CAD & Atherosclerosis

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.

Peggy Peterson Photograph

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.

Peggy Peterson Photograph

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.

Peggy Peterson Photograph

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.


 

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.

Catherine Hackett/MDedge News

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.”

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.

Catherine Hackett/MDedge News

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.”

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.

Catherine Hackett/MDedge News

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.”

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.

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.

Catherine Hackett/MDedge News

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.

Catherine Hackett/MDedge News

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.

Catherine Hackett/MDedge News

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.

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.

In a randomized trial of patients with angina and no obstructive coronary artery disease (ANOCA), 6 weeks of treatment with diltiazem did not improve coronary vasomotor dysfunction – apart from epicardial spasm – or angina symptoms and quality of life. 

The trial investigated whether this therapy would improve these outcomes in patients with two mutually exclusive subgroups, or endotypes, of coronary vasomotor dysfunction: coronary artery spasm (epicardial spasm, microvascular spasm) or coronary microvascular dysfunction indicated by coronary flow reserve (CFR) and index of microvascular resistance (IMR) values.

Treatment success, the primary study endpoint – defined as normalization of one of the abnormal endotypes and no normal endotype becoming abnormal – was similar after treatment with diltiazem, compared with placebo. Nor were there significant differences for secondary endpoints apart from improvements in epicardial spasm in the two groups.

Tijn Jansen, MD, presented these findings from the EDIT-CMD trial in a featured clinical research session at the annual scientific sessions of the American College of Cardiology. The study was simultaneously published online April 2, 2022, in JACC: Cardiovascular Imaging.

“This first study using repeated coronary function testing provides a platform for future research,” concluded Dr. Jansen, a PhD candidate in the department of cardiology, Radboud University, Nijmegen, the Netherlands.

“We were surprised indeed” that diltiazem did not meet its primary endpoint for successful treatment and did not reduce symptoms or improve quality of life, compared with placebo, unlike results of the CorMicA trial, he said in an interview.

“We did find a treatment success, however, of 21%, which was slightly lower than expected, but it was not better than just giving placebo. This was similar regarding symptoms and quality of life, where we did find an overall improvement with diltiazem, but again not higher than using placebo,” he added. “It seems that giving the diagnosis to these patients itself creates a reduction in symptoms,” that might be caused by a reduction in stress, Dr. Jansen suggested.

The clinical implication, he said, is that more randomized controlled trials in this patient population are needed to permit evidence-based patient-tailored treatment, based on the different endotypes. “It might even be imaginable to test effectiveness in each individual patient using coronary function testing,” he said.

These tests are more and more commonly used in clinical practice, Dr. Jansen noted. “In the Netherlands, we recently launched the NL-CFT registry, which enables the participating centers to perform the CFT with a standardized protocol, with the goal to collect data and increase knowledge in this patient population.”

Heterogeneous population?

“I think probably the reason this trial was negative is [that coronary vasomotor dysfunction is] just too heterogeneous,” assigned discussant, C. Noel Bairey Merz, MD, commented.

First RCT of diltiazem in patients with ANOCA

Up to 40% of patients undergoing coronary angiography for stable angina do not have obstructive coronary artery disease (CAD), and 60%-90% of these patients have coronary vasomotor dysfunction, Dr. Jansen noted.

The landmark CorMicA trial showed that diagnosing the specific endotype of coronary vasomotor dysfunction using coronary function testing allows for tailored medication that decreased angina and improved quality of life, the researchers noted.

A recent European Society of Cardiology position paper on ANOCA “recommends the use of various pharmacological treatments including calcium-channel blockers, beta-blockers, ACE inhibitors, statins, and nitric oxide modulators, of which CCBs have the most prominent role in both endotypes of coronary vasospasms” and coronary microvascular dysfunction, they wrote.

“However, evidence substantiating these recommendations is lacking,” the researchers added, “since it is based on studies in a different population, with small sample sizes, or not placebo controlled.”

To investigate this, between 2019 and 2021, EDIT-CMD enrolled 126 adults aged 18 years and older who had two or more chronic angina episodes per week and no signs of obstructive CAD, who were seen at three hospitals specializing in ANOCA in the Netherlands.

The participants underwent coronary function testing that consisted of an acetylcholine spasm provocation test to evaluate for epicardial spasm and microvascular spasm, and a bolus thermodilution test with adenosine, to assess CFR and IMR. Coronary microvascular dysfunction was defined as CFR less than 2.0 and IMR of 25 or greater.

Of 99 patients with vasospasm or microvascular dysfunction, 85 patients were randomly assigned to receive diltiazem (n = 41) or placebo (n = 44) for 6 weeks.

The patients in both groups had a mean age of 58 years, and 29% were male; 22% had previously undergone percutaneous coronary intervention, and 48% had severe angina (Canadian Cardiovascular Society grade III/IV).

At baseline, about 50% had epicardial spasm, 25% had microvascular spasm and 25% had no spasm, and 54% in the diltiazem group and 73% in the placebo group had microvascular dysfunction.

After 6 weeks, 73 patients (35 in the placebo group and 38 in the diltiazem group) were available for repeat coronary function testing.

For the primary outcome, after 6 weeks of treatment, the proportion of patients with normalization of one abnormal parameter of coronary vasomotor dysfunction, without any normal parameter becoming abnormal, occurred in 8 patients (21%) in the diltiazem group versus 10 patients (29%) in the placebo group (P = .46)

In secondary outcomes, after 6 weeks of treatment, there were no significant differences in the prevalence of microvascular dysfunction, in Seattle Angina Questionnaire scores for angina symptoms, or RAND-36 scores for quality of life between patients who received diltiazem vs those who received placebo.

However, more patients in the diltiazem group than in the placebo group progressed from epicardial spasm to microvascular or no spasm (47% vs. 6%; P = .006).

The EDIT-CMD trial was sponsored by Abbott. Dr. Jansen has no relevant financial disclosures. Dr. Bairey Merz discloses having a fiduciary role and shares in iRhythm and being on the advisory board for Sanofi.

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

In a randomized trial of patients with angina and no obstructive coronary artery disease (ANOCA), 6 weeks of treatment with diltiazem did not improve coronary vasomotor dysfunction – apart from epicardial spasm – or angina symptoms and quality of life. 

The trial investigated whether this therapy would improve these outcomes in patients with two mutually exclusive subgroups, or endotypes, of coronary vasomotor dysfunction: coronary artery spasm (epicardial spasm, microvascular spasm) or coronary microvascular dysfunction indicated by coronary flow reserve (CFR) and index of microvascular resistance (IMR) values.

Treatment success, the primary study endpoint – defined as normalization of one of the abnormal endotypes and no normal endotype becoming abnormal – was similar after treatment with diltiazem, compared with placebo. Nor were there significant differences for secondary endpoints apart from improvements in epicardial spasm in the two groups.

Tijn Jansen, MD, presented these findings from the EDIT-CMD trial in a featured clinical research session at the annual scientific sessions of the American College of Cardiology. The study was simultaneously published online April 2, 2022, in JACC: Cardiovascular Imaging.

“This first study using repeated coronary function testing provides a platform for future research,” concluded Dr. Jansen, a PhD candidate in the department of cardiology, Radboud University, Nijmegen, the Netherlands.

“We were surprised indeed” that diltiazem did not meet its primary endpoint for successful treatment and did not reduce symptoms or improve quality of life, compared with placebo, unlike results of the CorMicA trial, he said in an interview.

“We did find a treatment success, however, of 21%, which was slightly lower than expected, but it was not better than just giving placebo. This was similar regarding symptoms and quality of life, where we did find an overall improvement with diltiazem, but again not higher than using placebo,” he added. “It seems that giving the diagnosis to these patients itself creates a reduction in symptoms,” that might be caused by a reduction in stress, Dr. Jansen suggested.

