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Adolescent obesity, diabetes linked to atherosclerotic signs
significantly greater than their normal-weight peers, according to a longitudinal study published online in the Journal of the American Heart Association.
The study evaluated 448 adolescents over 5 years for changes in a variety of metrics to determine changes in arterial structure, including carotid intima media thickness (cIMT), carotid-femoral pulse-wave velocity (PWV), and augmentation index (Aix). The average age of the study group was 17.6 years. The three study groups broke down accordingly: 141 with normal weight, 156 with obesity, and 151 with type 2 diabetes. Patients were evaluated at baseline and 5 years later.
“The presence of obesity and especially type 2 diabetes in adolescents accelerates the early vascular aging process associated with several key risk factors,” wrote Justin R. Ryder, PhD, an assistant professor of pediatrics at the University of Minnesota, Minneapolis, and colleagues.
The researchers also noted that systolic hypertension was associated with changes in cIMT and arterial stiffness comparable to obesity and diabetes. “These data add further evidence underscoring the importance of efforts targeting prevention and treatment of obesity, type 2 diabetes, and elevated blood pressure among youth, with a goal of delaying and/or preventing the progression of early vascular aging,” Dr. Ryder and colleagues wrote.
Obese patients, when compared with normal-weight participants, had the following average increases: common cIMT by 0.05 mm, bulb cIMT by 0.02 mm, internal cIMT by 0.03 mm, and PWV carotid-femoral by 0.38 m/sec, all statistically significant differences. Patients with diabetes, compared with normal-weight participants, registered the following average increases: common cIMT by 0.05 mm, bulb cIMT by 0.06 mm, internal cIMT by 0.04 mm, Aix by 4.67%, and PWV carotid-femoral by 0.74 m/sec. All differences were highly significant at P less than .001.
The results also showed that higher baseline systolic blood pressure was associated with significantly greater average increases in the following factors: common cIMT by 0.007 mm, bulb cIMT by 0.009 mm, internal cIMT by 0.008 mm, and PWV carotid-femoral by 0.66 m/sec.
Drilling down into the data, the study reported that males had greater increases in bulb cIMT and incremental elastic modulus as well as reduced Aix, compared with females. Nonwhites also had greater increases in bulb cIMT than did whites. Age was associated with greater increases in bulb and internal cIMT and Aix.
“Our data support the concept that male sex is an independent and primary risk factor for accelerated early vascular aging,” Dr. Ryder and colleagues wrote. The study also determined that type 2 diabetes is a more prominent risk factor than obesity for early vascular aging.
The size of the study population, specifically adolescents with diabetes, is a study strength, Dr. Ryder and colleagues noted. Other strengths they pointed to are the 5-year duration and the robust panel of noninvasive measures, although not using hard cardiovascular outcomes is an acknowledged limitation.
“It should also be noted that many of the youth with type 2 diabetes were on medications for glycemic control, lipids, and/or blood pressure regulation,” Dr. Ryder and colleagues wrote. “Despite this, the vascular profiles worsened over time.”
The study showed “a really significant change” in the carotid anatomy in adolescents with obesity and type 2 diabetes over 5 years, Robert Eckel, MD, professor at the University of Colorado Anschutz Medical Campus, Aurora, said in an interview. “Notably, the PWV is not just anatomy; now we’re talking about function. In other words, the augmentation index and PWV will assess the compliance of the artery.”
The findings suggest that atherosclerosis begins with thickening of the arterial walls. “The question is, is thickness reversible?” Dr. Eckel said. “It’s probably not very reversible, so these are early changes that ultimately in the middle years or latter years are associated with major cardiovascular disease.”
They key lesson from the study, Dr. Eckel noted, is to “prevent obesity. If you prevent obesity in the teenage years, you basically prevent diabetes.”
Dr. Ryder disclosed receiving support from Boehringer Ingelheim in the form of drug/placebo. The National Institutes of Health provided funding. Dr. Eckel has no relevant relationships to disclose.
SOURCE: Ryder JR et al. J Am Heart Assoc. 2020 May 6:e014891. doi: 10.1161/JAHA.119.014891.
significantly greater than their normal-weight peers, according to a longitudinal study published online in the Journal of the American Heart Association.
The study evaluated 448 adolescents over 5 years for changes in a variety of metrics to determine changes in arterial structure, including carotid intima media thickness (cIMT), carotid-femoral pulse-wave velocity (PWV), and augmentation index (Aix). The average age of the study group was 17.6 years. The three study groups broke down accordingly: 141 with normal weight, 156 with obesity, and 151 with type 2 diabetes. Patients were evaluated at baseline and 5 years later.
“The presence of obesity and especially type 2 diabetes in adolescents accelerates the early vascular aging process associated with several key risk factors,” wrote Justin R. Ryder, PhD, an assistant professor of pediatrics at the University of Minnesota, Minneapolis, and colleagues.
The researchers also noted that systolic hypertension was associated with changes in cIMT and arterial stiffness comparable to obesity and diabetes. “These data add further evidence underscoring the importance of efforts targeting prevention and treatment of obesity, type 2 diabetes, and elevated blood pressure among youth, with a goal of delaying and/or preventing the progression of early vascular aging,” Dr. Ryder and colleagues wrote.
Obese patients, when compared with normal-weight participants, had the following average increases: common cIMT by 0.05 mm, bulb cIMT by 0.02 mm, internal cIMT by 0.03 mm, and PWV carotid-femoral by 0.38 m/sec, all statistically significant differences. Patients with diabetes, compared with normal-weight participants, registered the following average increases: common cIMT by 0.05 mm, bulb cIMT by 0.06 mm, internal cIMT by 0.04 mm, Aix by 4.67%, and PWV carotid-femoral by 0.74 m/sec. All differences were highly significant at P less than .001.
The results also showed that higher baseline systolic blood pressure was associated with significantly greater average increases in the following factors: common cIMT by 0.007 mm, bulb cIMT by 0.009 mm, internal cIMT by 0.008 mm, and PWV carotid-femoral by 0.66 m/sec.
Drilling down into the data, the study reported that males had greater increases in bulb cIMT and incremental elastic modulus as well as reduced Aix, compared with females. Nonwhites also had greater increases in bulb cIMT than did whites. Age was associated with greater increases in bulb and internal cIMT and Aix.
“Our data support the concept that male sex is an independent and primary risk factor for accelerated early vascular aging,” Dr. Ryder and colleagues wrote. The study also determined that type 2 diabetes is a more prominent risk factor than obesity for early vascular aging.
The size of the study population, specifically adolescents with diabetes, is a study strength, Dr. Ryder and colleagues noted. Other strengths they pointed to are the 5-year duration and the robust panel of noninvasive measures, although not using hard cardiovascular outcomes is an acknowledged limitation.
“It should also be noted that many of the youth with type 2 diabetes were on medications for glycemic control, lipids, and/or blood pressure regulation,” Dr. Ryder and colleagues wrote. “Despite this, the vascular profiles worsened over time.”
The study showed “a really significant change” in the carotid anatomy in adolescents with obesity and type 2 diabetes over 5 years, Robert Eckel, MD, professor at the University of Colorado Anschutz Medical Campus, Aurora, said in an interview. “Notably, the PWV is not just anatomy; now we’re talking about function. In other words, the augmentation index and PWV will assess the compliance of the artery.”
The findings suggest that atherosclerosis begins with thickening of the arterial walls. “The question is, is thickness reversible?” Dr. Eckel said. “It’s probably not very reversible, so these are early changes that ultimately in the middle years or latter years are associated with major cardiovascular disease.”
They key lesson from the study, Dr. Eckel noted, is to “prevent obesity. If you prevent obesity in the teenage years, you basically prevent diabetes.”
Dr. Ryder disclosed receiving support from Boehringer Ingelheim in the form of drug/placebo. The National Institutes of Health provided funding. Dr. Eckel has no relevant relationships to disclose.
SOURCE: Ryder JR et al. J Am Heart Assoc. 2020 May 6:e014891. doi: 10.1161/JAHA.119.014891.
significantly greater than their normal-weight peers, according to a longitudinal study published online in the Journal of the American Heart Association.
The study evaluated 448 adolescents over 5 years for changes in a variety of metrics to determine changes in arterial structure, including carotid intima media thickness (cIMT), carotid-femoral pulse-wave velocity (PWV), and augmentation index (Aix). The average age of the study group was 17.6 years. The three study groups broke down accordingly: 141 with normal weight, 156 with obesity, and 151 with type 2 diabetes. Patients were evaluated at baseline and 5 years later.
“The presence of obesity and especially type 2 diabetes in adolescents accelerates the early vascular aging process associated with several key risk factors,” wrote Justin R. Ryder, PhD, an assistant professor of pediatrics at the University of Minnesota, Minneapolis, and colleagues.
