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Dapagliflozin’s HFpEF benefit recasts heart failure treatment: DELIVER
BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.
These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).
The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.
The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.
A key finding of DELIVER, confirmed in several combined analyses also reported at the congress, was that the benefit of dapagliflozin treatment extended to patients with HFpEF in the highest ranges of ejection fraction, stressed Dr. Solomon, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
Combined analyses document consistency
Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.
The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.
A second, prespecified combined analysis coupled the DELIVER findings with the results of a prior large trial that assessed empagliflozin in patients with HFpEF, EMPEROR-Preserved, which had shown similar findings but with an apparent diminishment of activity in patients at the highest range of preserved left ventricular function, with ejection fractions in excess of about 65%, a tail-off of effect not seen in DELIVER.
In EMPEROR-Preserved alone, patients with ejection fractions of 60% or greater did not show a significant benefit from empagliflozin treatment, although the data showed a numerical trend toward fewer adverse outcome events. When combined with the DELIVER data in a total of 12,251 patients, the subgroup of more than 3,800 patients with an ejection fraction of at least 60% showed a significant 19% relative reduction, compared with placebo in the rate of cardiovascular death or hospitalization for heart failure, reported Muthiah Vaduganathan, MD, in a separate talk at the congress, a finding that confirms the efficacy of SGLT2 inhibitors in this subgroup of patients.
A third combined analysis, also presented by Dr. Vaduganathan, added to these 12,000 patients’ data from DAPA-HF, the empagliflozin trial in patients with HFrEF called EMPEROR-Reduced, and a study of a third SGLT2 inhibitor, sotagliflozin, SOLOIST-WHF, an amalgam of more than 21,000 patients. Again, the results showed cross-trial consistency, and a significant, overall 23% reduction, compared with placebo in the rate of cardiovascular death or hospitalization for heart failure, with a number-needed-to-treat of 25 to prevent one of these events during an average follow-up of 23 months.
“The totality of evidence supports prioritizing the use of SGLT2 inhibitors in all patients with heart failure irrespective of phenotype or care setting,” concluded Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital, Boston. Simultaneous with his talk the details of the two combined analyses he presented appeared in The Lancet.
A ‘swan song’ for ejection fraction
“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.
“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.
DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.
BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.
These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).
The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.
The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.
A key finding of DELIVER, confirmed in several combined analyses also reported at the congress, was that the benefit of dapagliflozin treatment extended to patients with HFpEF in the highest ranges of ejection fraction, stressed Dr. Solomon, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
Combined analyses document consistency
Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.
The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.
A second, prespecified combined analysis coupled the DELIVER findings with the results of a prior large trial that assessed empagliflozin in patients with HFpEF, EMPEROR-Preserved, which had shown similar findings but with an apparent diminishment of activity in patients at the highest range of preserved left ventricular function, with ejection fractions in excess of about 65%, a tail-off of effect not seen in DELIVER.
In EMPEROR-Preserved alone, patients with ejection fractions of 60% or greater did not show a significant benefit from empagliflozin treatment, although the data showed a numerical trend toward fewer adverse outcome events. When combined with the DELIVER data in a total of 12,251 patients, the subgroup of more than 3,800 patients with an ejection fraction of at least 60% showed a significant 19% relative reduction, compared with placebo in the rate of cardiovascular death or hospitalization for heart failure, reported Muthiah Vaduganathan, MD, in a separate talk at the congress, a finding that confirms the efficacy of SGLT2 inhibitors in this subgroup of patients.
A third combined analysis, also presented by Dr. Vaduganathan, added to these 12,000 patients’ data from DAPA-HF, the empagliflozin trial in patients with HFrEF called EMPEROR-Reduced, and a study of a third SGLT2 inhibitor, sotagliflozin, SOLOIST-WHF, an amalgam of more than 21,000 patients. Again, the results showed cross-trial consistency, and a significant, overall 23% reduction, compared with placebo in the rate of cardiovascular death or hospitalization for heart failure, with a number-needed-to-treat of 25 to prevent one of these events during an average follow-up of 23 months.
“The totality of evidence supports prioritizing the use of SGLT2 inhibitors in all patients with heart failure irrespective of phenotype or care setting,” concluded Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital, Boston. Simultaneous with his talk the details of the two combined analyses he presented appeared in The Lancet.
A ‘swan song’ for ejection fraction
“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.
“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.
DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.
BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.
These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).
The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.
The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.
A key finding of DELIVER, confirmed in several combined analyses also reported at the congress, was that the benefit of dapagliflozin treatment extended to patients with HFpEF in the highest ranges of ejection fraction, stressed Dr. Solomon, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
Combined analyses document consistency
Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.