The clinical implication, he said, is that more randomized controlled trials in this patient population are needed to permit evidence-based patient-tailored treatment, based on the different endotypes. “It might even be imaginable to test effectiveness in each individual patient using coronary function testing,” he said.

These tests are more and more commonly used in clinical practice, Dr. Jansen noted. “In the Netherlands, we recently launched the NL-CFT registry, which enables the participating centers to perform the CFT with a standardized protocol, with the goal to collect data and increase knowledge in this patient population.”

Heterogeneous population?

“I think probably the reason this trial was negative is [that coronary vasomotor dysfunction is] just too heterogeneous,” assigned discussant, C. Noel Bairey Merz, MD, commented.

First RCT of diltiazem in patients with ANOCA

Up to 40% of patients undergoing coronary angiography for stable angina do not have obstructive coronary artery disease (CAD), and 60%-90% of these patients have coronary vasomotor dysfunction, Dr. Jansen noted.

The landmark CorMicA trial showed that diagnosing the specific endotype of coronary vasomotor dysfunction using coronary function testing allows for tailored medication that decreased angina and improved quality of life, the researchers noted.

A recent European Society of Cardiology position paper on ANOCA “recommends the use of various pharmacological treatments including calcium-channel blockers, beta-blockers, ACE inhibitors, statins, and nitric oxide modulators, of which CCBs have the most prominent role in both endotypes of coronary vasospasms” and coronary microvascular dysfunction, they wrote.

“However, evidence substantiating these recommendations is lacking,” the researchers added, “since it is based on studies in a different population, with small sample sizes, or not placebo controlled.”

To investigate this, between 2019 and 2021, EDIT-CMD enrolled 126 adults aged 18 years and older who had two or more chronic angina episodes per week and no signs of obstructive CAD, who were seen at three hospitals specializing in ANOCA in the Netherlands.

The participants underwent coronary function testing that consisted of an acetylcholine spasm provocation test to evaluate for epicardial spasm and microvascular spasm, and a bolus thermodilution test with adenosine, to assess CFR and IMR. Coronary microvascular dysfunction was defined as CFR less than 2.0 and IMR of 25 or greater.

Of 99 patients with vasospasm or microvascular dysfunction, 85 patients were randomly assigned to receive diltiazem (n = 41) or placebo (n = 44) for 6 weeks.

The patients in both groups had a mean age of 58 years, and 29% were male; 22% had previously undergone percutaneous coronary intervention, and 48% had severe angina (Canadian Cardiovascular Society grade III/IV).

At baseline, about 50% had epicardial spasm, 25% had microvascular spasm and 25% had no spasm, and 54% in the diltiazem group and 73% in the placebo group had microvascular dysfunction.

After 6 weeks, 73 patients (35 in the placebo group and 38 in the diltiazem group) were available for repeat coronary function testing.

For the primary outcome, after 6 weeks of treatment, the proportion of patients with normalization of one abnormal parameter of coronary vasomotor dysfunction, without any normal parameter becoming abnormal, occurred in 8 patients (21%) in the diltiazem group versus 10 patients (29%) in the placebo group (P = .46)

In secondary outcomes, after 6 weeks of treatment, there were no significant differences in the prevalence of microvascular dysfunction, in Seattle Angina Questionnaire scores for angina symptoms, or RAND-36 scores for quality of life between patients who received diltiazem vs those who received placebo.

However, more patients in the diltiazem group than in the placebo group progressed from epicardial spasm to microvascular or no spasm (47% vs. 6%; P = .006).

The EDIT-CMD trial was sponsored by Abbott. Dr. Jansen has no relevant financial disclosures. Dr. Bairey Merz discloses having a fiduciary role and shares in iRhythm and being on the advisory board for Sanofi.

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

In a randomized trial of patients with angina and no obstructive coronary artery disease (ANOCA), 6 weeks of treatment with diltiazem did not improve coronary vasomotor dysfunction – apart from epicardial spasm – or angina symptoms and quality of life. 

The trial investigated whether this therapy would improve these outcomes in patients with two mutually exclusive subgroups, or endotypes, of coronary vasomotor dysfunction: coronary artery spasm (epicardial spasm, microvascular spasm) or coronary microvascular dysfunction indicated by coronary flow reserve (CFR) and index of microvascular resistance (IMR) values.

Treatment success, the primary study endpoint – defined as normalization of one of the abnormal endotypes and no normal endotype becoming abnormal – was similar after treatment with diltiazem, compared with placebo. Nor were there significant differences for secondary endpoints apart from improvements in epicardial spasm in the two groups.

Tijn Jansen, MD, presented these findings from the EDIT-CMD trial in a featured clinical research session at the annual scientific sessions of the American College of Cardiology. The study was simultaneously published online April 2, 2022, in JACC: Cardiovascular Imaging.

“This first study using repeated coronary function testing provides a platform for future research,” concluded Dr. Jansen, a PhD candidate in the department of cardiology, Radboud University, Nijmegen, the Netherlands.

“We were surprised indeed” that diltiazem did not meet its primary endpoint for successful treatment and did not reduce symptoms or improve quality of life, compared with placebo, unlike results of the CorMicA trial, he said in an interview.

“We did find a treatment success, however, of 21%, which was slightly lower than expected, but it was not better than just giving placebo. This was similar regarding symptoms and quality of life, where we did find an overall improvement with diltiazem, but again not higher than using placebo,” he added. “It seems that giving the diagnosis to these patients itself creates a reduction in symptoms,” that might be caused by a reduction in stress, Dr. Jansen suggested.

The clinical implication, he said, is that more randomized controlled trials in this patient population are needed to permit evidence-based patient-tailored treatment, based on the different endotypes. “It might even be imaginable to test effectiveness in each individual patient using coronary function testing,” he said.

These tests are more and more commonly used in clinical practice, Dr. Jansen noted. “In the Netherlands, we recently launched the NL-CFT registry, which enables the participating centers to perform the CFT with a standardized protocol, with the goal to collect data and increase knowledge in this patient population.”

Heterogeneous population?

“I think probably the reason this trial was negative is [that coronary vasomotor dysfunction is] just too heterogeneous,” assigned discussant, C. Noel Bairey Merz, MD, commented.

First RCT of diltiazem in patients with ANOCA

Up to 40% of patients undergoing coronary angiography for stable angina do not have obstructive coronary artery disease (CAD), and 60%-90% of these patients have coronary vasomotor dysfunction, Dr. Jansen noted.

The landmark CorMicA trial showed that diagnosing the specific endotype of coronary vasomotor dysfunction using coronary function testing allows for tailored medication that decreased angina and improved quality of life, the researchers noted.

A recent European Society of Cardiology position paper on ANOCA “recommends the use of various pharmacological treatments including calcium-channel blockers, beta-blockers, ACE inhibitors, statins, and nitric oxide modulators, of which CCBs have the most prominent role in both endotypes of coronary vasospasms” and coronary microvascular dysfunction, they wrote.

“However, evidence substantiating these recommendations is lacking,” the researchers added, “since it is based on studies in a different population, with small sample sizes, or not placebo controlled.”

To investigate this, between 2019 and 2021, EDIT-CMD enrolled 126 adults aged 18 years and older who had two or more chronic angina episodes per week and no signs of obstructive CAD, who were seen at three hospitals specializing in ANOCA in the Netherlands.

