol, apo B, or non-HDL cholesterol.
In comparison, evinacumab, a monoclonal antibody against ANGPTL3 that is thought to cause near-total suppression of ANGPTL3 activity, reduces apo B levels by more than 40% in adults with refractory hypercholesterolemia or homozygous familial hypercholesterolemia.
Asked why vupanorsen showed less of an effect on non-HDL cholesterol than evinacumab, Dr. Bergmark suggested that the monoclonal antibody may achieve greater inhibition of ANGPTL3. “It may be that near complete suppression is needed to obtain clinically meaningful reductions in apo B and non-HDL cholesterol. That is a speculative and simplistic explanation,” he commented.
Conversely, reductions in triglycerides with vupanorsen showed a dose-response relationship, mirroring the reduction in ANGPTL3 and consistent with the expected increases in lipoprotein lipase activity, the researchers reported.
They note that the “relatively muted effect on apo B levels” suggests that vupanorsen is primarily decreasing the triglyceride and, to a lesser extent, cholesterol content of very low-density lipoprotein cholesterol particles rather than reducing the number of such particles.
“These observations have important implications for the potential ability of this mechanism to reduce lipid-mediated cardiovascular risk, which largely appears to be a function of the number of ApoB-containing lipoproteins,” they said.
Designated discussant of the study at the ACC late-breaking session, Pradeep Natarajan, MD, director of preventive cardiology at Massachusetts General Hospital in Boston, asked Dr. Bergmark what minimum degree of non-HDL cholesterol reduction would be compelling for a new drug to be considered for wide-scale use.
Dr. Bergmark replied there was no clear to answer to that question, as it would depend on many factors, including the risk of the population and the time horizon involved. But he added: “I think a minimum of at least a 30%-40% reduction in non-HDL cholesterol would be needed for a meaningful reduction in cardiovascular risk across a variety of settings.”
The TRANSLATE-TIMI 70 study was funded by Pfizer. Dr. Bergmark is a member of the TIMI Study Group, which has received institutional grant support through Brigham and Women’s Hospital from numerous pharmaceutical companies. Dr. Bergmark also reported receiving grant support through Brigham and Women’s Hospital from Pfizer, Ionis, AstraZeneca, and Abbott Vascular and consulting/personal fees from Abiomed, CSI, Philips, Abbott Vascular, Servier, DaiichiSankyo, Janssen, and Quark.
A version of this article first appeared on Medscape.com.
An investigational drug targeting a novel cholesterol pathway has shown disappointing results in the TRANSLATE-TIMI 70 phase 2b study.
Vupanorsen is an antisense oligonucleotide targeting hepatic angiopoietin-like protein 3 (ANGPTL3), a protein that inhibits enzymes involved in the metabolism of triglyceride and cholesterol. Inhibition of ANGPTL3 is one of several novel targets for lowering triglycerides and non-HDL cholesterol.
Results of the TRANSLATE-TIMI 70 study were presented at the annual scientific sessions of the American College of Cardiology by Brian Bergmark, MD, a cardiologist at Brigham and Women’s Hospital, Boston. They were also simultaneously published online in Circulation.
“While vupanorsen significantly reduced triglycerides and non-HDL cholesterol, the reduction in non-HDL cholesterol of 22%-27% was not to a degree that was clinically meaningful for cardiovascular risk reduction, and there were also some potentially important safety issues,” Dr. Bergmark said in an interview.
Pfizer has announced that, after reviewing the results of this study, it is discontinuing development of vupanorsen and will return rights to Ionis, from which it licensed the investigational therapy in 2019.
In response to a question at an ACC press conference on whether there could be any future for the drug, Dr. Bergmark said that “the degree of lipid lowering was not as much as what had been suggested was potentially possible by acting on this pathway, and then there are the additional safety concerns. So, for the specific question of what we were looking at – cardiovascular risk reduction by impacting non-HDL cholesterol and apo [apolipoprotein] B – the modest efficacy paired with the safety concerns does not look favorable for future development of this drug.”
But he added: “Whether some other person or company wants to think about triglyceride lowering and try to find a dose that is a bit safer, that is not for me to say.”
In his ACC presentation, Dr. Bergmark explained that ANGPTL3 is a protein secreted by the liver that inhibits lipases, including lipoprotein lipase. Loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids and a monoclonal antibody targeting ANGPTL3, evinacumab (Evkeeza, Regeneron), is approved as an intravenous infusion for the treatment of familial hypercholesterolemia. Vupanorsen is a second-generation antisense oligonucleotide targeting hepatic ANGPTL3 messenger RNA with a potential role for cardiovascular risk reduction.