The researchers also noted that systolic hypertension was associated with changes in cIMT and arterial stiffness comparable to obesity and diabetes. “These data add further evidence underscoring the importance of efforts targeting prevention and treatment of obesity, type 2 diabetes, and elevated blood pressure among youth, with a goal of delaying and/or preventing the progression of early vascular aging,” Dr. Ryder and colleagues wrote.
Obese patients, when compared with normal-weight participants, had the following average increases: common cIMT by 0.05 mm, bulb cIMT by 0.02 mm, internal cIMT by 0.03 mm, and PWV carotid-femoral by 0.38 m/sec, all statistically significant differences. Patients with diabetes, compared with normal-weight participants, registered the following average increases: common cIMT by 0.05 mm, bulb cIMT by 0.06 mm, internal cIMT by 0.04 mm, Aix by 4.67%, and PWV carotid-femoral by 0.74 m/sec. All differences were highly significant at P less than .001.
The results also showed that higher baseline systolic blood pressure was associated with significantly greater average increases in the following factors: common cIMT by 0.007 mm, bulb cIMT by 0.009 mm, internal cIMT by 0.008 mm, and PWV carotid-femoral by 0.66 m/sec.
Drilling down into the data, the study reported that males had greater increases in bulb cIMT and incremental elastic modulus as well as reduced Aix, compared with females. Nonwhites also had greater increases in bulb cIMT than did whites. Age was associated with greater increases in bulb and internal cIMT and Aix.
“Our data support the concept that male sex is an independent and primary risk factor for accelerated early vascular aging,” Dr. Ryder and colleagues wrote. The study also determined that type 2 diabetes is a more prominent risk factor than obesity for early vascular aging.
The size of the study population, specifically adolescents with diabetes, is a study strength, Dr. Ryder and colleagues noted. Other strengths they pointed to are the 5-year duration and the robust panel of noninvasive measures, although not using hard cardiovascular outcomes is an acknowledged limitation.
“It should also be noted that many of the youth with type 2 diabetes were on medications for glycemic control, lipids, and/or blood pressure regulation,” Dr. Ryder and colleagues wrote. “Despite this, the vascular profiles worsened over time.”
The study showed “a really significant change” in the carotid anatomy in adolescents with obesity and type 2 diabetes over 5 years, Robert Eckel, MD, professor at the University of Colorado Anschutz Medical Campus, Aurora, said in an interview. “Notably, the PWV is not just anatomy; now we’re talking about function. In other words, the augmentation index and PWV will assess the compliance of the artery.”
The findings suggest that atherosclerosis begins with thickening of the arterial walls. “The question is, is thickness reversible?” Dr. Eckel said. “It’s probably not very reversible, so these are early changes that ultimately in the middle years or latter years are associated with major cardiovascular disease.”
They key lesson from the study, Dr. Eckel noted, is to “prevent obesity. If you prevent obesity in the teenage years, you basically prevent diabetes.”
Dr. Ryder disclosed receiving support from Boehringer Ingelheim in the form of drug/placebo. The National Institutes of Health provided funding. Dr. Eckel has no relevant relationships to disclose.
SOURCE: Ryder JR et al. J Am Heart Assoc. 2020 May 6:e014891. doi: 10.1161/JAHA.119.014891.
FROM JOURNAL OF THE AMERICAN HEART ASSOCIATION
FOURIER: Evolocumab follow-up shows no cognitive adverse effects
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
FROM JACC
Key clinical point: A cognition survey of a large number of trial participants showed no signal of adverse effects from evolocumab treatment.
Major finding: Survey results showed cognitive compromise in 3.7% of patients on evolocumab and in 3.6% control patients on placebo.
Study details:
Disclosures: FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Guigliano has received personal fees and research support from Amgen and from several other companies.
Source: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
High rate of fatty liver disease found among 9/11 first responders
First responders to the site of the 2001 World Trade Center attack may have an elevated risk of nonalcoholic fatty liver disease (NAFLD), according to investigators.
In a retrospective look at 236 first responders presenting with gastrointestinal symptoms to the World Trade Center Health Program, 195 (82.6%) had NAFLD, compared with 24%-45% of the general population, reported lead author Mishal Reja, MD, of Robert Wood Johnson University Hospital, New Brunswick, N.J.
The increased rate of NAFLD among first responders is likely because of toxin exposure at ground zero, which can cause a subtype of NAFLD known as toxin-associated fatty liver disease (TAFLD), Dr. Reja wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.
“I was not surprised [by these findings],” Dr. Reja said during a virtual press conference. “In the prior literature that did examine TAFLD, it did show that populations exposed to these specific chemicals ... at the ground zero site had extremely high rates – consistent with the rates we found in our study – of fatty liver disease.”
Dr. Reja said that 9/11 first responders were exposed to “many common toxins that are consistently in occupational and environmental toxicant literature.” In particular, he named polycyclic aromatic hydrocarbons and vinyl chloride.
“A lot of these toxins are ... included in industrial solvents as well as building demolition,” Dr. Reja said. “So they’ve been around for so long, and they’ve been studied for so long, [that we have] literature that shows these toxins are associated with fatty liver disease, which is how we arrived at the hypothesis in the first place.”
The first responders were stratified by roles, which were associated with varying levels of exposure. About 40% of individuals in the study were involved in moving debris from the site, a small group (4%) were involved in clean-up and maintenance, while approximately 30%-40% worked in more protected, administrative roles.
Comparing individuals in the study with TAFLD versus those without TAFLD revealed additional risk factors. Multivariate logistical regression analysis showed that obese individuals had a significantly increased risk of fatty liver disease, suggesting a synergistic effect.
“If you were exposed to these toxins in the World Trade Center, and you were obese, [then] you are actually between two to three times more likely to get [TAFLD],” Dr. Reja said, noting that hypertension and diabetes were also identified as independent risk factors.
Dr. Reja and colleagues are planning a prospective trial to investigate further. The study will likely involve 100-200 first responders with TAFLD, a similar number of individuals with NAFLD, and another group without liver disease.
The investigators reported no outside funding or conflicts of interest.
SOURCE: Reja M et al. DDW 2020, Abstracts available online May 2.
First responders to the site of the 2001 World Trade Center attack may have an elevated risk of nonalcoholic fatty liver disease (NAFLD), according to investigators.
In a retrospective look at 236 first responders presenting with gastrointestinal symptoms to the World Trade Center Health Program, 195 (82.6%) had NAFLD, compared with 24%-45% of the general population, reported lead author Mishal Reja, MD, of Robert Wood Johnson University Hospital, New Brunswick, N.J.
The increased rate of NAFLD among first responders is likely because of toxin exposure at ground zero, which can cause a subtype of NAFLD known as toxin-associated fatty liver disease (TAFLD), Dr. Reja wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.
“I was not surprised [by these findings],” Dr. Reja said during a virtual press conference. “In the prior literature that did examine TAFLD, it did show that populations exposed to these specific chemicals ... at the ground zero site had extremely high rates – consistent with the rates we found in our study – of fatty liver disease.”
Dr. Reja said that 9/11 first responders were exposed to “many common toxins that are consistently in occupational and environmental toxicant literature.” In particular, he named polycyclic aromatic hydrocarbons and vinyl chloride.
“A lot of these toxins are ... included in industrial solvents as well as building demolition,” Dr. Reja said. “So they’ve been around for so long, and they’ve been studied for so long, [that we have] literature that shows these toxins are associated with fatty liver disease, which is how we arrived at the hypothesis in the first place.”
The first responders were stratified by roles, which were associated with varying levels of exposure. About 40% of individuals in the study were involved in moving debris from the site, a small group (4%) were involved in clean-up and maintenance, while approximately 30%-40% worked in more protected, administrative roles.
Comparing individuals in the study with TAFLD versus those without TAFLD revealed additional risk factors. Multivariate logistical regression analysis showed that obese individuals had a significantly increased risk of fatty liver disease, suggesting a synergistic effect.
“If you were exposed to these toxins in the World Trade Center, and you were obese, [then] you are actually between two to three times more likely to get [TAFLD],” Dr. Reja said, noting that hypertension and diabetes were also identified as independent risk factors.
Dr. Reja and colleagues are planning a prospective trial to investigate further. The study will likely involve 100-200 first responders with TAFLD, a similar number of individuals with NAFLD, and another group without liver disease.
The investigators reported no outside funding or conflicts of interest.
SOURCE: Reja M et al. DDW 2020, Abstracts available online May 2.
First responders to the site of the 2001 World Trade Center attack may have an elevated risk of nonalcoholic fatty liver disease (NAFLD), according to investigators.