The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.
A second, prespecified combined analysis coupled the DELIVER findings with the results of a prior large trial that assessed empagliflozin in patients with HFpEF, EMPEROR-Preserved, which had shown similar findings but with an apparent diminishment of activity in patients at the highest range of preserved left ventricular function, with ejection fractions in excess of about 65%, a tail-off of effect not seen in DELIVER.
In EMPEROR-Preserved alone, patients with ejection fractions of 60% or greater did not show a significant benefit from empagliflozin treatment, although the data showed a numerical trend toward fewer adverse outcome events. When combined with the DELIVER data in a total of 12,251 patients, the subgroup of more than 3,800 patients with an ejection fraction of at least 60% showed a significant 19% relative reduction, compared with placebo in the rate of cardiovascular death or hospitalization for heart failure, reported Muthiah Vaduganathan, MD, in a separate talk at the congress, a finding that confirms the efficacy of SGLT2 inhibitors in this subgroup of patients.
A third combined analysis, also presented by Dr. Vaduganathan, added to these 12,000 patients’ data from DAPA-HF, the empagliflozin trial in patients with HFrEF called EMPEROR-Reduced, and a study of a third SGLT2 inhibitor, sotagliflozin, SOLOIST-WHF, an amalgam of more than 21,000 patients. Again, the results showed cross-trial consistency, and a significant, overall 23% reduction, compared with placebo in the rate of cardiovascular death or hospitalization for heart failure, with a number-needed-to-treat of 25 to prevent one of these events during an average follow-up of 23 months.
“The totality of evidence supports prioritizing the use of SGLT2 inhibitors in all patients with heart failure irrespective of phenotype or care setting,” concluded Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital, Boston. Simultaneous with his talk the details of the two combined analyses he presented appeared in The Lancet.
A ‘swan song’ for ejection fraction
“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.
“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.
DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.
AT ESC CONGRESS 2022
Secondary CV prevention benefit from polypill promises global health benefit
Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.
“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.
By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).
AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
SECURE trial is latest test of polypill concept
A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.
The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.
The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.
Multiple polypill versions permit dose titration
The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.
The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).
When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).
In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.
The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.
Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.
“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.
One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.
Polypill benefit documented in all subgroups
While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.
“This really validates the importance of the study,” Dr. Fuster said.
In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.
Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.
“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”
Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.
Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.
“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.
By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).
AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
SECURE trial is latest test of polypill concept
A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.
The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.
The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.
Multiple polypill versions permit dose titration
The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.
The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).
When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).
In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.
The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.
Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.
“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.
One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.
Polypill benefit documented in all subgroups
While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.
“This really validates the importance of the study,” Dr. Fuster said.
In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.
Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.
“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”
Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.
Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.
“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.
By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).
AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
SECURE trial is latest test of polypill concept
A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.
The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.
The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.
Multiple polypill versions permit dose titration
The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.
The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).
When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).
In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.
The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.
Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.
“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.
One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.
Polypill benefit documented in all subgroups
While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.
“This really validates the importance of the study,” Dr. Fuster said.
In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.
Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.
“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”
Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.
FROM ESC CONGRESS 2022
Congressman’s wife died after taking herbal remedy marketed for diabetes and weight loss
The wife of a Northern California congressman died late in 2021 after ingesting a plant that is generally considered safe and is used as an herbal remedy for a variety of ailments, including diabetes, obesity, and high cholesterol.
Lori McClintock, the wife of U.S. Rep. Tom McClintock, died from dehydration due to gastroenteritis – an inflammation of the stomach and intestines – that was caused by “adverse effects of white mulberry leaf ingestion,” according to a report from the Sacramento County coroner that is dated March 10 but was not immediately released to the public. KHN obtained that report – in addition to the autopsy report and an amended death certificate containing an updated cause of death – in July.
The coroner’s office ruled her death an accident. The original death certificate, dated Dec. 20, 2021, listed the cause of death as “pending.”
Tom McClintock, a Republican who represents a district that spans multiple counties in northern and central California, found his 61-year-old wife unresponsive at their Elk Grove, Calif., home on Dec. 15, 2021, according to the coroner’s report. He had just returned from Washington after voting in Congress the night before.
It’s unclear from the autopsy report whether Lori McClintock took a dietary supplement containing white mulberry leaf, ate fresh or dried leaves, or drank them in a tea, but a “partially intact” white mulberry leaf was found in her stomach, according to the report.
Ms. McClintock’s death underscores the risks of the vast, booming market of dietary supplements and herbal remedies, which have grown into a $54 billion industry in the United States – one that both lawmakers and health care experts say needs more government scrutiny.