The participants underwent coronary function testing that consisted of an acetylcholine spasm provocation test to evaluate for epicardial spasm and microvascular spasm, and a bolus thermodilution test with adenosine, to assess CFR and IMR. Coronary microvascular dysfunction was defined as CFR less than 2.0 and IMR of 25 or greater.

Of 99 patients with vasospasm or microvascular dysfunction, 85 patients were randomly assigned to receive diltiazem (n = 41) or placebo (n = 44) for 6 weeks.

The patients in both groups had a mean age of 58 years, and 29% were male; 22% had previously undergone percutaneous coronary intervention, and 48% had severe angina (Canadian Cardiovascular Society grade III/IV).

At baseline, about 50% had epicardial spasm, 25% had microvascular spasm and 25% had no spasm, and 54% in the diltiazem group and 73% in the placebo group had microvascular dysfunction.

After 6 weeks, 73 patients (35 in the placebo group and 38 in the diltiazem group) were available for repeat coronary function testing.

For the primary outcome, after 6 weeks of treatment, the proportion of patients with normalization of one abnormal parameter of coronary vasomotor dysfunction, without any normal parameter becoming abnormal, occurred in 8 patients (21%) in the diltiazem group versus 10 patients (29%) in the placebo group (P = .46)

In secondary outcomes, after 6 weeks of treatment, there were no significant differences in the prevalence of microvascular dysfunction, in Seattle Angina Questionnaire scores for angina symptoms, or RAND-36 scores for quality of life between patients who received diltiazem vs those who received placebo.

However, more patients in the diltiazem group than in the placebo group progressed from epicardial spasm to microvascular or no spasm (47% vs. 6%; P = .006).

The EDIT-CMD trial was sponsored by Abbott. Dr. Jansen has no relevant financial disclosures. Dr. Bairey Merz discloses having a fiduciary role and shares in iRhythm and being on the advisory board for Sanofi.

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

A new subanalysis of the FAME 3 trial, which failed to show that percutaneous intervention (PCI) guided by fractional flow reserve (FFR) is noninferior to coronary artery bypass grafting (CABG) for treating three-vessel coronary artery disease, has associated PCI with early quality of life (QOL) advantages, according to findings presented at the annual scientific sessions of the American College of Cardiology.

Despite a modestly greater risk of major adverse cardiac events (MACE) at the end of 12 months’ follow-up among those treated with FFR-guided PCI, the greater QOL early after the procedure might be relevant to patients weighing these options, according to Frederik M. Zimmerman, MD, of Catharina Hospital in Eindhoven, the Netherlands.

“FFR-guided PCI results in a faster improvement in quality of life than CABG during the first year after revascularization, and it improved working status in patients younger than 65 years of age,” Dr. Zimmermann said.

The primary results of FAME 3 were presented at the 2021 Transcatheter Cardiovascular Therapeutics annual meeting by lead author William F. Fearon, MD, of Stanford (Calif.) University and published simultaneously in the New England Journal of Medicine.

Rather than confirming the hypothesis that FFR-guided PCI is comparable with CABG for the primary composite MACE outcome death from any cause, myocardial infarction, stroke, or revascularization, the incidence of MACE at 12 months was 10.6% in those randomized to PCI and 6.9% in the group assigned to CABG.

This translated into a hazard ratio for MACE of 1.5, signifying a 50% increase in risk for FFR-guided PCI relative to CABG for the primary outcome, a difference that negated the study definition of noninferiority (P = .35).

In this new health-related subanalysis, which was published simultaneously with his ACC presentation, the groups were compared over 12 months for QOL as measured with European Quality of Life–5 dimensions (EQ-5D) scale, angina as measured with the Canadian Cardiovascular Classification (CCC) system, and employment.

Outcomes data available in >85% of patients

Of the 1,500 patients enrolled and randomized in FAME 3 (757 to FFR-guided PCI and 743 to CABG), this health outcomes subanalysis was performed with complete data at 12 months from 89% of those in the PCI group and 88% of those in the CABG group.

Ultimately, the study did not show differences in any of these measures at the end of 12 months, but there were significant differences in QOL and employment at earlier time points. In particular, the significantly different (P < .001) trajectory for QOL improvement at 1 and 6 months favored FFR-guided PCI whether evaluated with the EQ-5D instrument or an EQ visual analog scale.

Rates of angina defined by as CCC class of at least 2 were low after revascularization in both arms of the study, negating any opportunity for differences, but patients aged younger than 65 years were almost twice as likely to have returned to full- or part-time work 1 month after revascularization (60.2% vs. 33.1%), and they remained at higher odds for working at 12 months (68.1% vs. 57.4%).

In patients aged older than 65 years, return-to-work rates did not differ significantly at any time point.

These results suggest potentially clinically meaningful early advantages for FFR-guided PCI, but some experts questioned the rationale for reporting positive secondary findings from a negative trial.

“This subanalysis is curious,” said Allen Jeremias, MD, director of interventional cardiology research, Saint Francis Hospital, Roslyn, N.Y. He pointed out that reporting these data is an anomaly.
 

Subanalyses uncommon in negative trials

“CABG was found to be better, so why look at QOL,” said Dr. Jeremias, who was an ACC-invited expert to discuss the results. However, he went on to say, “this could be an exception to the rule.”

The reason, according to Dr. Jeremias, is that the absolute difference at 12 months between FFR-guided PCI and CABG for the MACE events of greatest concern – death, MI, or stroke – was only about 2% greater in the FFR-guided PCI group (7.3% vs. 5.2%). The biggest contributor to the difference in MACE in FAME 3 at 12 months was the higher rate of repeat revascularization (5.9% vs. 3.9%).

Moreover, patients randomized to FFR-guided PCI had lower rates of many adverse events. This included risk of bleeding (1.6% vs. 3.8%; P = .009 as defined by type ≥3 Bleeding Academic Research Consortium , acute kidney injury (0.1% vs. 0.9%; P = .04), atrial fibrillation (2.4% vs. 14.1%; P < .001) and rehospitalization within 30 days (5.5% vs. 10.2%; P < .001).

In the context of a modest increase in risk of MACE and the lower rate of several important treatment-related adverse events, the QOL advantages identified in this subanalysis “might be a reasonable topic for patient-shared decision-making,” Dr. Jeremias suggested.
 

New data might inform patient decision-making

He granted the possibility that well-informed patients might accept the modestly increased risk of MACE for one or more of the outcomes, such as a higher likelihood of an early return to work, that favored FFR-guided PCI.

This is the point of this subanalysis, agreed Dr. Zimmermann.

“It is all about shared decision-making,” he said. Also emphasizing that the negative trial endpoint of FAME 3 “was driven largely by an increased risk of revascularization,” he believes that these new data might be a basis for discussions with patients weighing relative risks and benefits.

There are more data to come, according to Dr. Zimmermann, who said that follow-up of up to 5 years is planned. The 3-year data will be made available in 2023.

Dr. Zimmermann reported no potential conflicts of interest. Dr. Jeremias reported financial relationships with Abbott, ACIST, Boston Scientific, and Volcano. The investigator-initiated trial received research grants from Abbott Vascular and Medtronic.

A new subanalysis of the FAME 3 trial, which failed to show that percutaneous intervention (PCI) guided by fractional flow reserve (FFR) is noninferior to coronary artery bypass grafting (CABG) for treating three-vessel coronary artery disease, has associated PCI with early quality of life (QOL) advantages, according to findings presented at the annual scientific sessions of the American College of Cardiology.

Despite a modestly greater risk of major adverse cardiac events (MACE) at the end of 12 months’ follow-up among those treated with FFR-guided PCI, the greater QOL early after the procedure might be relevant to patients weighing these options, according to Frederik M. Zimmerman, MD, of Catharina Hospital in Eindhoven, the Netherlands.