In a retrospective look at 236 first responders presenting with gastrointestinal symptoms to the World Trade Center Health Program, 195 (82.6%) had NAFLD, compared with 24%-45% of the general population, reported lead author Mishal Reja, MD, of Robert Wood Johnson University Hospital, New Brunswick, N.J.
The increased rate of NAFLD among first responders is likely because of toxin exposure at ground zero, which can cause a subtype of NAFLD known as toxin-associated fatty liver disease (TAFLD), Dr. Reja wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.
“I was not surprised [by these findings],” Dr. Reja said during a virtual press conference. “In the prior literature that did examine TAFLD, it did show that populations exposed to these specific chemicals ... at the ground zero site had extremely high rates – consistent with the rates we found in our study – of fatty liver disease.”
Dr. Reja said that 9/11 first responders were exposed to “many common toxins that are consistently in occupational and environmental toxicant literature.” In particular, he named polycyclic aromatic hydrocarbons and vinyl chloride.
“A lot of these toxins are ... included in industrial solvents as well as building demolition,” Dr. Reja said. “So they’ve been around for so long, and they’ve been studied for so long, [that we have] literature that shows these toxins are associated with fatty liver disease, which is how we arrived at the hypothesis in the first place.”
The first responders were stratified by roles, which were associated with varying levels of exposure. About 40% of individuals in the study were involved in moving debris from the site, a small group (4%) were involved in clean-up and maintenance, while approximately 30%-40% worked in more protected, administrative roles.
Comparing individuals in the study with TAFLD versus those without TAFLD revealed additional risk factors. Multivariate logistical regression analysis showed that obese individuals had a significantly increased risk of fatty liver disease, suggesting a synergistic effect.
“If you were exposed to these toxins in the World Trade Center, and you were obese, [then] you are actually between two to three times more likely to get [TAFLD],” Dr. Reja said, noting that hypertension and diabetes were also identified as independent risk factors.
Dr. Reja and colleagues are planning a prospective trial to investigate further. The study will likely involve 100-200 first responders with TAFLD, a similar number of individuals with NAFLD, and another group without liver disease.
The investigators reported no outside funding or conflicts of interest.
SOURCE: Reja M et al. DDW 2020, Abstracts available online May 2.
FROM DDW 2020
Key clinical point: First responders to the site of the 2001 World Trade Center attack may have a higher risk of fatty liver disease.
Major finding: Eighty-three percent of first responders presenting with gastrointestinal symptoms had toxin-associated fatty liver disease (TAFLD), a subtype of nonalcoholic fatty liver disease (NAFLD).
Study details: A retrospective study involving 236 first responders presenting with gastrointestinal symptoms to the World Trade Center Health Program between January 2014 and August 2019.
Disclosures: The investigators reported no outside funding or conflicts of interest.
Source: Reja M et al. DDW 2020, Abstracts available online May 2.
Noninvasive tests boost risk stratification in obese compensated ACLD
Readily available and inexpensive noninvasive tests, when used in combination with liver markers obtained with the extra-large probe, can improve the ability to predict risk for decompensation and other adverse outcomes in obese and overweight patients with compensated advanced chronic liver disease (cACLD), according to study results reported in the upcoming issue of the journal Clinical Gastroenterology and Hepatology.
The retrospective study of 272 obese and overweight patients in Bern, Switzerland, and Montreal with cACLD is the first to fully assess the noninvasive marker of portal hypertension along with using the extra-large probe for controlled attenuation parameter (CAP) to determine risk, wrote Yuly Mendoza, MD, of the University of Bern and colleagues. Decompensation in cACLD carries a higher risk of death. The study noted that portal hypertension is a key driver of progression to decompensation, “and as such, it should be identified as soon as possible and treated as needed.”
“Prediction of prognosis in cACLD is challenging, and noninvasive tests are important tools for clinicians to avoid as much as possible the use of more invasive tests,” wrote Dr. Mendoza and colleagues. Based on the extra-large probe, 76% (n = 206) of study patients had metabolic syndrome, sometimes with other etiologies of liver disease, and 57% (n = 154) had cACLD because of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH).
Twelve patients had decompensation and five developed severe bacterial infections.
“Readily available noninvasive tests can be used to identify obese or overweight patients with cACLD who are at increased risk for decompensation and severe bacterial infections,” wrote the researchers.
The study noted that obesity is a challenge for noninvasive tests and is a major limitation to liver stiffness measurement on transient elastography using the standard M probe. The XL probe has been specifically designed to overcome this challenge in obese patients, but it hasn’t been evaluated for the prediction of clinical decompensation in obese patients with cACLD.
This study claimed to provide further evidence that liver stiffness measurement in combination with noninvasive tests for liver stiffness measurement, spleen size/platelet count (LSPS), portal hypertension and portal hypertension risk score can help identify patients at risk for clinical decompensation and severe bacterial infections.
The study used average area under the receiving operator curve (AUC) to calculate the ability of the markers to distinguish risk, all with 95% confidence interval: 0.803 for liver stiffness measurement, 0.829 for portal hypertension risk score, and 0.845 for LSPS (P < .001). The markers showed an even better ability to differentiate between patients at risk for developing classical clinical decompensation in follow-up from those not at risk (all 95% CI): 0.848 for liver stiffness measurement, 0.881 for portal hypertension risk score, and 0.890 for LSPS (P < .001).
“The results of the present study validate the use of [extra-large] probe for liver stiffness measurement and CAP to stratify the risk of clinical decompensation and clinically relevant events in overweight/obese patients with cACLD, particularly in case of NAFLD/NASH etiology,” wrote Dr. Mendoza and colleagues.
All study participants were followed for at least 6 months, with a median of 17 months. Patients who developed decompensation or severe bacterial infections had slightly worse liver function (higher international normalized ratio and lower albumin), lower mean platelet count (117 vs. 179 x 109/L; P < .001) and lower mean CAP (297 vs. 318 dBm; P = .030) than did patients who stayed compensated.
CAP above 220 dB/m was marginally associated with a lower risk of decompensation or severe bacterial infections on univariate analysis, as were elevated Model for End-Stage Liver Disease score, elevated Child Pugh score, low platelet count, low serum albumin, elevated serum bilirubin and increased liver stiffness measurement, LSPS, and portal hypertension risk scores.
Dr. Mendoza and colleagues have no relevant financial disclosures. The study received funding from the Swiss government.
SOURCE: Mendoza Y et al. Clin Gastroenterol Hepatol. 2020. doi: 10.1016/j.cgh.2020.04.018.
Readily available and inexpensive noninvasive tests, when used in combination with liver markers obtained with the extra-large probe, can improve the ability to predict risk for decompensation and other adverse outcomes in obese and overweight patients with compensated advanced chronic liver disease (cACLD), according to study results reported in the upcoming issue of the journal Clinical Gastroenterology and Hepatology.
The retrospective study of 272 obese and overweight patients in Bern, Switzerland, and Montreal with cACLD is the first to fully assess the noninvasive marker of portal hypertension along with using the extra-large probe for controlled attenuation parameter (CAP) to determine risk, wrote Yuly Mendoza, MD, of the University of Bern and colleagues. Decompensation in cACLD carries a higher risk of death. The study noted that portal hypertension is a key driver of progression to decompensation, “and as such, it should be identified as soon as possible and treated as needed.”
“Prediction of prognosis in cACLD is challenging, and noninvasive tests are important tools for clinicians to avoid as much as possible the use of more invasive tests,” wrote Dr. Mendoza and colleagues. Based on the extra-large probe, 76% (n = 206) of study patients had metabolic syndrome, sometimes with other etiologies of liver disease, and 57% (n = 154) had cACLD because of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH).
Twelve patients had decompensation and five developed severe bacterial infections.
“Readily available noninvasive tests can be used to identify obese or overweight patients with cACLD who are at increased risk for decompensation and severe bacterial infections,” wrote the researchers.
The study noted that obesity is a challenge for noninvasive tests and is a major limitation to liver stiffness measurement on transient elastography using the standard M probe. The XL probe has been specifically designed to overcome this challenge in obese patients, but it hasn’t been evaluated for the prediction of clinical decompensation in obese patients with cACLD.
This study claimed to provide further evidence that liver stiffness measurement in combination with noninvasive tests for liver stiffness measurement, spleen size/platelet count (LSPS), portal hypertension and portal hypertension risk score can help identify patients at risk for clinical decompensation and severe bacterial infections.
The study used average area under the receiving operator curve (AUC) to calculate the ability of the markers to distinguish risk, all with 95% confidence interval: 0.803 for liver stiffness measurement, 0.829 for portal hypertension risk score, and 0.845 for LSPS (P < .001). The markers showed an even better ability to differentiate between patients at risk for developing classical clinical decompensation in follow-up from those not at risk (all 95% CI): 0.848 for liver stiffness measurement, 0.881 for portal hypertension risk score, and 0.890 for LSPS (P < .001).