“Many people assume if that product is sold in the United States of America, somebody has inspected it, and it must be safe. Unfortunately, that’s not always true,” U.S. Sen. Richard Durbin (D-Ill.) said on the Senate floor this spring when he introduced legislation to strengthen oversight of dietary supplements.
Daniel Fabricant, CEO and president of the Natural Products Association, which represents the dietary supplements industry, questioned whether Ms. McClintock’s death was related to a supplement.
“It’s completely speculative. There’s a science to this. It’s not just what a coroner feels,” said Mr. Fabricant, who oversaw dietary supplements at the Food and Drug Administration during the Obama administration. “People unfortunately pass from dehydration every day, and there’s a lot of different reasons and a lot of different causes.”
Mr. Fabricant said it would have been ideal had the coroner or the family reported her death to the FDA so the agency could have launched an investigation.
Such reports are voluntary, and it’s not clear whether anyone reported her death to the agency. FDA spokesperson Courtney Rhodes said the agency does not discuss possible or ongoing investigations.
The FDA, Mr. Fabricant added, has a system in place to investigate deaths that might be linked to a supplement or drug. “It’s casework,” he said. “It’s good, old-fashioned police work that needs to be done.”
Tom McClintock has remained mostly silent about his wife’s death since he released a statement on Dec. 19, 2021, announcing it and gave a tribute to her at her Jan. 4 funeral. Until now, the cause of death had not been reported.
Mr. McClintock, contacted multiple times by phone and email Wednesday, was not immediately available for comment.
At his wife’s funeral, McClintock told mourners that she was fine when he spoke with her the day before he returned. She had told a friend that “she was on a roll” at a new job she loved in a Sacramento real estate office, he said, and “she was carefully dieting.”
“She just joined a gym,” he said. “At home, she was counting down the days to Christmas, wrapping all the gifts and making all the plans to make it the best family Christmas ever, and it would have been.”
According to the coroner’s report, however, the day before her death, “she had complaints of an upset stomach.”
Sacramento County spokesperson Kim Nava said via email Wednesday that the law prohibits the coroner’s office from discussing many details of specific cases. As part of any death investigation, the office “attempts to locate and review medical records and speak to family/witnesses to establish events leading up to and surrounding a death,” she said.
If any medications or supplements are found at the scene or if pertinent information is in the person’s medical records, those are passed along to the pathologist to help establish cause of death, Ms. Nava said.
“Any information the office obtains from medical records can’t be disseminated to a third party except by court order,” she said.
The leaves and fruit of the white mulberry tree, which is native to China, have been used for centuries in traditional medicine. Academic studies over the past decade have found that the extract from its leaves can lower blood sugar levels and help with weight loss. People take it in capsule or pill form, as an extract or powder. They can also brew the leaves as an herbal tea.
Lori McClintock’s reaction seems unusual. No deaths from the white mulberry plant have been reported to poison control officials in the past 10 years, according to the American Association of Poison Control Centers.
Since 2012, 148 cases of white mulberry plant ingestion were voluntarily reported to poison control officials nationally, most involving accidental ingestion by children 12 and under, said Kaitlyn Brown, clinical managing director for the association. Only one case required medical follow-up, she said.
While poison control centers track exposures to the white mulberry plant, the FDA oversees dietary supplements, such as products that contain white mulberry leaf extract. Since 2004, two cases of people sickened by mulberry supplements have been reported to the FDA, according to its database that tracks “adverse events.” It relies heavily on voluntary reports from health care professionals and consumers. At least one of those cases led to hospitalization.
White mulberry leaf can have side effects, including nausea and diarrhea, according to research. Independent lab tests ordered by the coroner’s office showed Ms. McClintock’s body had elevated levels of nitrogen, sodium, and creatinine – all signs of dehydration, according to three pathologists who reviewed the coroner’s documents, which KHN redacted to remove Ms. McClintock’s name.
White mulberry leaves “do tend to cause dehydration, and part of the uses for that can be to help someone lose weight, mostly through fluid loss, which in this case was just kind of excessive,” said D’Michelle DuPre, MD, a retired forensic pathologist and a former medical examiner in South Carolina who reviewed the documents.
Dietary supplements, which include a broad range of vitamins, herbs, and minerals, are regulated by the FDA. However, they are classified as food and don’t undergo the rigorous scientific and safety testing the government requires of prescription drugs and over-the-counter medicines.
Lawmakers aren’t proposing to put supplements into the same category as pharmaceuticals, but some say they are alarmed that neither the FDA nor the industry knows how many dietary supplements are out there – making it almost impossible for the government to oversee them and punish bad actors.
The FDA estimates 40,000 to 80,000 supplement products are on the market in the United States, and industry surveys estimate 80% of Americans use them.