“FFR-guided PCI results in a faster improvement in quality of life than CABG during the first year after revascularization, and it improved working status in patients younger than 65 years of age,” Dr. Zimmermann said.

The primary results of FAME 3 were presented at the 2021 Transcatheter Cardiovascular Therapeutics annual meeting by lead author William F. Fearon, MD, of Stanford (Calif.) University and published simultaneously in the New England Journal of Medicine.

Rather than confirming the hypothesis that FFR-guided PCI is comparable with CABG for the primary composite MACE outcome death from any cause, myocardial infarction, stroke, or revascularization, the incidence of MACE at 12 months was 10.6% in those randomized to PCI and 6.9% in the group assigned to CABG.

This translated into a hazard ratio for MACE of 1.5, signifying a 50% increase in risk for FFR-guided PCI relative to CABG for the primary outcome, a difference that negated the study definition of noninferiority (P = .35).

In this new health-related subanalysis, which was published simultaneously with his ACC presentation, the groups were compared over 12 months for QOL as measured with European Quality of Life–5 dimensions (EQ-5D) scale, angina as measured with the Canadian Cardiovascular Classification (CCC) system, and employment.

Outcomes data available in >85% of patients

Of the 1,500 patients enrolled and randomized in FAME 3 (757 to FFR-guided PCI and 743 to CABG), this health outcomes subanalysis was performed with complete data at 12 months from 89% of those in the PCI group and 88% of those in the CABG group.

Ultimately, the study did not show differences in any of these measures at the end of 12 months, but there were significant differences in QOL and employment at earlier time points. In particular, the significantly different (P < .001) trajectory for QOL improvement at 1 and 6 months favored FFR-guided PCI whether evaluated with the EQ-5D instrument or an EQ visual analog scale.

Rates of angina defined by as CCC class of at least 2 were low after revascularization in both arms of the study, negating any opportunity for differences, but patients aged younger than 65 years were almost twice as likely to have returned to full- or part-time work 1 month after revascularization (60.2% vs. 33.1%), and they remained at higher odds for working at 12 months (68.1% vs. 57.4%).

In patients aged older than 65 years, return-to-work rates did not differ significantly at any time point.

These results suggest potentially clinically meaningful early advantages for FFR-guided PCI, but some experts questioned the rationale for reporting positive secondary findings from a negative trial.

“This subanalysis is curious,” said Allen Jeremias, MD, director of interventional cardiology research, Saint Francis Hospital, Roslyn, N.Y. He pointed out that reporting these data is an anomaly.
 

Subanalyses uncommon in negative trials

“CABG was found to be better, so why look at QOL,” said Dr. Jeremias, who was an ACC-invited expert to discuss the results. However, he went on to say, “this could be an exception to the rule.”

The reason, according to Dr. Jeremias, is that the absolute difference at 12 months between FFR-guided PCI and CABG for the MACE events of greatest concern – death, MI, or stroke – was only about 2% greater in the FFR-guided PCI group (7.3% vs. 5.2%). The biggest contributor to the difference in MACE in FAME 3 at 12 months was the higher rate of repeat revascularization (5.9% vs. 3.9%).

Moreover, patients randomized to FFR-guided PCI had lower rates of many adverse events. This included risk of bleeding (1.6% vs. 3.8%; P = .009 as defined by type ≥3 Bleeding Academic Research Consortium , acute kidney injury (0.1% vs. 0.9%; P = .04), atrial fibrillation (2.4% vs. 14.1%; P < .001) and rehospitalization within 30 days (5.5% vs. 10.2%; P < .001).

In the context of a modest increase in risk of MACE and the lower rate of several important treatment-related adverse events, the QOL advantages identified in this subanalysis “might be a reasonable topic for patient-shared decision-making,” Dr. Jeremias suggested.
 

New data might inform patient decision-making

He granted the possibility that well-informed patients might accept the modestly increased risk of MACE for one or more of the outcomes, such as a higher likelihood of an early return to work, that favored FFR-guided PCI.

This is the point of this subanalysis, agreed Dr. Zimmermann.

“It is all about shared decision-making,” he said. Also emphasizing that the negative trial endpoint of FAME 3 “was driven largely by an increased risk of revascularization,” he believes that these new data might be a basis for discussions with patients weighing relative risks and benefits.

There are more data to come, according to Dr. Zimmermann, who said that follow-up of up to 5 years is planned. The 3-year data will be made available in 2023.

Dr. Zimmermann reported no potential conflicts of interest. Dr. Jeremias reported financial relationships with Abbott, ACIST, Boston Scientific, and Volcano. The investigator-initiated trial received research grants from Abbott Vascular and Medtronic.

A new subanalysis of the FAME 3 trial, which failed to show that percutaneous intervention (PCI) guided by fractional flow reserve (FFR) is noninferior to coronary artery bypass grafting (CABG) for treating three-vessel coronary artery disease, has associated PCI with early quality of life (QOL) advantages, according to findings presented at the annual scientific sessions of the American College of Cardiology.

Despite a modestly greater risk of major adverse cardiac events (MACE) at the end of 12 months’ follow-up among those treated with FFR-guided PCI, the greater QOL early after the procedure might be relevant to patients weighing these options, according to Frederik M. Zimmerman, MD, of Catharina Hospital in Eindhoven, the Netherlands.

“FFR-guided PCI results in a faster improvement in quality of life than CABG during the first year after revascularization, and it improved working status in patients younger than 65 years of age,” Dr. Zimmermann said.

The primary results of FAME 3 were presented at the 2021 Transcatheter Cardiovascular Therapeutics annual meeting by lead author William F. Fearon, MD, of Stanford (Calif.) University and published simultaneously in the New England Journal of Medicine.

Rather than confirming the hypothesis that FFR-guided PCI is comparable with CABG for the primary composite MACE outcome death from any cause, myocardial infarction, stroke, or revascularization, the incidence of MACE at 12 months was 10.6% in those randomized to PCI and 6.9% in the group assigned to CABG.

This translated into a hazard ratio for MACE of 1.5, signifying a 50% increase in risk for FFR-guided PCI relative to CABG for the primary outcome, a difference that negated the study definition of noninferiority (P = .35).

In this new health-related subanalysis, which was published simultaneously with his ACC presentation, the groups were compared over 12 months for QOL as measured with European Quality of Life–5 dimensions (EQ-5D) scale, angina as measured with the Canadian Cardiovascular Classification (CCC) system, and employment.

Outcomes data available in >85% of patients

Of the 1,500 patients enrolled and randomized in FAME 3 (757 to FFR-guided PCI and 743 to CABG), this health outcomes subanalysis was performed with complete data at 12 months from 89% of those in the PCI group and 88% of those in the CABG group.

Ultimately, the study did not show differences in any of these measures at the end of 12 months, but there were significant differences in QOL and employment at earlier time points. In particular, the significantly different (P < .001) trajectory for QOL improvement at 1 and 6 months favored FFR-guided PCI whether evaluated with the EQ-5D instrument or an EQ visual analog scale.

Rates of angina defined by as CCC class of at least 2 were low after revascularization in both arms of the study, negating any opportunity for differences, but patients aged younger than 65 years were almost twice as likely to have returned to full- or part-time work 1 month after revascularization (60.2% vs. 33.1%), and they remained at higher odds for working at 12 months (68.1% vs. 57.4%).

In patients aged older than 65 years, return-to-work rates did not differ significantly at any time point.

These results suggest potentially clinically meaningful early advantages for FFR-guided PCI, but some experts questioned the rationale for reporting positive secondary findings from a negative trial.