“The results of the present study validate the use of [extra-large] probe for liver stiffness measurement and CAP to stratify the risk of clinical decompensation and clinically relevant events in overweight/obese patients with cACLD, particularly in case of NAFLD/NASH etiology,” wrote Dr. Mendoza and colleagues.
All study participants were followed for at least 6 months, with a median of 17 months. Patients who developed decompensation or severe bacterial infections had slightly worse liver function (higher international normalized ratio and lower albumin), lower mean platelet count (117 vs. 179 x 109/L; P < .001) and lower mean CAP (297 vs. 318 dBm; P = .030) than did patients who stayed compensated.
CAP above 220 dB/m was marginally associated with a lower risk of decompensation or severe bacterial infections on univariate analysis, as were elevated Model for End-Stage Liver Disease score, elevated Child Pugh score, low platelet count, low serum albumin, elevated serum bilirubin and increased liver stiffness measurement, LSPS, and portal hypertension risk scores.
Dr. Mendoza and colleagues have no relevant financial disclosures. The study received funding from the Swiss government.
SOURCE: Mendoza Y et al. Clin Gastroenterol Hepatol. 2020. doi: 10.1016/j.cgh.2020.04.018.
Readily available and inexpensive noninvasive tests, when used in combination with liver markers obtained with the extra-large probe, can improve the ability to predict risk for decompensation and other adverse outcomes in obese and overweight patients with compensated advanced chronic liver disease (cACLD), according to study results reported in the upcoming issue of the journal Clinical Gastroenterology and Hepatology.
The retrospective study of 272 obese and overweight patients in Bern, Switzerland, and Montreal with cACLD is the first to fully assess the noninvasive marker of portal hypertension along with using the extra-large probe for controlled attenuation parameter (CAP) to determine risk, wrote Yuly Mendoza, MD, of the University of Bern and colleagues. Decompensation in cACLD carries a higher risk of death. The study noted that portal hypertension is a key driver of progression to decompensation, “and as such, it should be identified as soon as possible and treated as needed.”
“Prediction of prognosis in cACLD is challenging, and noninvasive tests are important tools for clinicians to avoid as much as possible the use of more invasive tests,” wrote Dr. Mendoza and colleagues. Based on the extra-large probe, 76% (n = 206) of study patients had metabolic syndrome, sometimes with other etiologies of liver disease, and 57% (n = 154) had cACLD because of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH).
Twelve patients had decompensation and five developed severe bacterial infections.
“Readily available noninvasive tests can be used to identify obese or overweight patients with cACLD who are at increased risk for decompensation and severe bacterial infections,” wrote the researchers.
The study noted that obesity is a challenge for noninvasive tests and is a major limitation to liver stiffness measurement on transient elastography using the standard M probe. The XL probe has been specifically designed to overcome this challenge in obese patients, but it hasn’t been evaluated for the prediction of clinical decompensation in obese patients with cACLD.
This study claimed to provide further evidence that liver stiffness measurement in combination with noninvasive tests for liver stiffness measurement, spleen size/platelet count (LSPS), portal hypertension and portal hypertension risk score can help identify patients at risk for clinical decompensation and severe bacterial infections.
The study used average area under the receiving operator curve (AUC) to calculate the ability of the markers to distinguish risk, all with 95% confidence interval: 0.803 for liver stiffness measurement, 0.829 for portal hypertension risk score, and 0.845 for LSPS (P < .001). The markers showed an even better ability to differentiate between patients at risk for developing classical clinical decompensation in follow-up from those not at risk (all 95% CI): 0.848 for liver stiffness measurement, 0.881 for portal hypertension risk score, and 0.890 for LSPS (P < .001).
“The results of the present study validate the use of [extra-large] probe for liver stiffness measurement and CAP to stratify the risk of clinical decompensation and clinically relevant events in overweight/obese patients with cACLD, particularly in case of NAFLD/NASH etiology,” wrote Dr. Mendoza and colleagues.
All study participants were followed for at least 6 months, with a median of 17 months. Patients who developed decompensation or severe bacterial infections had slightly worse liver function (higher international normalized ratio and lower albumin), lower mean platelet count (117 vs. 179 x 109/L; P < .001) and lower mean CAP (297 vs. 318 dBm; P = .030) than did patients who stayed compensated.
CAP above 220 dB/m was marginally associated with a lower risk of decompensation or severe bacterial infections on univariate analysis, as were elevated Model for End-Stage Liver Disease score, elevated Child Pugh score, low platelet count, low serum albumin, elevated serum bilirubin and increased liver stiffness measurement, LSPS, and portal hypertension risk scores.
Dr. Mendoza and colleagues have no relevant financial disclosures. The study received funding from the Swiss government.
SOURCE: Mendoza Y et al. Clin Gastroenterol Hepatol. 2020. doi: 10.1016/j.cgh.2020.04.018.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Consensus recommendations on AMI management during COVID-19
A consensus statement from the American College of Cardiology (ACC), the American College of Emergency Physicians (ACEP), and the Society for Cardiovascular Angiography & Interventions (SCAI) outlines recommendations for a systematic approach for the care of patients with an acute myocardial infarction (AMI) during the COVID-19 pandemic.
The statement was published in the Journal of the American College of Cardiology.
During the COVID-19 pandemic, percutaneous coronary intervention (PCI) remains the standard of care for patients with ST-segment elevation MI (STEMI) at PCI-capable hospitals when it can be provided in a timely fashion in a dedicated cardiac catheterization laboratory with an expert care team wearing personal protection equipment (PPE), the writing group advised.
“A fibrinolysis-based strategy may be entertained at non-PCI capable referral hospitals or in specific situations where primary PCI cannot be executed or is not deemed the best option,” they said.
SCAI President Ehtisham Mahmud, MD, of the University of California, San Diego, and the writing group also said that clinicians should recognize that cardiovascular manifestations of COVID-19 are “complex” in patients presenting with AMI, myocarditis simulating a STEMI, stress cardiomyopathy, nonischemic cardiomyopathy, coronary spasm, or nonspecific myocardial injury.
A “broad differential diagnosis for ST elevations (including COVID-associated myocarditis) should be considered in the ED prior to choosing a reperfusion strategy,” they advised.
In the absence of hemodynamic instability or ongoing ischemic symptoms, non-STEMI patients with known or suspected COVID-19 are best managed with an initial medical stabilization strategy, the group said.
They also said it is “imperative that health care workers use appropriate PPE for all invasive procedures during this pandemic” and that new rapid COVID-19 testing be “expeditiously” disseminated to all hospitals that manage patients with AMI.
Major challenges are that the prevalence of the COVID-19 in the United States remains unknown and there is the risk for asymptomatic spread.
The writing group said it’s “critical” to “inform the public that we can minimize exposure to the coronavirus so they can continue to call the Emergency Medical System (EMS) for acute ischemic heart disease symptoms and therefore get the appropriate level of cardiac care that their presentation warrants.”
This research had no commercial funding. Dr. Mahmud reported receiving clinical trial research support from Corindus, Abbott Vascular, and CSI; consulting with Medtronic; and consulting and equity with Abiomed. A complete list of author disclosures is included with the original article.
A version of this article originally appeared on Medscape.com.
A consensus statement from the American College of Cardiology (ACC), the American College of Emergency Physicians (ACEP), and the Society for Cardiovascular Angiography & Interventions (SCAI) outlines recommendations for a systematic approach for the care of patients with an acute myocardial infarction (AMI) during the COVID-19 pandemic.
The statement was published in the Journal of the American College of Cardiology.
During the COVID-19 pandemic, percutaneous coronary intervention (PCI) remains the standard of care for patients with ST-segment elevation MI (STEMI) at PCI-capable hospitals when it can be provided in a timely fashion in a dedicated cardiac catheterization laboratory with an expert care team wearing personal protection equipment (PPE), the writing group advised.
“A fibrinolysis-based strategy may be entertained at non-PCI capable referral hospitals or in specific situations where primary PCI cannot be executed or is not deemed the best option,” they said.
SCAI President Ehtisham Mahmud, MD, of the University of California, San Diego, and the writing group also said that clinicians should recognize that cardiovascular manifestations of COVID-19 are “complex” in patients presenting with AMI, myocarditis simulating a STEMI, stress cardiomyopathy, nonischemic cardiomyopathy, coronary spasm, or nonspecific myocardial injury.
A “broad differential diagnosis for ST elevations (including COVID-associated myocarditis) should be considered in the ED prior to choosing a reperfusion strategy,” they advised.
In the absence of hemodynamic instability or ongoing ischemic symptoms, non-STEMI patients with known or suspected COVID-19 are best managed with an initial medical stabilization strategy, the group said.