Legislation by Sen. Durbin and U.S. Sen. Mike Braun (R-Ind.) would require manufacturers to register with the FDA and provide a public list of ingredients in their products, two provisions that are backed by the Council for Responsible Nutrition, another industry group that represents supplement makers.
But the council is lobbying against a provision that would require supplement makers to provide consumers with the ingredient amounts – or the blend – in their products, something they say is akin to giving a recipe to competitors. That’s proprietary information only government regulators should have access to, said Megan Olsen, the group’s senior vice president and general counsel.
Ms. Olsen explained that supplement manufacturers are regulated just like other food companies and are subject to strict labeling requirements and inspections by the FDA. They also must inform the agency about any adverse effects reported by consumers or doctors.
“Companies are testing products throughout the process, are reviewing how they’re being manufactured and what’s going into them,” Ms. Olsen said. “All of that is overseen and dictated by FDA regulation.”
The dietary supplement provisions were rolled into a larger Senate health committee bill that reauthorizes FDA programs, and senators are currently in negotiations with the House of Representatives. The Natural Products Association opposes all of the dietary supplement provisions.
Because dietary pills, teas, and other supplements are regulated as food products, manufacturers can’t advertise them as treatments or cures for health issues. But they can make claims about how the supplements affect the body. So someone who wants to lose weight or get their diabetes under control might reach for a bottle of white mulberry leaf extract because some supplement makers advertise it as a natural remedy that can lower blood sugar levels and promote weight loss.
Those kinds of claims are appealing to Americans and have been especially potent during the pandemic, as people sought to boost their immune systems and fend off COVID-19, said Debbie Petitpain, a registered dietitian nutritionist and a spokesperson for the Academy of Nutrition and Dietetics.
But dietary supplements can be dangerous and don’t affect everyone the same way. Mixing supplements and prescription medicines can compound the problem, according to the FDA.
“I think a lot of people are thinking, ‘Oh, it’s a plant.’ Or, ‘Oh, it’s just a vitamin. Certainly, that means that it’s not going to hurt me,’ ” Ms. Petitpain said. “But there’s always a risk for taking anything.”
It’s not clear why Lori McClintock was taking white mulberry leaf. Friends and family who gathered for her funeral described a vibrant, happy woman who loved her family and her work and already had wrapped Christmas presents under the tree in mid-December. She was planning to buy a recreational vehicle with her husband in retirement.
“We grieve the loss because of all the things she was looking forward to doing and all the years yet ahead,” Tom McClintock told mourners. “And we grieve for something else, because we’ve all lost a genuinely good person in our lives.”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
The wife of a Northern California congressman died late in 2021 after ingesting a plant that is generally considered safe and is used as an herbal remedy for a variety of ailments, including diabetes, obesity, and high cholesterol.
Lori McClintock, the wife of U.S. Rep. Tom McClintock, died from dehydration due to gastroenteritis – an inflammation of the stomach and intestines – that was caused by “adverse effects of white mulberry leaf ingestion,” according to a report from the Sacramento County coroner that is dated March 10 but was not immediately released to the public. KHN obtained that report – in addition to the autopsy report and an amended death certificate containing an updated cause of death – in July.
The coroner’s office ruled her death an accident. The original death certificate, dated Dec. 20, 2021, listed the cause of death as “pending.”
Tom McClintock, a Republican who represents a district that spans multiple counties in northern and central California, found his 61-year-old wife unresponsive at their Elk Grove, Calif., home on Dec. 15, 2021, according to the coroner’s report. He had just returned from Washington after voting in Congress the night before.
It’s unclear from the autopsy report whether Lori McClintock took a dietary supplement containing white mulberry leaf, ate fresh or dried leaves, or drank them in a tea, but a “partially intact” white mulberry leaf was found in her stomach, according to the report.
Ms. McClintock’s death underscores the risks of the vast, booming market of dietary supplements and herbal remedies, which have grown into a $54 billion industry in the United States – one that both lawmakers and health care experts say needs more government scrutiny.
“Many people assume if that product is sold in the United States of America, somebody has inspected it, and it must be safe. Unfortunately, that’s not always true,” U.S. Sen. Richard Durbin (D-Ill.) said on the Senate floor this spring when he introduced legislation to strengthen oversight of dietary supplements.
Daniel Fabricant, CEO and president of the Natural Products Association, which represents the dietary supplements industry, questioned whether Ms. McClintock’s death was related to a supplement.
“It’s completely speculative. There’s a science to this. It’s not just what a coroner feels,” said Mr. Fabricant, who oversaw dietary supplements at the Food and Drug Administration during the Obama administration. “People unfortunately pass from dehydration every day, and there’s a lot of different reasons and a lot of different causes.”