A previous phase 2a study of vupanorsen in patients with hypertriglyceridemia, hepatic steatosis, and type 2 diabetes mellitus showed significant reductions in triglycerides at all doses studied, as well as reductions in non-HDL cholesterol at the highest doses (80 mg per month given by subcutaneous injection).
Dr. Bergmark noted that, because a potential cardiovascular benefit of vupanorsen would best be reflected by its effects on non-HDL cholesterol, the current TRANSLATE-TIMI 70 trial was designed to assess the effect of escalating doses of vupanorsen on non-HDL cholesterol levels in statin-treated adults with hyperlipidemia.
For the study, 286 adults with non-HDL cholesterol levels of 100 mg/dL or greater (median, 132 mg/dL) and triglyceride levels of 150-500 mg/dL (median, 216 mg/dL) who were receiving statin therapy were randomly assigned to placebo or one of seven vupanorsen dose regimens (80, 120, or 160 mg every 4 weeks or 60, 80, 120, or 160 mg every 2 weeks). All doses were given by subcutaneous injection.
The study population was said to reflect “a typical cohort intended for cardiovascular risk reduction, with type 2 diabetes in approximately one-half of patients and prevalent atherosclerotic cardiovascular disease in a substantial portion,” the researchers wrote in the published report.
The primary endpoint was placebo-adjusted percentage change from baseline in non-HDL cholesterol at 24 weeks. Secondary endpoints included placebo-adjusted percentage changes from baseline in triglycerides, LDL cholesterol, apo B, and ANGPTL3.
Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL cholesterol ranging from 22.0% in the group receiving 60 mg every 2 weeks to 27.7% in the group receiving 80 mg every 2 weeks, but there did not appear to be a dose response.
Regarding additional lipid endpoints, vupanorsen reduced triglyceride levels in a dose-dependent manner, ranging from 41.3% in the group receiving 120 mg every 4 weeks to 56.8% in the group receiving 160 mg every 2 weeks.
The effects of vupanorsen on LDL cholesterol and apo B were more modest and without a clear dose response. Vupanorsen also lowered HDL cholesterol levels at all doses studied, and there was no significant change in high-sensitivity C-reactive protein at any dose.
Liver enzymes and hepatic fat increases of concern
In terms of safety, vupanorsen treatment was linked to liver enzyme elevations; more than three-times elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively). Injection site reactions were also an issue, including recall reactions at sites of previous injections when subsequent injections were given. In addition, there was a dose-related increase (up to 76%) in hepatic fat fraction.
In the Circulation paper, the researchers say it is unclear whether the increases in hepatic fat fraction and liver enzymes reflect a metabolic effect of vupanorsen specifically or an off-target effect resulting from hepatic targeting of ANGPTL3. “Regardless, these are medically meaningful findings with important safety ramifications,” they wrote.
They pointed out that, whereas the reduction in ANGPTL3 levels increased with total monthly dose of vupanorsen, there was no clear dose-response reduction in LDL cholesterol, apo B, or non-HDL cholesterol.
In comparison, evinacumab, a monoclonal antibody against ANGPTL3 that is thought to cause near-total suppression of ANGPTL3 activity, reduces apo B levels by more than 40% in adults with refractory hypercholesterolemia or homozygous familial hypercholesterolemia.
Asked why vupanorsen showed less of an effect on non-HDL cholesterol than evinacumab, Dr. Bergmark suggested that the monoclonal antibody may achieve greater inhibition of ANGPTL3. “It may be that near complete suppression is needed to obtain clinically meaningful reductions in apo B and non-HDL cholesterol. That is a speculative and simplistic explanation,” he commented.
Conversely, reductions in triglycerides with vupanorsen showed a dose-response relationship, mirroring the reduction in ANGPTL3 and consistent with the expected increases in lipoprotein lipase activity, the researchers reported.
They note that the “relatively muted effect on apo B levels” suggests that vupanorsen is primarily decreasing the triglyceride and, to a lesser extent, cholesterol content of very low-density lipoprotein cholesterol particles rather than reducing the number of such particles.
“These observations have important implications for the potential ability of this mechanism to reduce lipid-mediated cardiovascular risk, which largely appears to be a function of the number of ApoB-containing lipoproteins,” they said.