They also said it is “imperative that health care workers use appropriate PPE for all invasive procedures during this pandemic” and that new rapid COVID-19 testing be “expeditiously” disseminated to all hospitals that manage patients with AMI.
Major challenges are that the prevalence of the COVID-19 in the United States remains unknown and there is the risk for asymptomatic spread.
The writing group said it’s “critical” to “inform the public that we can minimize exposure to the coronavirus so they can continue to call the Emergency Medical System (EMS) for acute ischemic heart disease symptoms and therefore get the appropriate level of cardiac care that their presentation warrants.”
This research had no commercial funding. Dr. Mahmud reported receiving clinical trial research support from Corindus, Abbott Vascular, and CSI; consulting with Medtronic; and consulting and equity with Abiomed. A complete list of author disclosures is included with the original article.
A version of this article originally appeared on Medscape.com.
A consensus statement from the American College of Cardiology (ACC), the American College of Emergency Physicians (ACEP), and the Society for Cardiovascular Angiography & Interventions (SCAI) outlines recommendations for a systematic approach for the care of patients with an acute myocardial infarction (AMI) during the COVID-19 pandemic.
The statement was published in the Journal of the American College of Cardiology.
During the COVID-19 pandemic, percutaneous coronary intervention (PCI) remains the standard of care for patients with ST-segment elevation MI (STEMI) at PCI-capable hospitals when it can be provided in a timely fashion in a dedicated cardiac catheterization laboratory with an expert care team wearing personal protection equipment (PPE), the writing group advised.
“A fibrinolysis-based strategy may be entertained at non-PCI capable referral hospitals or in specific situations where primary PCI cannot be executed or is not deemed the best option,” they said.
SCAI President Ehtisham Mahmud, MD, of the University of California, San Diego, and the writing group also said that clinicians should recognize that cardiovascular manifestations of COVID-19 are “complex” in patients presenting with AMI, myocarditis simulating a STEMI, stress cardiomyopathy, nonischemic cardiomyopathy, coronary spasm, or nonspecific myocardial injury.
A “broad differential diagnosis for ST elevations (including COVID-associated myocarditis) should be considered in the ED prior to choosing a reperfusion strategy,” they advised.
In the absence of hemodynamic instability or ongoing ischemic symptoms, non-STEMI patients with known or suspected COVID-19 are best managed with an initial medical stabilization strategy, the group said.
They also said it is “imperative that health care workers use appropriate PPE for all invasive procedures during this pandemic” and that new rapid COVID-19 testing be “expeditiously” disseminated to all hospitals that manage patients with AMI.
Major challenges are that the prevalence of the COVID-19 in the United States remains unknown and there is the risk for asymptomatic spread.
The writing group said it’s “critical” to “inform the public that we can minimize exposure to the coronavirus so they can continue to call the Emergency Medical System (EMS) for acute ischemic heart disease symptoms and therefore get the appropriate level of cardiac care that their presentation warrants.”
This research had no commercial funding. Dr. Mahmud reported receiving clinical trial research support from Corindus, Abbott Vascular, and CSI; consulting with Medtronic; and consulting and equity with Abiomed. A complete list of author disclosures is included with the original article.
A version of this article originally appeared on Medscape.com.
PCSK9 inhibitors unexpectedly link with lower VTE, aortic stenosis
Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.
The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.
One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.
The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).
The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.
In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).
The aortic stenosis connection
A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.
During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.
Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.
The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
What it could mean
These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.
“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.
“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”
“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.
“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.
“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
How it might work
A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).
Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”
Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.
The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”
Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
The future of Lp(a) lowering
This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).
“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”
“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.
Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”
FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.
Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.
The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.
One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.
The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).
The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.
In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).
The aortic stenosis connection
A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.
During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.
Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.
The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
What it could mean
These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.
“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.
“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”
“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.
“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.
“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
How it might work
A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).
Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”
Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.
The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”
Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
The future of Lp(a) lowering
This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).
“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”
“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.
Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”
FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.
Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.
The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.
One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.
The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).
The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.
In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).
The aortic stenosis connection
A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.
During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.
Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.
The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
What it could mean
These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.
“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.
“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”
“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.
“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.
“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
How it might work
A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).
Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”
Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.
The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”
Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
The future of Lp(a) lowering
This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).
“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”
“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.
Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”
FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.
REPORTING FROM ACC 20
Year-long synbiotic regimen fails to improve NAFLD
Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.
NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.
“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”
To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.
Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.
At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.
But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.
“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.
Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.
“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.
Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.
“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”
The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.
SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.
Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.
NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.
“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”
To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.
Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.
At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.
But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.
“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.
Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.
“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.
Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.
“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”
The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.
SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.
Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.
NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.
“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”
To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.
Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.
At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.
But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.
“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.
Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.
“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.
Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.
“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”
The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.
SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.
FROM GASTROENTEROLOGY
Noninvasive fibrosis scores not sensitive in people with fatty liver disease and T2D
Noninvasive fibrosis scores, which are widely used to predict advanced fibrosis in people with nonalcoholic fatty liver disease (NAFLD), do not do a good job of picking up advanced fibrosis in patients with underlying diabetes, according to a new study.
Advanced fibrosis is associated with an increased risk of cirrhosis, end-stage liver disease, and liver failure. Underlying diabetes is a risk factor for both advanced fibrosis and death in patients with NAFLD.
While liver biopsy remains the gold standard for detecting advanced fibrosis, high costs and risks limit its use. Noninvasive scores such as the AST/ALT ratio; AST to platelet ratio index (APRI); fibrosis-4 (FIB-4) index; and NAFLD fibrosis score (NFS) have gained popularity in recent years, as they offer the compelling advantage of using easily and cheaply attained clinical and laboratory measures to assess likelihood of disease.
But their accuracy has come into question, particularly for people with diabetes.
In research published in the Journal of Clinical Gastroenterology, Amandeep Singh, MD, and colleagues at the Cleveland Clinic looked at their center’s records for 1,157 patients with type 2 diabetes (65% women, 88% white, 85% with obesity) who had undergone a liver biopsy for suspected advanced fibrosis between 2000 and 2015. Biopsy results revealed that a third of the cohort (32%) was positive for advanced fibrosis.
The investigators then pulled patients’ laboratory results for AST, ALT, cholesterol, triglycerides, fasting glucose, hemoglobin A1c, bilirubin, albumin, platelet count, alkaline phosphatase, albumin, and lipid levels, all collected within a year of biopsy. After plugging these into the algorithms of four different scoring systems for advanced fibrosis, they compared results with results from the biopsies.
The scores of AST/ALT greater than 1.4, APRI of at least 1.5, NFS greater than 0.676, and FIB-4 index greater than 2.67 had high specificities of 84%, 97%, 70%, and 93%, respectively, but sensitivities of only 27%, 17%, 64%, and 44%. Even when the cutoff measures were tightened, the scoring systems still missed a lot of disease. This suggests, Dr. Singh and colleagues wrote, that “the presence of diabetes could decrease the predictive value of these scores to detect advanced disease in NAFLD patients.” Reliable noninvasive biomarkers are “urgently needed” for this patient population.
In an interview, Dr. Singh advised that clinicians continue to use current noninvasive scores in patients with diabetes – preferably the NFS – “until we have a better scoring system.” If clinicians suspect advanced fibrosis based on lab tests and clinical data, then “liver biopsy should be considered,” he said.
The investigators described among the limitations of their study its retrospective, single-center design, with patients who were mostly white and from one geographic region.
Dr. Singh and colleagues reported no conflicts of interest or outside funding for their study.
SOURCE: Singh A et al. J Clin Gastroenterol. 2020 Mar 11. doi: 10.1097/MCG.0000000000001339.
Noninvasive fibrosis scores, which are widely used to predict advanced fibrosis in people with nonalcoholic fatty liver disease (NAFLD), do not do a good job of picking up advanced fibrosis in patients with underlying diabetes, according to a new study.
Advanced fibrosis is associated with an increased risk of cirrhosis, end-stage liver disease, and liver failure. Underlying diabetes is a risk factor for both advanced fibrosis and death in patients with NAFLD.
While liver biopsy remains the gold standard for detecting advanced fibrosis, high costs and risks limit its use. Noninvasive scores such as the AST/ALT ratio; AST to platelet ratio index (APRI); fibrosis-4 (FIB-4) index; and NAFLD fibrosis score (NFS) have gained popularity in recent years, as they offer the compelling advantage of using easily and cheaply attained clinical and laboratory measures to assess likelihood of disease.
But their accuracy has come into question, particularly for people with diabetes.