“This subanalysis is curious,” said Allen Jeremias, MD, director of interventional cardiology research, Saint Francis Hospital, Roslyn, N.Y. He pointed out that reporting these data is an anomaly.
 

Subanalyses uncommon in negative trials

“CABG was found to be better, so why look at QOL,” said Dr. Jeremias, who was an ACC-invited expert to discuss the results. However, he went on to say, “this could be an exception to the rule.”

The reason, according to Dr. Jeremias, is that the absolute difference at 12 months between FFR-guided PCI and CABG for the MACE events of greatest concern – death, MI, or stroke – was only about 2% greater in the FFR-guided PCI group (7.3% vs. 5.2%). The biggest contributor to the difference in MACE in FAME 3 at 12 months was the higher rate of repeat revascularization (5.9% vs. 3.9%).

Moreover, patients randomized to FFR-guided PCI had lower rates of many adverse events. This included risk of bleeding (1.6% vs. 3.8%; P = .009 as defined by type ≥3 Bleeding Academic Research Consortium , acute kidney injury (0.1% vs. 0.9%; P = .04), atrial fibrillation (2.4% vs. 14.1%; P < .001) and rehospitalization within 30 days (5.5% vs. 10.2%; P < .001).

In the context of a modest increase in risk of MACE and the lower rate of several important treatment-related adverse events, the QOL advantages identified in this subanalysis “might be a reasonable topic for patient-shared decision-making,” Dr. Jeremias suggested.
 

New data might inform patient decision-making

He granted the possibility that well-informed patients might accept the modestly increased risk of MACE for one or more of the outcomes, such as a higher likelihood of an early return to work, that favored FFR-guided PCI.

This is the point of this subanalysis, agreed Dr. Zimmermann.

“It is all about shared decision-making,” he said. Also emphasizing that the negative trial endpoint of FAME 3 “was driven largely by an increased risk of revascularization,” he believes that these new data might be a basis for discussions with patients weighing relative risks and benefits.

There are more data to come, according to Dr. Zimmermann, who said that follow-up of up to 5 years is planned. The 3-year data will be made available in 2023.

Dr. Zimmermann reported no potential conflicts of interest. Dr. Jeremias reported financial relationships with Abbott, ACIST, Boston Scientific, and Volcano. The investigator-initiated trial received research grants from Abbott Vascular and Medtronic.

WASHINGTON – Results from new analyses further fleshed out the potent effect by the investigational SGLT1&2 inhibitor sotagliflozin on major cardiovascular adverse events in patients with type 2 diabetes, chronic kidney disease, and at high risk for cardiovascular disease in the SCORED trial that randomized more than 10,000 patients.

In prespecified, secondary analyses of the SCORED results, treatment with sotagliflozin during a median of 16 months was linked to a significant 21% risk reduction relative to placebo for the combined incidence of total major adverse cardiovascular events (MACE), which included cardiovascular death, first and recurrent episodes of nonfatal MI, and nonfatal stroke among the 5,144 randomized patients who entered the trial with a history of cardiovascular disease (CVD), Deepak L. Bhatt, MD, said at the annual scientific sessions of the American College of Cardiology.

Mitchel L. Zoler/MDedge News

Among the 5,440 patients in the study who did not have a history of CVD (although they did have at least one major risk factor or at least two minor risk factors), treatment with sotagliflozin was linked to a significant 26% relative risk reduction in total MACE events.

Part of these overall MACE benefits resulted from similar improvements from sotagliflozin treatment on the individual outcomes of total nonfatal MI and total nonfatal strokes. Treatment with sotagliflozin cut these MIs by a significant 31% in patients with a history of CVD relative to patients who received placebo, and by a relative 34% in those without a CVD event in their history, a difference compared with placebo that fell short of significance, said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Health, both in Boston.

Treatment with sotagliflozin also cut total nonfatal strokes by 31% relative to placebo in patients with a history of CVD, and by a relative 38% in those without a CVD history. Both differences fell short of significance.
 

An early MACE benefit and a stroke benefit

“This stroke benefit has not been clearly seen” with any agent from the closely related sodium-glucose cotransport-2 (SGLT2) inhibitor class, and “the MACE benefit appeared very early,” within 3 months from the start of sotagliflozin treatment, “which may be because of the SGLT1 inhibition,” Dr. Bhatt said during his report.

The SGLT1 receptor is the primary mechanism cells in the gut use to absorb glucose and galactose in the human gastrointestinal tract, Dr. Bhatt explained, while the SGLT2 receptor appears on kidney cells and is the major player in the reabsorption of filtered glucose. The SGLT2 inhibitor class includes the agents canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), while sotagliflozin inhibits both SGLT1 and SGLT2.

Main results from SCORED appeared in a report first released in late 2020, and showed that for the study’s primary endpoint treatment with sotagliflozin linked with a significant 26% relative risk reduction for the composite of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure (N Engl J Med. 2021 Jan 14;384[2]:129-39). Patient follow-up in SCORED was not as long as originally planned when the study stopped early due to a loss of funding from a sponsor that was triggered by the COVID-19 pandemic.

MACE results ‘heterogeneous’ from SGLT2 inhibitors

Sotagliflozin and agents from the SGLT2 inhibitor class “have been consistent” in their benefits for reducing cardiovascular death and hospitalization for heart failure, but for MACE, the results from the SGLT2 inhibitors “have been more heterogeneous,” and the effect of sotagliflozin on MACE “were different in SCORED,” commented Michelle L. O’Donoghue, MD, MPH, a cardiologist at Brigham and Women’s Hospital in Boston who was not involved with this work.

Mitchel L. Zoler/MDedge News

“The results suggest a benefit [from sotagliflozin] on atherosclerotic events, which could be a potential advantage” compared with the SGLT2 inhibitors, “but the heterogeneity of this effect” among these agents means that more confirmatory data are needed for sotagliflozin, Dr. O’Donoghue said in an interview.

“There is a lot of enthusiasm for the concept” of combined inhibition of the SGLT1 and 2 receptors, and if more evidence for unique benefits of this effect accumulate “it may lead to increased enthusiasm for sotagliflozin,” she said. “A lot will also depend on pricing decisions” for sotagliflozin, if it receives U.S. marketing approval from the Food and Drug Administration. Decisions about which agent from the SGLT2 inhibitor class to prescribe “are often being made based on price right now,” Dr. O’Donoghue said.

Lexicon Pharmaceuticals, the company developing sotagliflozin, has announced plans to resubmit its new drug application for sotagliflozin to the FDA later in 2022, with the agency’s approval decision likely occurring late in 2022 or sometime during 2023. In February, the company withdrew its December 2021 application to correct a “technical issue” it had found.

An additional analysis reported by Dr. Bhatt used combined data from SCORED as well as several additional randomized trials of sotagliflozin involving a total of more than 20,000 patients that showed a significant 21% reduction in the incidence of MACE compared with placebo.

During his talk, Dr. Bhatt said that sotagliflozin was potentially superior to the agents that inhibit only SGLT2. In an interview, he based this tentative assessment on at least four attributes of sotagliflozin that have emerged from trial results:

• The drug’s ability to significantly reduce MACE and to have this effect apparent within a few months of treatment onset;
• The significantly reduced rate of stroke with sotagliflozin (when patients are not subdivided into those with or without a history of CVD) that has not yet been seen with any SGLT2 inhibitor;
• The ability of sotagliflozin to reduce hemoglobin A1c levels in patients with type 2 diabetes even when their estimated glomerular filtration rate is less than 30 mL/min per 1.73 m², an effect not seen with SGLT2 inhibitors and possibly explained by sotagliflozin having an effect on gut absorption of glucose in addition to its SGLT2 inhibitory effect in the kidney;
• And the proven ability of sotagliflozin to be safe and effective when initiated in patients hospitalized for heart failure, a property that so far has only also been shown for the SGLT2 inhibitor empagliflozin in the EMPULSE trial (Nature Med. 2022 Mar;28: 568-74).