Designated discussant of the study at the ACC late-breaking session, Pradeep Natarajan, MD, director of preventive cardiology at Massachusetts General Hospital in Boston, asked Dr. Bergmark what minimum degree of non-HDL cholesterol reduction would be compelling for a new drug to be considered for wide-scale use.
Dr. Bergmark replied there was no clear to answer to that question, as it would depend on many factors, including the risk of the population and the time horizon involved. But he added: “I think a minimum of at least a 30%-40% reduction in non-HDL cholesterol would be needed for a meaningful reduction in cardiovascular risk across a variety of settings.”
The TRANSLATE-TIMI 70 study was funded by Pfizer. Dr. Bergmark is a member of the TIMI Study Group, which has received institutional grant support through Brigham and Women’s Hospital from numerous pharmaceutical companies. Dr. Bergmark also reported receiving grant support through Brigham and Women’s Hospital from Pfizer, Ionis, AstraZeneca, and Abbott Vascular and consulting/personal fees from Abiomed, CSI, Philips, Abbott Vascular, Servier, DaiichiSankyo, Janssen, and Quark.
A version of this article first appeared on Medscape.com.
An investigational drug targeting a novel cholesterol pathway has shown disappointing results in the TRANSLATE-TIMI 70 phase 2b study.
Vupanorsen is an antisense oligonucleotide targeting hepatic angiopoietin-like protein 3 (ANGPTL3), a protein that inhibits enzymes involved in the metabolism of triglyceride and cholesterol. Inhibition of ANGPTL3 is one of several novel targets for lowering triglycerides and non-HDL cholesterol.
Results of the TRANSLATE-TIMI 70 study were presented at the annual scientific sessions of the American College of Cardiology by Brian Bergmark, MD, a cardiologist at Brigham and Women’s Hospital, Boston. They were also simultaneously published online in Circulation.
“While vupanorsen significantly reduced triglycerides and non-HDL cholesterol, the reduction in non-HDL cholesterol of 22%-27% was not to a degree that was clinically meaningful for cardiovascular risk reduction, and there were also some potentially important safety issues,” Dr. Bergmark said in an interview.
Pfizer has announced that, after reviewing the results of this study, it is discontinuing development of vupanorsen and will return rights to Ionis, from which it licensed the investigational therapy in 2019.
In response to a question at an ACC press conference on whether there could be any future for the drug, Dr. Bergmark said that “the degree of lipid lowering was not as much as what had been suggested was potentially possible by acting on this pathway, and then there are the additional safety concerns. So, for the specific question of what we were looking at – cardiovascular risk reduction by impacting non-HDL cholesterol and apo [apolipoprotein] B – the modest efficacy paired with the safety concerns does not look favorable for future development of this drug.”
But he added: “Whether some other person or company wants to think about triglyceride lowering and try to find a dose that is a bit safer, that is not for me to say.”
In his ACC presentation, Dr. Bergmark explained that ANGPTL3 is a protein secreted by the liver that inhibits lipases, including lipoprotein lipase. Loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids and a monoclonal antibody targeting ANGPTL3, evinacumab (Evkeeza, Regeneron), is approved as an intravenous infusion for the treatment of familial hypercholesterolemia. Vupanorsen is a second-generation antisense oligonucleotide targeting hepatic ANGPTL3 messenger RNA with a potential role for cardiovascular risk reduction.
A previous phase 2a study of vupanorsen in patients with hypertriglyceridemia, hepatic steatosis, and type 2 diabetes mellitus showed significant reductions in triglycerides at all doses studied, as well as reductions in non-HDL cholesterol at the highest doses (80 mg per month given by subcutaneous injection).
Dr. Bergmark noted that, because a potential cardiovascular benefit of vupanorsen would best be reflected by its effects on non-HDL cholesterol, the current TRANSLATE-TIMI 70 trial was designed to assess the effect of escalating doses of vupanorsen on non-HDL cholesterol levels in statin-treated adults with hyperlipidemia.
For the study, 286 adults with non-HDL cholesterol levels of 100 mg/dL or greater (median, 132 mg/dL) and triglyceride levels of 150-500 mg/dL (median, 216 mg/dL) who were receiving statin therapy were randomly assigned to placebo or one of seven vupanorsen dose regimens (80, 120, or 160 mg every 4 weeks or 60, 80, 120, or 160 mg every 2 weeks). All doses were given by subcutaneous injection.