In research published in the Journal of Clinical Gastroenterology, Amandeep Singh, MD, and colleagues at the Cleveland Clinic looked at their center’s records for 1,157 patients with type 2 diabetes (65% women, 88% white, 85% with obesity) who had undergone a liver biopsy for suspected advanced fibrosis between 2000 and 2015. Biopsy results revealed that a third of the cohort (32%) was positive for advanced fibrosis.
The investigators then pulled patients’ laboratory results for AST, ALT, cholesterol, triglycerides, fasting glucose, hemoglobin A1c, bilirubin, albumin, platelet count, alkaline phosphatase, albumin, and lipid levels, all collected within a year of biopsy. After plugging these into the algorithms of four different scoring systems for advanced fibrosis, they compared results with results from the biopsies.
The scores of AST/ALT greater than 1.4, APRI of at least 1.5, NFS greater than 0.676, and FIB-4 index greater than 2.67 had high specificities of 84%, 97%, 70%, and 93%, respectively, but sensitivities of only 27%, 17%, 64%, and 44%. Even when the cutoff measures were tightened, the scoring systems still missed a lot of disease. This suggests, Dr. Singh and colleagues wrote, that “the presence of diabetes could decrease the predictive value of these scores to detect advanced disease in NAFLD patients.” Reliable noninvasive biomarkers are “urgently needed” for this patient population.
In an interview, Dr. Singh advised that clinicians continue to use current noninvasive scores in patients with diabetes – preferably the NFS – “until we have a better scoring system.” If clinicians suspect advanced fibrosis based on lab tests and clinical data, then “liver biopsy should be considered,” he said.
The investigators described among the limitations of their study its retrospective, single-center design, with patients who were mostly white and from one geographic region.
Dr. Singh and colleagues reported no conflicts of interest or outside funding for their study.
SOURCE: Singh A et al. J Clin Gastroenterol. 2020 Mar 11. doi: 10.1097/MCG.0000000000001339.
Noninvasive fibrosis scores, which are widely used to predict advanced fibrosis in people with nonalcoholic fatty liver disease (NAFLD), do not do a good job of picking up advanced fibrosis in patients with underlying diabetes, according to a new study.
Advanced fibrosis is associated with an increased risk of cirrhosis, end-stage liver disease, and liver failure. Underlying diabetes is a risk factor for both advanced fibrosis and death in patients with NAFLD.
While liver biopsy remains the gold standard for detecting advanced fibrosis, high costs and risks limit its use. Noninvasive scores such as the AST/ALT ratio; AST to platelet ratio index (APRI); fibrosis-4 (FIB-4) index; and NAFLD fibrosis score (NFS) have gained popularity in recent years, as they offer the compelling advantage of using easily and cheaply attained clinical and laboratory measures to assess likelihood of disease.
But their accuracy has come into question, particularly for people with diabetes.
In research published in the Journal of Clinical Gastroenterology, Amandeep Singh, MD, and colleagues at the Cleveland Clinic looked at their center’s records for 1,157 patients with type 2 diabetes (65% women, 88% white, 85% with obesity) who had undergone a liver biopsy for suspected advanced fibrosis between 2000 and 2015. Biopsy results revealed that a third of the cohort (32%) was positive for advanced fibrosis.
The investigators then pulled patients’ laboratory results for AST, ALT, cholesterol, triglycerides, fasting glucose, hemoglobin A1c, bilirubin, albumin, platelet count, alkaline phosphatase, albumin, and lipid levels, all collected within a year of biopsy. After plugging these into the algorithms of four different scoring systems for advanced fibrosis, they compared results with results from the biopsies.
The scores of AST/ALT greater than 1.4, APRI of at least 1.5, NFS greater than 0.676, and FIB-4 index greater than 2.67 had high specificities of 84%, 97%, 70%, and 93%, respectively, but sensitivities of only 27%, 17%, 64%, and 44%. Even when the cutoff measures were tightened, the scoring systems still missed a lot of disease. This suggests, Dr. Singh and colleagues wrote, that “the presence of diabetes could decrease the predictive value of these scores to detect advanced disease in NAFLD patients.” Reliable noninvasive biomarkers are “urgently needed” for this patient population.
In an interview, Dr. Singh advised that clinicians continue to use current noninvasive scores in patients with diabetes – preferably the NFS – “until we have a better scoring system.” If clinicians suspect advanced fibrosis based on lab tests and clinical data, then “liver biopsy should be considered,” he said.
The investigators described among the limitations of their study its retrospective, single-center design, with patients who were mostly white and from one geographic region.
Dr. Singh and colleagues reported no conflicts of interest or outside funding for their study.
SOURCE: Singh A et al. J Clin Gastroenterol. 2020 Mar 11. doi: 10.1097/MCG.0000000000001339.
FROM THE JOURNAL OF CLINICAL GASTROENTEROLOGY
New lipid-lowering drug class slashes LDL in HoFH patients
Evinacumab, the first agent from a new class of lipid-lowering drugs, showed a “remarkable” and unprecedented level of LDL-cholesterol lowering in a pivotal trial with 65 patients with homozygous familial hypercholesterolemia.
Monthly intravenous infusions of evinacumab cut LDL cholesterol levels by an average of 135 mg/dL from baseline, a 47% mean reduction, after 24 weeks of treatment in 43 homozygous familial hypercholesterolemia (HoFH) patients, Frederick Raal, MBChB, said on March 30 in a video presentation of his research at the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
Evinacumab is a human monoclonal antibody inhibitor of angiopoietin-like 3, a liver protein that boosts levels of LDL cholesterol and triglycerides (TG).
Another notable effect of the novel agent was that it was equally effective in the roughly one-third of patients with a minimal residual level of LDL receptor activity, patients know as having “null/null” mutations. “For the first time, we see HoFH patients getting to [lipid] targets that we never thought would be possible,” said Dr. Raal, professor and head of endocrinology and metabolism at the University of Witwatersrand in Johannesburg, South Africa. “This works in patients without residual LDL receptor function.” The drug was also generally very well tolerated, he said, causing no treatment-related serious adverse events during the brief treatment period of 24 weeks.
“One of the major, remarkable findings in this study was the effect on null/null patients,” which contrasts with the effects of other, more established drugs for treating dyslipidemia like statins and PCSK9 inhibitors, which work by increasing the number of LDL receptors on cells. The demonstrated efficacy and safety of evinacumab in null/null patients “is a definite advance,” commented Anne C. Goldberg, MD, a lipidologist and professor of medicine at Washington University in St. Louis.
The placebo-controlled trial randomized patients at 30 sites in 11 countries who were at least 12 years old and had documented mutations in both of their LDL receptor genes and a serum level of LDL cholesterol that was at least 500 mg/dL on no treatment. Patients averaged about 40 years of age; about 30% had null/null mutations, more than 90% were on statin treatment, and about three-quarters were receiving regular treatment with a PCSK9 inhibitor. At baseline, LDL cholesterol levels averaged about 250 mg/dL.
The study’s primary endpoint was the between-group percentage change in LDL cholesterol level after 24 weeks, which fell by 47% from baseline with evinacumab treatment and increased by an average of 2% among 22 patients who received placebo injections; so evinacumab cut this measure by 49%, compared with placebo after 24 weeks, a statistically significant difference. A cut of baseline LDL cholesterol by at least 50% occurred in 56% of the evinacumab-treated patients and in 5% of controls.
In addition to its LDL reduction, another notable effect of evinacumab was that it trimmed baseline triglyceride levels by half, consistent with prior reports of the drug’s effect on this measure, although average triglyceride levels in the enrolled patients fell within the normal range prior to treatment.
Evinacumab “will probably be very effective in treating patients with hypertriglyceridemia; those studies are ongoing,” noted Dr. Raal. But, he added, “this drug will probably be reserved for severe” dyslipidemia cases, not for “the garden variety of moderate hypertriglyceridemia or hypercholesterolemia.”
Evinacumab “may be a fairly broad-spectrum lipid-lowering drug, but it should be reserved for severe cases,” agreed Dirk Blom, MBChB, head of lipidology at the University of Capetown, South Africa. “This will likely remain a fairly expensive drug, and we wouldn’t want to use it across the board, but for difficult to treat patients with either severe hypercholesterolemia or hypertriglyceridemia, I think this will have very significant advantages,” he commented.
“Drugs that reduce triglycerides by large amounts may prove to have cardiovascular disease benefits, but that remains to be proven in large, long-term outcome trials,” commented Deepak Bhatt, MD, professor of medicine at Harvard Medical School and executive director of interventional cardiology programs at Brigham and Women’s Hospital, both in Boston. “But for right now, for most patients with more common forms of elevated LDL cholesterol, the treatment options include statins, ezetimibe [Zetia], and PCSK9 inhibitors, and for more common levels of elevated triglycerides, it’s icosapent ethyl [Vascepa],” Dr. Bhatt said.