Mr. Fabricant said it would have been ideal had the coroner or the family reported her death to the FDA so the agency could have launched an investigation.
Such reports are voluntary, and it’s not clear whether anyone reported her death to the agency. FDA spokesperson Courtney Rhodes said the agency does not discuss possible or ongoing investigations.
The FDA, Mr. Fabricant added, has a system in place to investigate deaths that might be linked to a supplement or drug. “It’s casework,” he said. “It’s good, old-fashioned police work that needs to be done.”
Tom McClintock has remained mostly silent about his wife’s death since he released a statement on Dec. 19, 2021, announcing it and gave a tribute to her at her Jan. 4 funeral. Until now, the cause of death had not been reported.
Mr. McClintock, contacted multiple times by phone and email Wednesday, was not immediately available for comment.
At his wife’s funeral, McClintock told mourners that she was fine when he spoke with her the day before he returned. She had told a friend that “she was on a roll” at a new job she loved in a Sacramento real estate office, he said, and “she was carefully dieting.”
“She just joined a gym,” he said. “At home, she was counting down the days to Christmas, wrapping all the gifts and making all the plans to make it the best family Christmas ever, and it would have been.”
According to the coroner’s report, however, the day before her death, “she had complaints of an upset stomach.”
Sacramento County spokesperson Kim Nava said via email Wednesday that the law prohibits the coroner’s office from discussing many details of specific cases. As part of any death investigation, the office “attempts to locate and review medical records and speak to family/witnesses to establish events leading up to and surrounding a death,” she said.
If any medications or supplements are found at the scene or if pertinent information is in the person’s medical records, those are passed along to the pathologist to help establish cause of death, Ms. Nava said.
“Any information the office obtains from medical records can’t be disseminated to a third party except by court order,” she said.
The leaves and fruit of the white mulberry tree, which is native to China, have been used for centuries in traditional medicine. Academic studies over the past decade have found that the extract from its leaves can lower blood sugar levels and help with weight loss. People take it in capsule or pill form, as an extract or powder. They can also brew the leaves as an herbal tea.
Lori McClintock’s reaction seems unusual. No deaths from the white mulberry plant have been reported to poison control officials in the past 10 years, according to the American Association of Poison Control Centers.
Since 2012, 148 cases of white mulberry plant ingestion were voluntarily reported to poison control officials nationally, most involving accidental ingestion by children 12 and under, said Kaitlyn Brown, clinical managing director for the association. Only one case required medical follow-up, she said.
While poison control centers track exposures to the white mulberry plant, the FDA oversees dietary supplements, such as products that contain white mulberry leaf extract. Since 2004, two cases of people sickened by mulberry supplements have been reported to the FDA, according to its database that tracks “adverse events.” It relies heavily on voluntary reports from health care professionals and consumers. At least one of those cases led to hospitalization.
White mulberry leaf can have side effects, including nausea and diarrhea, according to research. Independent lab tests ordered by the coroner’s office showed Ms. McClintock’s body had elevated levels of nitrogen, sodium, and creatinine – all signs of dehydration, according to three pathologists who reviewed the coroner’s documents, which KHN redacted to remove Ms. McClintock’s name.
White mulberry leaves “do tend to cause dehydration, and part of the uses for that can be to help someone lose weight, mostly through fluid loss, which in this case was just kind of excessive,” said D’Michelle DuPre, MD, a retired forensic pathologist and a former medical examiner in South Carolina who reviewed the documents.
Dietary supplements, which include a broad range of vitamins, herbs, and minerals, are regulated by the FDA. However, they are classified as food and don’t undergo the rigorous scientific and safety testing the government requires of prescription drugs and over-the-counter medicines.
Lawmakers aren’t proposing to put supplements into the same category as pharmaceuticals, but some say they are alarmed that neither the FDA nor the industry knows how many dietary supplements are out there – making it almost impossible for the government to oversee them and punish bad actors.
The FDA estimates 40,000 to 80,000 supplement products are on the market in the United States, and industry surveys estimate 80% of Americans use them.
Legislation by Sen. Durbin and U.S. Sen. Mike Braun (R-Ind.) would require manufacturers to register with the FDA and provide a public list of ingredients in their products, two provisions that are backed by the Council for Responsible Nutrition, another industry group that represents supplement makers.
But the council is lobbying against a provision that would require supplement makers to provide consumers with the ingredient amounts – or the blend – in their products, something they say is akin to giving a recipe to competitors. That’s proprietary information only government regulators should have access to, said Megan Olsen, the group’s senior vice president and general counsel.