The study population was said to reflect “a typical cohort intended for cardiovascular risk reduction, with type 2 diabetes in approximately one-half of patients and prevalent atherosclerotic cardiovascular disease in a substantial portion,” the researchers wrote in the published report.
The primary endpoint was placebo-adjusted percentage change from baseline in non-HDL cholesterol at 24 weeks. Secondary endpoints included placebo-adjusted percentage changes from baseline in triglycerides, LDL cholesterol, apo B, and ANGPTL3.
Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL cholesterol ranging from 22.0% in the group receiving 60 mg every 2 weeks to 27.7% in the group receiving 80 mg every 2 weeks, but there did not appear to be a dose response.
Regarding additional lipid endpoints, vupanorsen reduced triglyceride levels in a dose-dependent manner, ranging from 41.3% in the group receiving 120 mg every 4 weeks to 56.8% in the group receiving 160 mg every 2 weeks.
The effects of vupanorsen on LDL cholesterol and apo B were more modest and without a clear dose response. Vupanorsen also lowered HDL cholesterol levels at all doses studied, and there was no significant change in high-sensitivity C-reactive protein at any dose.
Liver enzymes and hepatic fat increases of concern
In terms of safety, vupanorsen treatment was linked to liver enzyme elevations; more than three-times elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively). Injection site reactions were also an issue, including recall reactions at sites of previous injections when subsequent injections were given. In addition, there was a dose-related increase (up to 76%) in hepatic fat fraction.
In the Circulation paper, the researchers say it is unclear whether the increases in hepatic fat fraction and liver enzymes reflect a metabolic effect of vupanorsen specifically or an off-target effect resulting from hepatic targeting of ANGPTL3. “Regardless, these are medically meaningful findings with important safety ramifications,” they wrote.
They pointed out that, whereas the reduction in ANGPTL3 levels increased with total monthly dose of vupanorsen, there was no clear dose-response reduction in LDL cholesterol, apo B, or non-HDL cholesterol.
In comparison, evinacumab, a monoclonal antibody against ANGPTL3 that is thought to cause near-total suppression of ANGPTL3 activity, reduces apo B levels by more than 40% in adults with refractory hypercholesterolemia or homozygous familial hypercholesterolemia.
Asked why vupanorsen showed less of an effect on non-HDL cholesterol than evinacumab, Dr. Bergmark suggested that the monoclonal antibody may achieve greater inhibition of ANGPTL3. “It may be that near complete suppression is needed to obtain clinically meaningful reductions in apo B and non-HDL cholesterol. That is a speculative and simplistic explanation,” he commented.
Conversely, reductions in triglycerides with vupanorsen showed a dose-response relationship, mirroring the reduction in ANGPTL3 and consistent with the expected increases in lipoprotein lipase activity, the researchers reported.
They note that the “relatively muted effect on apo B levels” suggests that vupanorsen is primarily decreasing the triglyceride and, to a lesser extent, cholesterol content of very low-density lipoprotein cholesterol particles rather than reducing the number of such particles.
“These observations have important implications for the potential ability of this mechanism to reduce lipid-mediated cardiovascular risk, which largely appears to be a function of the number of ApoB-containing lipoproteins,” they said.
Designated discussant of the study at the ACC late-breaking session, Pradeep Natarajan, MD, director of preventive cardiology at Massachusetts General Hospital in Boston, asked Dr. Bergmark what minimum degree of non-HDL cholesterol reduction would be compelling for a new drug to be considered for wide-scale use.
Dr. Bergmark replied there was no clear to answer to that question, as it would depend on many factors, including the risk of the population and the time horizon involved. But he added: “I think a minimum of at least a 30%-40% reduction in non-HDL cholesterol would be needed for a meaningful reduction in cardiovascular risk across a variety of settings.”
The TRANSLATE-TIMI 70 study was funded by Pfizer. Dr. Bergmark is a member of the TIMI Study Group, which has received institutional grant support through Brigham and Women’s Hospital from numerous pharmaceutical companies. Dr. Bergmark also reported receiving grant support through Brigham and Women’s Hospital from Pfizer, Ionis, AstraZeneca, and Abbott Vascular and consulting/personal fees from Abiomed, CSI, Philips, Abbott Vascular, Servier, DaiichiSankyo, Janssen, and Quark.
A version of this article first appeared on Medscape.com.
FROM ACC 2022