The study was sponsored by Regeneron, the company developing evinacumab and which is partially owned by Sanofi. Dr. Raal has received personal fees and/or research funding from Regeneron, Sanofi Aventis, Amgen, and The Medicines Company. Dr. Goldberg has received research funding and/or consulting fees from Regeneron and Sanofi, Akcea, Amarin, Amgen, Esperion, Ionis, Merck, Novartis, and Pfizer. Dr. Blom has been a consultant to and/or received research funding from Regeneron, Sanofi, Aegerium, Akcea, Amgen, Amryt, AstraZeneca, Eli Lilly, Esperion, Gemphire, MSD, and Novo Nordisk. Dr. Bhatt has received research funding from many companies including Regeneron and Sanofi.
SOURCE: Raal F. ACC 20. Abstract 411-12.
Evinacumab, the first agent from a new class of lipid-lowering drugs, showed a “remarkable” and unprecedented level of LDL-cholesterol lowering in a pivotal trial with 65 patients with homozygous familial hypercholesterolemia.
Monthly intravenous infusions of evinacumab cut LDL cholesterol levels by an average of 135 mg/dL from baseline, a 47% mean reduction, after 24 weeks of treatment in 43 homozygous familial hypercholesterolemia (HoFH) patients, Frederick Raal, MBChB, said on March 30 in a video presentation of his research at the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
Evinacumab is a human monoclonal antibody inhibitor of angiopoietin-like 3, a liver protein that boosts levels of LDL cholesterol and triglycerides (TG).
Another notable effect of the novel agent was that it was equally effective in the roughly one-third of patients with a minimal residual level of LDL receptor activity, patients know as having “null/null” mutations. “For the first time, we see HoFH patients getting to [lipid] targets that we never thought would be possible,” said Dr. Raal, professor and head of endocrinology and metabolism at the University of Witwatersrand in Johannesburg, South Africa. “This works in patients without residual LDL receptor function.” The drug was also generally very well tolerated, he said, causing no treatment-related serious adverse events during the brief treatment period of 24 weeks.
“One of the major, remarkable findings in this study was the effect on null/null patients,” which contrasts with the effects of other, more established drugs for treating dyslipidemia like statins and PCSK9 inhibitors, which work by increasing the number of LDL receptors on cells. The demonstrated efficacy and safety of evinacumab in null/null patients “is a definite advance,” commented Anne C. Goldberg, MD, a lipidologist and professor of medicine at Washington University in St. Louis.
The placebo-controlled trial randomized patients at 30 sites in 11 countries who were at least 12 years old and had documented mutations in both of their LDL receptor genes and a serum level of LDL cholesterol that was at least 500 mg/dL on no treatment. Patients averaged about 40 years of age; about 30% had null/null mutations, more than 90% were on statin treatment, and about three-quarters were receiving regular treatment with a PCSK9 inhibitor. At baseline, LDL cholesterol levels averaged about 250 mg/dL.
The study’s primary endpoint was the between-group percentage change in LDL cholesterol level after 24 weeks, which fell by 47% from baseline with evinacumab treatment and increased by an average of 2% among 22 patients who received placebo injections; so evinacumab cut this measure by 49%, compared with placebo after 24 weeks, a statistically significant difference. A cut of baseline LDL cholesterol by at least 50% occurred in 56% of the evinacumab-treated patients and in 5% of controls.
In addition to its LDL reduction, another notable effect of evinacumab was that it trimmed baseline triglyceride levels by half, consistent with prior reports of the drug’s effect on this measure, although average triglyceride levels in the enrolled patients fell within the normal range prior to treatment.
Evinacumab “will probably be very effective in treating patients with hypertriglyceridemia; those studies are ongoing,” noted Dr. Raal. But, he added, “this drug will probably be reserved for severe” dyslipidemia cases, not for “the garden variety of moderate hypertriglyceridemia or hypercholesterolemia.”
Evinacumab “may be a fairly broad-spectrum lipid-lowering drug, but it should be reserved for severe cases,” agreed Dirk Blom, MBChB, head of lipidology at the University of Capetown, South Africa. “This will likely remain a fairly expensive drug, and we wouldn’t want to use it across the board, but for difficult to treat patients with either severe hypercholesterolemia or hypertriglyceridemia, I think this will have very significant advantages,” he commented.
“Drugs that reduce triglycerides by large amounts may prove to have cardiovascular disease benefits, but that remains to be proven in large, long-term outcome trials,” commented Deepak Bhatt, MD, professor of medicine at Harvard Medical School and executive director of interventional cardiology programs at Brigham and Women’s Hospital, both in Boston. “But for right now, for most patients with more common forms of elevated LDL cholesterol, the treatment options include statins, ezetimibe [Zetia], and PCSK9 inhibitors, and for more common levels of elevated triglycerides, it’s icosapent ethyl [Vascepa],” Dr. Bhatt said.
The study was sponsored by Regeneron, the company developing evinacumab and which is partially owned by Sanofi. Dr. Raal has received personal fees and/or research funding from Regeneron, Sanofi Aventis, Amgen, and The Medicines Company. Dr. Goldberg has received research funding and/or consulting fees from Regeneron and Sanofi, Akcea, Amarin, Amgen, Esperion, Ionis, Merck, Novartis, and Pfizer. Dr. Blom has been a consultant to and/or received research funding from Regeneron, Sanofi, Aegerium, Akcea, Amgen, Amryt, AstraZeneca, Eli Lilly, Esperion, Gemphire, MSD, and Novo Nordisk. Dr. Bhatt has received research funding from many companies including Regeneron and Sanofi.
SOURCE: Raal F. ACC 20. Abstract 411-12.
Evinacumab, the first agent from a new class of lipid-lowering drugs, showed a “remarkable” and unprecedented level of LDL-cholesterol lowering in a pivotal trial with 65 patients with homozygous familial hypercholesterolemia.
Monthly intravenous infusions of evinacumab cut LDL cholesterol levels by an average of 135 mg/dL from baseline, a 47% mean reduction, after 24 weeks of treatment in 43 homozygous familial hypercholesterolemia (HoFH) patients, Frederick Raal, MBChB, said on March 30 in a video presentation of his research at the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
Evinacumab is a human monoclonal antibody inhibitor of angiopoietin-like 3, a liver protein that boosts levels of LDL cholesterol and triglycerides (TG).
Another notable effect of the novel agent was that it was equally effective in the roughly one-third of patients with a minimal residual level of LDL receptor activity, patients know as having “null/null” mutations. “For the first time, we see HoFH patients getting to [lipid] targets that we never thought would be possible,” said Dr. Raal, professor and head of endocrinology and metabolism at the University of Witwatersrand in Johannesburg, South Africa. “This works in patients without residual LDL receptor function.” The drug was also generally very well tolerated, he said, causing no treatment-related serious adverse events during the brief treatment period of 24 weeks.
“One of the major, remarkable findings in this study was the effect on null/null patients,” which contrasts with the effects of other, more established drugs for treating dyslipidemia like statins and PCSK9 inhibitors, which work by increasing the number of LDL receptors on cells. The demonstrated efficacy and safety of evinacumab in null/null patients “is a definite advance,” commented Anne C. Goldberg, MD, a lipidologist and professor of medicine at Washington University in St. Louis.
The placebo-controlled trial randomized patients at 30 sites in 11 countries who were at least 12 years old and had documented mutations in both of their LDL receptor genes and a serum level of LDL cholesterol that was at least 500 mg/dL on no treatment. Patients averaged about 40 years of age; about 30% had null/null mutations, more than 90% were on statin treatment, and about three-quarters were receiving regular treatment with a PCSK9 inhibitor. At baseline, LDL cholesterol levels averaged about 250 mg/dL.
The study’s primary endpoint was the between-group percentage change in LDL cholesterol level after 24 weeks, which fell by 47% from baseline with evinacumab treatment and increased by an average of 2% among 22 patients who received placebo injections; so evinacumab cut this measure by 49%, compared with placebo after 24 weeks, a statistically significant difference. A cut of baseline LDL cholesterol by at least 50% occurred in 56% of the evinacumab-treated patients and in 5% of controls.
In addition to its LDL reduction, another notable effect of evinacumab was that it trimmed baseline triglyceride levels by half, consistent with prior reports of the drug’s effect on this measure, although average triglyceride levels in the enrolled patients fell within the normal range prior to treatment.
Evinacumab “will probably be very effective in treating patients with hypertriglyceridemia; those studies are ongoing,” noted Dr. Raal. But, he added, “this drug will probably be reserved for severe” dyslipidemia cases, not for “the garden variety of moderate hypertriglyceridemia or hypercholesterolemia.”