SCORED was sponsored by Sanofi and Lexicon Pharmaceuticals, the companies originally developing sotagliflozin, although with the withdrawal of Sanofi’s support, further development is now sponsored entirely by Lexicon. Dr. Bhatt received research funding from Sanofi and Lexicon that was paid to Brigham and Women’s Health, and he has been an advisor to numerous companies. Dr. O’Donoghue has been a consultant to Amgen, Janssen, and Novartis, and has received research funding from Amgen, AZ MedImmune, Intarcia, Janssen, Merck, and Novartis.
 

WASHINGTON – Results from new analyses further fleshed out the potent effect by the investigational SGLT1&2 inhibitor sotagliflozin on major cardiovascular adverse events in patients with type 2 diabetes, chronic kidney disease, and at high risk for cardiovascular disease in the SCORED trial that randomized more than 10,000 patients.

In prespecified, secondary analyses of the SCORED results, treatment with sotagliflozin during a median of 16 months was linked to a significant 21% risk reduction relative to placebo for the combined incidence of total major adverse cardiovascular events (MACE), which included cardiovascular death, first and recurrent episodes of nonfatal MI, and nonfatal stroke among the 5,144 randomized patients who entered the trial with a history of cardiovascular disease (CVD), Deepak L. Bhatt, MD, said at the annual scientific sessions of the American College of Cardiology.

Mitchel L. Zoler/MDedge News

Among the 5,440 patients in the study who did not have a history of CVD (although they did have at least one major risk factor or at least two minor risk factors), treatment with sotagliflozin was linked to a significant 26% relative risk reduction in total MACE events.

Part of these overall MACE benefits resulted from similar improvements from sotagliflozin treatment on the individual outcomes of total nonfatal MI and total nonfatal strokes. Treatment with sotagliflozin cut these MIs by a significant 31% in patients with a history of CVD relative to patients who received placebo, and by a relative 34% in those without a CVD event in their history, a difference compared with placebo that fell short of significance, said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Health, both in Boston.

Treatment with sotagliflozin also cut total nonfatal strokes by 31% relative to placebo in patients with a history of CVD, and by a relative 38% in those without a CVD history. Both differences fell short of significance.
 

An early MACE benefit and a stroke benefit

“This stroke benefit has not been clearly seen” with any agent from the closely related sodium-glucose cotransport-2 (SGLT2) inhibitor class, and “the MACE benefit appeared very early,” within 3 months from the start of sotagliflozin treatment, “which may be because of the SGLT1 inhibition,” Dr. Bhatt said during his report.

The SGLT1 receptor is the primary mechanism cells in the gut use to absorb glucose and galactose in the human gastrointestinal tract, Dr. Bhatt explained, while the SGLT2 receptor appears on kidney cells and is the major player in the reabsorption of filtered glucose. The SGLT2 inhibitor class includes the agents canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), while sotagliflozin inhibits both SGLT1 and SGLT2.

Main results from SCORED appeared in a report first released in late 2020, and showed that for the study’s primary endpoint treatment with sotagliflozin linked with a significant 26% relative risk reduction for the composite of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure (N Engl J Med. 2021 Jan 14;384[2]:129-39). Patient follow-up in SCORED was not as long as originally planned when the study stopped early due to a loss of funding from a sponsor that was triggered by the COVID-19 pandemic.

MACE results ‘heterogeneous’ from SGLT2 inhibitors

Sotagliflozin and agents from the SGLT2 inhibitor class “have been consistent” in their benefits for reducing cardiovascular death and hospitalization for heart failure, but for MACE, the results from the SGLT2 inhibitors “have been more heterogeneous,” and the effect of sotagliflozin on MACE “were different in SCORED,” commented Michelle L. O’Donoghue, MD, MPH, a cardiologist at Brigham and Women’s Hospital in Boston who was not involved with this work.

Mitchel L. Zoler/MDedge News

“The results suggest a benefit [from sotagliflozin] on atherosclerotic events, which could be a potential advantage” compared with the SGLT2 inhibitors, “but the heterogeneity of this effect” among these agents means that more confirmatory data are needed for sotagliflozin, Dr. O’Donoghue said in an interview.

“There is a lot of enthusiasm for the concept” of combined inhibition of the SGLT1 and 2 receptors, and if more evidence for unique benefits of this effect accumulate “it may lead to increased enthusiasm for sotagliflozin,” she said. “A lot will also depend on pricing decisions” for sotagliflozin, if it receives U.S. marketing approval from the Food and Drug Administration. Decisions about which agent from the SGLT2 inhibitor class to prescribe “are often being made based on price right now,” Dr. O’Donoghue said.

Lexicon Pharmaceuticals, the company developing sotagliflozin, has announced plans to resubmit its new drug application for sotagliflozin to the FDA later in 2022, with the agency’s approval decision likely occurring late in 2022 or sometime during 2023. In February, the company withdrew its December 2021 application to correct a “technical issue” it had found.

An additional analysis reported by Dr. Bhatt used combined data from SCORED as well as several additional randomized trials of sotagliflozin involving a total of more than 20,000 patients that showed a significant 21% reduction in the incidence of MACE compared with placebo.

During his talk, Dr. Bhatt said that sotagliflozin was potentially superior to the agents that inhibit only SGLT2. In an interview, he based this tentative assessment on at least four attributes of sotagliflozin that have emerged from trial results:

• The drug’s ability to significantly reduce MACE and to have this effect apparent within a few months of treatment onset;
• The significantly reduced rate of stroke with sotagliflozin (when patients are not subdivided into those with or without a history of CVD) that has not yet been seen with any SGLT2 inhibitor;
• The ability of sotagliflozin to reduce hemoglobin A1c levels in patients with type 2 diabetes even when their estimated glomerular filtration rate is less than 30 mL/min per 1.73 m², an effect not seen with SGLT2 inhibitors and possibly explained by sotagliflozin having an effect on gut absorption of glucose in addition to its SGLT2 inhibitory effect in the kidney;
• And the proven ability of sotagliflozin to be safe and effective when initiated in patients hospitalized for heart failure, a property that so far has only also been shown for the SGLT2 inhibitor empagliflozin in the EMPULSE trial (Nature Med. 2022 Mar;28: 568-74).

SCORED was sponsored by Sanofi and Lexicon Pharmaceuticals, the companies originally developing sotagliflozin, although with the withdrawal of Sanofi’s support, further development is now sponsored entirely by Lexicon. Dr. Bhatt received research funding from Sanofi and Lexicon that was paid to Brigham and Women’s Health, and he has been an advisor to numerous companies. Dr. O’Donoghue has been a consultant to Amgen, Janssen, and Novartis, and has received research funding from Amgen, AZ MedImmune, Intarcia, Janssen, Merck, and Novartis.
 

WASHINGTON – Results from new analyses further fleshed out the potent effect by the investigational SGLT1&2 inhibitor sotagliflozin on major cardiovascular adverse events in patients with type 2 diabetes, chronic kidney disease, and at high risk for cardiovascular disease in the SCORED trial that randomized more than 10,000 patients.

In prespecified, secondary analyses of the SCORED results, treatment with sotagliflozin during a median of 16 months was linked to a significant 21% risk reduction relative to placebo for the combined incidence of total major adverse cardiovascular events (MACE), which included cardiovascular death, first and recurrent episodes of nonfatal MI, and nonfatal stroke among the 5,144 randomized patients who entered the trial with a history of cardiovascular disease (CVD), Deepak L. Bhatt, MD, said at the annual scientific sessions of the American College of Cardiology.