Ms. Olsen explained that supplement manufacturers are regulated just like other food companies and are subject to strict labeling requirements and inspections by the FDA. They also must inform the agency about any adverse effects reported by consumers or doctors.
“Companies are testing products throughout the process, are reviewing how they’re being manufactured and what’s going into them,” Ms. Olsen said. “All of that is overseen and dictated by FDA regulation.”
The dietary supplement provisions were rolled into a larger Senate health committee bill that reauthorizes FDA programs, and senators are currently in negotiations with the House of Representatives. The Natural Products Association opposes all of the dietary supplement provisions.
Because dietary pills, teas, and other supplements are regulated as food products, manufacturers can’t advertise them as treatments or cures for health issues. But they can make claims about how the supplements affect the body. So someone who wants to lose weight or get their diabetes under control might reach for a bottle of white mulberry leaf extract because some supplement makers advertise it as a natural remedy that can lower blood sugar levels and promote weight loss.
Those kinds of claims are appealing to Americans and have been especially potent during the pandemic, as people sought to boost their immune systems and fend off COVID-19, said Debbie Petitpain, a registered dietitian nutritionist and a spokesperson for the Academy of Nutrition and Dietetics.
But dietary supplements can be dangerous and don’t affect everyone the same way. Mixing supplements and prescription medicines can compound the problem, according to the FDA.
“I think a lot of people are thinking, ‘Oh, it’s a plant.’ Or, ‘Oh, it’s just a vitamin. Certainly, that means that it’s not going to hurt me,’ ” Ms. Petitpain said. “But there’s always a risk for taking anything.”
It’s not clear why Lori McClintock was taking white mulberry leaf. Friends and family who gathered for her funeral described a vibrant, happy woman who loved her family and her work and already had wrapped Christmas presents under the tree in mid-December. She was planning to buy a recreational vehicle with her husband in retirement.
“We grieve the loss because of all the things she was looking forward to doing and all the years yet ahead,” Tom McClintock told mourners. “And we grieve for something else, because we’ve all lost a genuinely good person in our lives.”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
The wife of a Northern California congressman died late in 2021 after ingesting a plant that is generally considered safe and is used as an herbal remedy for a variety of ailments, including diabetes, obesity, and high cholesterol.
Lori McClintock, the wife of U.S. Rep. Tom McClintock, died from dehydration due to gastroenteritis – an inflammation of the stomach and intestines – that was caused by “adverse effects of white mulberry leaf ingestion,” according to a report from the Sacramento County coroner that is dated March 10 but was not immediately released to the public. KHN obtained that report – in addition to the autopsy report and an amended death certificate containing an updated cause of death – in July.
The coroner’s office ruled her death an accident. The original death certificate, dated Dec. 20, 2021, listed the cause of death as “pending.”
Tom McClintock, a Republican who represents a district that spans multiple counties in northern and central California, found his 61-year-old wife unresponsive at their Elk Grove, Calif., home on Dec. 15, 2021, according to the coroner’s report. He had just returned from Washington after voting in Congress the night before.
It’s unclear from the autopsy report whether Lori McClintock took a dietary supplement containing white mulberry leaf, ate fresh or dried leaves, or drank them in a tea, but a “partially intact” white mulberry leaf was found in her stomach, according to the report.
Ms. McClintock’s death underscores the risks of the vast, booming market of dietary supplements and herbal remedies, which have grown into a $54 billion industry in the United States – one that both lawmakers and health care experts say needs more government scrutiny.
“Many people assume if that product is sold in the United States of America, somebody has inspected it, and it must be safe. Unfortunately, that’s not always true,” U.S. Sen. Richard Durbin (D-Ill.) said on the Senate floor this spring when he introduced legislation to strengthen oversight of dietary supplements.
Daniel Fabricant, CEO and president of the Natural Products Association, which represents the dietary supplements industry, questioned whether Ms. McClintock’s death was related to a supplement.
“It’s completely speculative. There’s a science to this. It’s not just what a coroner feels,” said Mr. Fabricant, who oversaw dietary supplements at the Food and Drug Administration during the Obama administration. “People unfortunately pass from dehydration every day, and there’s a lot of different reasons and a lot of different causes.”
Mr. Fabricant said it would have been ideal had the coroner or the family reported her death to the FDA so the agency could have launched an investigation.
Such reports are voluntary, and it’s not clear whether anyone reported her death to the agency. FDA spokesperson Courtney Rhodes said the agency does not discuss possible or ongoing investigations.
The FDA, Mr. Fabricant added, has a system in place to investigate deaths that might be linked to a supplement or drug. “It’s casework,” he said. “It’s good, old-fashioned police work that needs to be done.”