Evinacumab “may be a fairly broad-spectrum lipid-lowering drug, but it should be reserved for severe cases,” agreed Dirk Blom, MBChB, head of lipidology at the University of Capetown, South Africa. “This will likely remain a fairly expensive drug, and we wouldn’t want to use it across the board, but for difficult to treat patients with either severe hypercholesterolemia or hypertriglyceridemia, I think this will have very significant advantages,” he commented.
“Drugs that reduce triglycerides by large amounts may prove to have cardiovascular disease benefits, but that remains to be proven in large, long-term outcome trials,” commented Deepak Bhatt, MD, professor of medicine at Harvard Medical School and executive director of interventional cardiology programs at Brigham and Women’s Hospital, both in Boston. “But for right now, for most patients with more common forms of elevated LDL cholesterol, the treatment options include statins, ezetimibe [Zetia], and PCSK9 inhibitors, and for more common levels of elevated triglycerides, it’s icosapent ethyl [Vascepa],” Dr. Bhatt said.
The study was sponsored by Regeneron, the company developing evinacumab and which is partially owned by Sanofi. Dr. Raal has received personal fees and/or research funding from Regeneron, Sanofi Aventis, Amgen, and The Medicines Company. Dr. Goldberg has received research funding and/or consulting fees from Regeneron and Sanofi, Akcea, Amarin, Amgen, Esperion, Ionis, Merck, Novartis, and Pfizer. Dr. Blom has been a consultant to and/or received research funding from Regeneron, Sanofi, Aegerium, Akcea, Amgen, Amryt, AstraZeneca, Eli Lilly, Esperion, Gemphire, MSD, and Novo Nordisk. Dr. Bhatt has received research funding from many companies including Regeneron and Sanofi.
SOURCE: Raal F. ACC 20. Abstract 411-12.
REPORTING FROM ACC 2020
Alirocumab effective in homozygous FH
Alirocumab achieved a mean 63-mg/dL reduction in LDL cholesterol in the ODYSSEY HoFH study, the largest-ever randomized, placebo-controlled clinical trial of lipid-lowering in adults with homozygous familial hypercholesterolemia (HoFH), Dirk Blom, MD, said in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
“We’re not getting most patients to goal, but we’re certainly getting them closer to goal. A lot of patients will still need further therapies that don’t rely on up-regulation of the LDL receptor, such as lipoprotein apheresis,” observed Dr. Blom, head of the division of lipidology at the University of Cape Town (South Africa).
Of the patients on alirocumab, 57%had at least a 30% reduction in LDL at 12 weeks, and 27% had a 50% reduction or more.
Alirocumab had salutary effects on other atherogenic lipids: roughly a 20% reduction from baseline in lipoprotein (a), a 23% decrease in apolipoprotein B, and a 25% reduction in non-HDL cholesterol.
Dr. Blom noted that, as is also the case for statins in HoFH, the LDL response to alirocumab in patients with this genetically complex disorder is more variable and generally weaker than in other hypercholesterolemic populations.
“We saw some patients getting up to 60%-70% LDL reduction in alirocumab, but a lot of patients getting much less,” he said.
Alirocumab was well tolerated in adults with HoFH, with the same favorable safety profile that’s been established in other patient populations.
Discussant Raul Santos, MD, commented that the ODYSSEY HoFH results are quite similar to those reported in patients with HoFH in an earlier study of evolocumab (Repatha), another PCSK9 inhibitor. The magnitude of LDL-lowering achieved with these biologic agents is such that, were treatment to start early in life, patients with HoFH might expect to experience an extra 10-15 years of life free of cardiovascular events.
“Certainly PCSK9 inhibitors should be the next step after statins and ezetimibe. They’re much less expensive and more available than apheresis,” said Dr. Santos, director of the lipid clinic at the Heart Institute of the University of São Paulo.
Since many patients with this rare disorder experience their first cardiovascular event in adolescence or young adulthood, Dr. Santos said, it’s very important to expand PCSK9 inhibitor therapy to the pediatric HoFH population. Two studies are ongoing in childlren.
The ODYSSEY HoFH trial was funded by Regeneron and Sanofi. Dr. Blom reported serving as a paid consultant to Sanofi, Akcea, Amgen, and Gemphire.
Alirocumab achieved a mean 63-mg/dL reduction in LDL cholesterol in the ODYSSEY HoFH study, the largest-ever randomized, placebo-controlled clinical trial of lipid-lowering in adults with homozygous familial hypercholesterolemia (HoFH), Dirk Blom, MD, said in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
“We’re not getting most patients to goal, but we’re certainly getting them closer to goal. A lot of patients will still need further therapies that don’t rely on up-regulation of the LDL receptor, such as lipoprotein apheresis,” observed Dr. Blom, head of the division of lipidology at the University of Cape Town (South Africa).
Of the patients on alirocumab, 57%had at least a 30% reduction in LDL at 12 weeks, and 27% had a 50% reduction or more.
Alirocumab had salutary effects on other atherogenic lipids: roughly a 20% reduction from baseline in lipoprotein (a), a 23% decrease in apolipoprotein B, and a 25% reduction in non-HDL cholesterol.
Dr. Blom noted that, as is also the case for statins in HoFH, the LDL response to alirocumab in patients with this genetically complex disorder is more variable and generally weaker than in other hypercholesterolemic populations.
“We saw some patients getting up to 60%-70% LDL reduction in alirocumab, but a lot of patients getting much less,” he said.
Alirocumab was well tolerated in adults with HoFH, with the same favorable safety profile that’s been established in other patient populations.
Discussant Raul Santos, MD, commented that the ODYSSEY HoFH results are quite similar to those reported in patients with HoFH in an earlier study of evolocumab (Repatha), another PCSK9 inhibitor. The magnitude of LDL-lowering achieved with these biologic agents is such that, were treatment to start early in life, patients with HoFH might expect to experience an extra 10-15 years of life free of cardiovascular events.
“Certainly PCSK9 inhibitors should be the next step after statins and ezetimibe. They’re much less expensive and more available than apheresis,” said Dr. Santos, director of the lipid clinic at the Heart Institute of the University of São Paulo.
Since many patients with this rare disorder experience their first cardiovascular event in adolescence or young adulthood, Dr. Santos said, it’s very important to expand PCSK9 inhibitor therapy to the pediatric HoFH population. Two studies are ongoing in childlren.
The ODYSSEY HoFH trial was funded by Regeneron and Sanofi. Dr. Blom reported serving as a paid consultant to Sanofi, Akcea, Amgen, and Gemphire.
Alirocumab achieved a mean 63-mg/dL reduction in LDL cholesterol in the ODYSSEY HoFH study, the largest-ever randomized, placebo-controlled clinical trial of lipid-lowering in adults with homozygous familial hypercholesterolemia (HoFH), Dirk Blom, MD, said in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
“We’re not getting most patients to goal, but we’re certainly getting them closer to goal. A lot of patients will still need further therapies that don’t rely on up-regulation of the LDL receptor, such as lipoprotein apheresis,” observed Dr. Blom, head of the division of lipidology at the University of Cape Town (South Africa).
Of the patients on alirocumab, 57%had at least a 30% reduction in LDL at 12 weeks, and 27% had a 50% reduction or more.
Alirocumab had salutary effects on other atherogenic lipids: roughly a 20% reduction from baseline in lipoprotein (a), a 23% decrease in apolipoprotein B, and a 25% reduction in non-HDL cholesterol.
Dr. Blom noted that, as is also the case for statins in HoFH, the LDL response to alirocumab in patients with this genetically complex disorder is more variable and generally weaker than in other hypercholesterolemic populations.
“We saw some patients getting up to 60%-70% LDL reduction in alirocumab, but a lot of patients getting much less,” he said.
Alirocumab was well tolerated in adults with HoFH, with the same favorable safety profile that’s been established in other patient populations.
Discussant Raul Santos, MD, commented that the ODYSSEY HoFH results are quite similar to those reported in patients with HoFH in an earlier study of evolocumab (Repatha), another PCSK9 inhibitor. The magnitude of LDL-lowering achieved with these biologic agents is such that, were treatment to start early in life, patients with HoFH might expect to experience an extra 10-15 years of life free of cardiovascular events.
“Certainly PCSK9 inhibitors should be the next step after statins and ezetimibe. They’re much less expensive and more available than apheresis,” said Dr. Santos, director of the lipid clinic at the Heart Institute of the University of São Paulo.
Since many patients with this rare disorder experience their first cardiovascular event in adolescence or young adulthood, Dr. Santos said, it’s very important to expand PCSK9 inhibitor therapy to the pediatric HoFH population. Two studies are ongoing in childlren.
The ODYSSEY HoFH trial was funded by Regeneron and Sanofi. Dr. Blom reported serving as a paid consultant to Sanofi, Akcea, Amgen, and Gemphire.
REPORTING FROM ACC 2020