Mitchel L. Zoler/MDedge News

Among the 5,440 patients in the study who did not have a history of CVD (although they did have at least one major risk factor or at least two minor risk factors), treatment with sotagliflozin was linked to a significant 26% relative risk reduction in total MACE events.

Part of these overall MACE benefits resulted from similar improvements from sotagliflozin treatment on the individual outcomes of total nonfatal MI and total nonfatal strokes. Treatment with sotagliflozin cut these MIs by a significant 31% in patients with a history of CVD relative to patients who received placebo, and by a relative 34% in those without a CVD event in their history, a difference compared with placebo that fell short of significance, said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Health, both in Boston.

Treatment with sotagliflozin also cut total nonfatal strokes by 31% relative to placebo in patients with a history of CVD, and by a relative 38% in those without a CVD history. Both differences fell short of significance.
 

An early MACE benefit and a stroke benefit

“This stroke benefit has not been clearly seen” with any agent from the closely related sodium-glucose cotransport-2 (SGLT2) inhibitor class, and “the MACE benefit appeared very early,” within 3 months from the start of sotagliflozin treatment, “which may be because of the SGLT1 inhibition,” Dr. Bhatt said during his report.

The SGLT1 receptor is the primary mechanism cells in the gut use to absorb glucose and galactose in the human gastrointestinal tract, Dr. Bhatt explained, while the SGLT2 receptor appears on kidney cells and is the major player in the reabsorption of filtered glucose. The SGLT2 inhibitor class includes the agents canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), while sotagliflozin inhibits both SGLT1 and SGLT2.

Main results from SCORED appeared in a report first released in late 2020, and showed that for the study’s primary endpoint treatment with sotagliflozin linked with a significant 26% relative risk reduction for the composite of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure (N Engl J Med. 2021 Jan 14;384[2]:129-39). Patient follow-up in SCORED was not as long as originally planned when the study stopped early due to a loss of funding from a sponsor that was triggered by the COVID-19 pandemic.

MACE results ‘heterogeneous’ from SGLT2 inhibitors

Sotagliflozin and agents from the SGLT2 inhibitor class “have been consistent” in their benefits for reducing cardiovascular death and hospitalization for heart failure, but for MACE, the results from the SGLT2 inhibitors “have been more heterogeneous,” and the effect of sotagliflozin on MACE “were different in SCORED,” commented Michelle L. O’Donoghue, MD, MPH, a cardiologist at Brigham and Women’s Hospital in Boston who was not involved with this work.

Mitchel L. Zoler/MDedge News

“The results suggest a benefit [from sotagliflozin] on atherosclerotic events, which could be a potential advantage” compared with the SGLT2 inhibitors, “but the heterogeneity of this effect” among these agents means that more confirmatory data are needed for sotagliflozin, Dr. O’Donoghue said in an interview.

“There is a lot of enthusiasm for the concept” of combined inhibition of the SGLT1 and 2 receptors, and if more evidence for unique benefits of this effect accumulate “it may lead to increased enthusiasm for sotagliflozin,” she said. “A lot will also depend on pricing decisions” for sotagliflozin, if it receives U.S. marketing approval from the Food and Drug Administration. Decisions about which agent from the SGLT2 inhibitor class to prescribe “are often being made based on price right now,” Dr. O’Donoghue said.

Lexicon Pharmaceuticals, the company developing sotagliflozin, has announced plans to resubmit its new drug application for sotagliflozin to the FDA later in 2022, with the agency’s approval decision likely occurring late in 2022 or sometime during 2023. In February, the company withdrew its December 2021 application to correct a “technical issue” it had found.

An additional analysis reported by Dr. Bhatt used combined data from SCORED as well as several additional randomized trials of sotagliflozin involving a total of more than 20,000 patients that showed a significant 21% reduction in the incidence of MACE compared with placebo.

During his talk, Dr. Bhatt said that sotagliflozin was potentially superior to the agents that inhibit only SGLT2. In an interview, he based this tentative assessment on at least four attributes of sotagliflozin that have emerged from trial results:

• The drug’s ability to significantly reduce MACE and to have this effect apparent within a few months of treatment onset;
• The significantly reduced rate of stroke with sotagliflozin (when patients are not subdivided into those with or without a history of CVD) that has not yet been seen with any SGLT2 inhibitor;
• The ability of sotagliflozin to reduce hemoglobin A1c levels in patients with type 2 diabetes even when their estimated glomerular filtration rate is less than 30 mL/min per 1.73 m², an effect not seen with SGLT2 inhibitors and possibly explained by sotagliflozin having an effect on gut absorption of glucose in addition to its SGLT2 inhibitory effect in the kidney;
• And the proven ability of sotagliflozin to be safe and effective when initiated in patients hospitalized for heart failure, a property that so far has only also been shown for the SGLT2 inhibitor empagliflozin in the EMPULSE trial (Nature Med. 2022 Mar;28: 568-74).

SCORED was sponsored by Sanofi and Lexicon Pharmaceuticals, the companies originally developing sotagliflozin, although with the withdrawal of Sanofi’s support, further development is now sponsored entirely by Lexicon. Dr. Bhatt received research funding from Sanofi and Lexicon that was paid to Brigham and Women’s Health, and he has been an advisor to numerous companies. Dr. O’Donoghue has been a consultant to Amgen, Janssen, and Novartis, and has received research funding from Amgen, AZ MedImmune, Intarcia, Janssen, Merck, and Novartis.
 

A prospective study that followed more than 110,000 men and women for more than 30 years suggests that eating two servings of avocado a week reduces the risk of developing cardiovascular disease (CVD).

Researchers also found that replacing half a serving of butter, cheese, bacon, or other animal product with an equivalent amount of avocado was associated with up to 22% lower risk for CVD events.

tookapic/Pixabay

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

A prospective study that followed more than 110,000 men and women for more than 30 years suggests that eating two servings of avocado a week reduces the risk of developing cardiovascular disease (CVD).

Researchers also found that replacing half a serving of butter, cheese, bacon, or other animal product with an equivalent amount of avocado was associated with up to 22% lower risk for CVD events.

tookapic/Pixabay

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

A prospective study that followed more than 110,000 men and women for more than 30 years suggests that eating two servings of avocado a week reduces the risk of developing cardiovascular disease (CVD).

Researchers also found that replacing half a serving of butter, cheese, bacon, or other animal product with an equivalent amount of avocado was associated with up to 22% lower risk for CVD events.

tookapic/Pixabay

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

The risk for sudden cardiac death (SCD) climbs steadily in tandem with coronary artery calcium (CAC) burden, independent of more conventional risk factors, in primary-prevention patients considered low- to intermediate-risk, researchers say.

The findings, based on a large cohort study, strengthen the case for initial CAC imaging as a gatekeeper to further testing in such patients who have mostly subclinical atherosclerotic cardiovascular disease (ASCVD), they conclude.

The CAC scan is “evolving into a primary-prevention screening test, not only for initiating statin therapy, but now as a screening modality for risk stratifying someone for sudden cardiac arrest,” Alexander C. Razavi, MD, MPH, PhD, Johns Hopkins University School of Medicine, Baltimore, told this news organization.

“Our data reinforce this and give some quantitative measures of when we should start to consider that.”

A CAC score of 100 to 399 in this “primarily asymptomatic,” predominantly White and male cohort elevated the risk for SCD over an average of 10.6 years by a factor of 2.8, compared with a score of 0. The risk went up four times with CAC scores of 400-999, and almost five times with scores above 1,000.