Tom McClintock has remained mostly silent about his wife’s death since he released a statement on Dec. 19, 2021, announcing it and gave a tribute to her at her Jan. 4 funeral. Until now, the cause of death had not been reported.
Mr. McClintock, contacted multiple times by phone and email Wednesday, was not immediately available for comment.
At his wife’s funeral, McClintock told mourners that she was fine when he spoke with her the day before he returned. She had told a friend that “she was on a roll” at a new job she loved in a Sacramento real estate office, he said, and “she was carefully dieting.”
“She just joined a gym,” he said. “At home, she was counting down the days to Christmas, wrapping all the gifts and making all the plans to make it the best family Christmas ever, and it would have been.”
According to the coroner’s report, however, the day before her death, “she had complaints of an upset stomach.”
Sacramento County spokesperson Kim Nava said via email Wednesday that the law prohibits the coroner’s office from discussing many details of specific cases. As part of any death investigation, the office “attempts to locate and review medical records and speak to family/witnesses to establish events leading up to and surrounding a death,” she said.
If any medications or supplements are found at the scene or if pertinent information is in the person’s medical records, those are passed along to the pathologist to help establish cause of death, Ms. Nava said.
“Any information the office obtains from medical records can’t be disseminated to a third party except by court order,” she said.
The leaves and fruit of the white mulberry tree, which is native to China, have been used for centuries in traditional medicine. Academic studies over the past decade have found that the extract from its leaves can lower blood sugar levels and help with weight loss. People take it in capsule or pill form, as an extract or powder. They can also brew the leaves as an herbal tea.
Lori McClintock’s reaction seems unusual. No deaths from the white mulberry plant have been reported to poison control officials in the past 10 years, according to the American Association of Poison Control Centers.
Since 2012, 148 cases of white mulberry plant ingestion were voluntarily reported to poison control officials nationally, most involving accidental ingestion by children 12 and under, said Kaitlyn Brown, clinical managing director for the association. Only one case required medical follow-up, she said.
While poison control centers track exposures to the white mulberry plant, the FDA oversees dietary supplements, such as products that contain white mulberry leaf extract. Since 2004, two cases of people sickened by mulberry supplements have been reported to the FDA, according to its database that tracks “adverse events.” It relies heavily on voluntary reports from health care professionals and consumers. At least one of those cases led to hospitalization.
White mulberry leaf can have side effects, including nausea and diarrhea, according to research. Independent lab tests ordered by the coroner’s office showed Ms. McClintock’s body had elevated levels of nitrogen, sodium, and creatinine – all signs of dehydration, according to three pathologists who reviewed the coroner’s documents, which KHN redacted to remove Ms. McClintock’s name.
White mulberry leaves “do tend to cause dehydration, and part of the uses for that can be to help someone lose weight, mostly through fluid loss, which in this case was just kind of excessive,” said D’Michelle DuPre, MD, a retired forensic pathologist and a former medical examiner in South Carolina who reviewed the documents.
Dietary supplements, which include a broad range of vitamins, herbs, and minerals, are regulated by the FDA. However, they are classified as food and don’t undergo the rigorous scientific and safety testing the government requires of prescription drugs and over-the-counter medicines.
Lawmakers aren’t proposing to put supplements into the same category as pharmaceuticals, but some say they are alarmed that neither the FDA nor the industry knows how many dietary supplements are out there – making it almost impossible for the government to oversee them and punish bad actors.
The FDA estimates 40,000 to 80,000 supplement products are on the market in the United States, and industry surveys estimate 80% of Americans use them.
Legislation by Sen. Durbin and U.S. Sen. Mike Braun (R-Ind.) would require manufacturers to register with the FDA and provide a public list of ingredients in their products, two provisions that are backed by the Council for Responsible Nutrition, another industry group that represents supplement makers.
But the council is lobbying against a provision that would require supplement makers to provide consumers with the ingredient amounts – or the blend – in their products, something they say is akin to giving a recipe to competitors. That’s proprietary information only government regulators should have access to, said Megan Olsen, the group’s senior vice president and general counsel.
Ms. Olsen explained that supplement manufacturers are regulated just like other food companies and are subject to strict labeling requirements and inspections by the FDA. They also must inform the agency about any adverse effects reported by consumers or doctors.
“Companies are testing products throughout the process, are reviewing how they’re being manufactured and what’s going into them,” Ms. Olsen said. “All of that is overseen and dictated by FDA regulation.”
The dietary supplement provisions were rolled into a larger Senate health committee bill that reauthorizes FDA programs, and senators are currently in negotiations with the House of Representatives. The Natural Products Association opposes all of the dietary supplement provisions.