The risk association was independent of age and sex but also diabetes, smoking, hypertension, dyslipidemia, and family history of heart disease.

That and other findings, Dr. Razavi said, suggest CAC scores in low- to intermediate-risk patients like those studied may sharpen SCD risk-stratification beyond what is possible using traditional risk factors.

Dr. Razavi is lead author on the study’s March 21 publication in JACC Cardiovascular Imaging, and is slated to present the results April 2 during the American College of Cardiology (ACC) 2022 Scientific Session, to be held virtually and in-person in Washington, D.C.

The study’s 66,636 primary-prevention patients, part of the Coronary Artery Calcium Consortium observational cohort, were without known coronary disease at enrollment, from 1991-2010, at four major American centers. They had been referred to CAC imaging because of the presence of at least one ASCVD risk factor, such as dyslipidemia, family history of premature heart disease, hypertension, or diabetes, the researchers note.

They observed 211 SCD events, for a rate of about 0.3%, over a median of 10.6 years. The adjusted stepwise higher risk (SHR) for an SCD event went up continuously with CAC scores (P for trend < .001). The SHR values, compared with a CAC score of 0, were:

• 1.3 (95% CI, 0.7-2.4) for a CAC score score of 1 to 99
• 2.8 (95% CI, 1.6-5.0) for a CAC score of 100 to 399
• 4.0 (95% CI, 2.2-7.3) for a CAC score of 400 to 999
• 4.9 (95% CI, 2.6-9.9) for a CAC score above 1,000

The magnitude of the CAC score’s association with SCD risk in the study was “surprising,” Dr. Razavi said. The CAC score, starting at about 100, seems “more strongly associated with a sudden cardiac arrest” than more familiar SCD risk predictors, such as prolonged heart-rate-corrected QT interval or QRS duration.

Dr. Razavi reported no conflicts. Disclosures for the other authors are in the report.

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

The risk for sudden cardiac death (SCD) climbs steadily in tandem with coronary artery calcium (CAC) burden, independent of more conventional risk factors, in primary-prevention patients considered low- to intermediate-risk, researchers say.

The findings, based on a large cohort study, strengthen the case for initial CAC imaging as a gatekeeper to further testing in such patients who have mostly subclinical atherosclerotic cardiovascular disease (ASCVD), they conclude.

The CAC scan is “evolving into a primary-prevention screening test, not only for initiating statin therapy, but now as a screening modality for risk stratifying someone for sudden cardiac arrest,” Alexander C. Razavi, MD, MPH, PhD, Johns Hopkins University School of Medicine, Baltimore, told this news organization.

“Our data reinforce this and give some quantitative measures of when we should start to consider that.”

A CAC score of 100 to 399 in this “primarily asymptomatic,” predominantly White and male cohort elevated the risk for SCD over an average of 10.6 years by a factor of 2.8, compared with a score of 0. The risk went up four times with CAC scores of 400-999, and almost five times with scores above 1,000.

The risk association was independent of age and sex but also diabetes, smoking, hypertension, dyslipidemia, and family history of heart disease.

That and other findings, Dr. Razavi said, suggest CAC scores in low- to intermediate-risk patients like those studied may sharpen SCD risk-stratification beyond what is possible using traditional risk factors.

Dr. Razavi is lead author on the study’s March 21 publication in JACC Cardiovascular Imaging, and is slated to present the results April 2 during the American College of Cardiology (ACC) 2022 Scientific Session, to be held virtually and in-person in Washington, D.C.

The study’s 66,636 primary-prevention patients, part of the Coronary Artery Calcium Consortium observational cohort, were without known coronary disease at enrollment, from 1991-2010, at four major American centers. They had been referred to CAC imaging because of the presence of at least one ASCVD risk factor, such as dyslipidemia, family history of premature heart disease, hypertension, or diabetes, the researchers note.

They observed 211 SCD events, for a rate of about 0.3%, over a median of 10.6 years. The adjusted stepwise higher risk (SHR) for an SCD event went up continuously with CAC scores (P for trend < .001). The SHR values, compared with a CAC score of 0, were:

• 1.3 (95% CI, 0.7-2.4) for a CAC score score of 1 to 99
• 2.8 (95% CI, 1.6-5.0) for a CAC score of 100 to 399
• 4.0 (95% CI, 2.2-7.3) for a CAC score of 400 to 999
• 4.9 (95% CI, 2.6-9.9) for a CAC score above 1,000

The magnitude of the CAC score’s association with SCD risk in the study was “surprising,” Dr. Razavi said. The CAC score, starting at about 100, seems “more strongly associated with a sudden cardiac arrest” than more familiar SCD risk predictors, such as prolonged heart-rate-corrected QT interval or QRS duration.

Dr. Razavi reported no conflicts. Disclosures for the other authors are in the report.

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

The risk for sudden cardiac death (SCD) climbs steadily in tandem with coronary artery calcium (CAC) burden, independent of more conventional risk factors, in primary-prevention patients considered low- to intermediate-risk, researchers say.

The findings, based on a large cohort study, strengthen the case for initial CAC imaging as a gatekeeper to further testing in such patients who have mostly subclinical atherosclerotic cardiovascular disease (ASCVD), they conclude.

The CAC scan is “evolving into a primary-prevention screening test, not only for initiating statin therapy, but now as a screening modality for risk stratifying someone for sudden cardiac arrest,” Alexander C. Razavi, MD, MPH, PhD, Johns Hopkins University School of Medicine, Baltimore, told this news organization.

“Our data reinforce this and give some quantitative measures of when we should start to consider that.”

A CAC score of 100 to 399 in this “primarily asymptomatic,” predominantly White and male cohort elevated the risk for SCD over an average of 10.6 years by a factor of 2.8, compared with a score of 0. The risk went up four times with CAC scores of 400-999, and almost five times with scores above 1,000.

The risk association was independent of age and sex but also diabetes, smoking, hypertension, dyslipidemia, and family history of heart disease.

That and other findings, Dr. Razavi said, suggest CAC scores in low- to intermediate-risk patients like those studied may sharpen SCD risk-stratification beyond what is possible using traditional risk factors.

Dr. Razavi is lead author on the study’s March 21 publication in JACC Cardiovascular Imaging, and is slated to present the results April 2 during the American College of Cardiology (ACC) 2022 Scientific Session, to be held virtually and in-person in Washington, D.C.

The study’s 66,636 primary-prevention patients, part of the Coronary Artery Calcium Consortium observational cohort, were without known coronary disease at enrollment, from 1991-2010, at four major American centers. They had been referred to CAC imaging because of the presence of at least one ASCVD risk factor, such as dyslipidemia, family history of premature heart disease, hypertension, or diabetes, the researchers note.

They observed 211 SCD events, for a rate of about 0.3%, over a median of 10.6 years. The adjusted stepwise higher risk (SHR) for an SCD event went up continuously with CAC scores (P for trend < .001). The SHR values, compared with a CAC score of 0, were:

• 1.3 (95% CI, 0.7-2.4) for a CAC score score of 1 to 99
• 2.8 (95% CI, 1.6-5.0) for a CAC score of 100 to 399
• 4.0 (95% CI, 2.2-7.3) for a CAC score of 400 to 999
• 4.9 (95% CI, 2.6-9.9) for a CAC score above 1,000

The magnitude of the CAC score’s association with SCD risk in the study was “surprising,” Dr. Razavi said. The CAC score, starting at about 100, seems “more strongly associated with a sudden cardiac arrest” than more familiar SCD risk predictors, such as prolonged heart-rate-corrected QT interval or QRS duration.

Dr. Razavi reported no conflicts. Disclosures for the other authors are in the report.

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