Because dietary pills, teas, and other supplements are regulated as food products, manufacturers can’t advertise them as treatments or cures for health issues. But they can make claims about how the supplements affect the body. So someone who wants to lose weight or get their diabetes under control might reach for a bottle of white mulberry leaf extract because some supplement makers advertise it as a natural remedy that can lower blood sugar levels and promote weight loss.
Those kinds of claims are appealing to Americans and have been especially potent during the pandemic, as people sought to boost their immune systems and fend off COVID-19, said Debbie Petitpain, a registered dietitian nutritionist and a spokesperson for the Academy of Nutrition and Dietetics.
But dietary supplements can be dangerous and don’t affect everyone the same way. Mixing supplements and prescription medicines can compound the problem, according to the FDA.
“I think a lot of people are thinking, ‘Oh, it’s a plant.’ Or, ‘Oh, it’s just a vitamin. Certainly, that means that it’s not going to hurt me,’ ” Ms. Petitpain said. “But there’s always a risk for taking anything.”
It’s not clear why Lori McClintock was taking white mulberry leaf. Friends and family who gathered for her funeral described a vibrant, happy woman who loved her family and her work and already had wrapped Christmas presents under the tree in mid-December. She was planning to buy a recreational vehicle with her husband in retirement.
“We grieve the loss because of all the things she was looking forward to doing and all the years yet ahead,” Tom McClintock told mourners. “And we grieve for something else, because we’ve all lost a genuinely good person in our lives.”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
First drug therapy approved for childhood GVHD
Specifically, the indication is for pediatric patients with cGVHD who have already been treated with one or more lines of systemic therapy. The manufacturers have also launched a new oral suspension formulation, in addition to capsules and tablets, which were already available.
Ibrutinib is already approved for use in adults with cGVHD.
The drug is also approved for use in several blood cancers, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia. All these approvals are for adult patients.
This is the first pediatric indication for the product and is “incredibly meaningful,” said Gauri Sunkersett, DO, associate medical director at AbbVie, which markets the drug together with Jansen. “As a pediatric oncologist, when my patients describe the physical pain they experience from simply hugging their parents, due to their cGVHD, the importance of researching alternative treatment options in this patient population is further validated.”
These children have already been through a lot, having been diagnosed with a leukemia or lymphoma and then undergoing chemotherapy and/or radiotherapy for a stem cell transplant. Just over half (52%-65%) of children who receive allogeneic transplants go on to develop cGVHD, in which the donor bone marrow or stem cells attack the recipient.
“Imagine going through a transplant and then being told you have a moderate to severe chronic disease that can sometimes also be life-threatening,” commented Paul A. Carpenter, MD, attending physician at Seattle Children’s Hospital. “If these children were between 1 and 12 and didn’t respond to steroid treatment, we didn’t have any rigorously studied treatment options – until now.”
The new indication was approved by the U.S. Food and Drug Administration on the basis of results from the iMAGINE trial, for which Dr. Carpenter was a principal investigator.
The phase 1/2 iMAGINE trial was an open-label, multicenter, single-arm trial conducted with 47 patients (mean age, 13 years; range, 1-19 years) with relapsed/refractory cGVHD who had received at least one prior systemic therapy. Ibrutinib was given at a dose of 420 mg orally once daily to patients aged 12 and older and at a dose of 240 mg/m2 orally once daily to patients who were younger than 12 years.
The overall response rate through week 25 was 60% (confidence interval, 95%, 44%-74%). The median duration of response was 5.3 months (95% CI, 2.8-8.8).
The safety profile was consistent with the established profile for ibrutinib. Observed adverse events in pediatric patients were consistent with those observed in adult patients with moderate to severe cGVHD, the companies noted.
The FDA noted that the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.
Full prescribing information for ibrutinib is available here.
A version of this article first appeared on Medscape.com.
Specifically, the indication is for pediatric patients with cGVHD who have already been treated with one or more lines of systemic therapy. The manufacturers have also launched a new oral suspension formulation, in addition to capsules and tablets, which were already available.
Ibrutinib is already approved for use in adults with cGVHD.
The drug is also approved for use in several blood cancers, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia. All these approvals are for adult patients.
This is the first pediatric indication for the product and is “incredibly meaningful,” said Gauri Sunkersett, DO, associate medical director at AbbVie, which markets the drug together with Jansen. “As a pediatric oncologist, when my patients describe the physical pain they experience from simply hugging their parents, due to their cGVHD, the importance of researching alternative treatment options in this patient population is further validated.”
These children have already been through a lot, having been diagnosed with a leukemia or lymphoma and then undergoing chemotherapy and/or radiotherapy for a stem cell transplant. Just over half (52%-65%) of children who receive allogeneic transplants go on to develop cGVHD, in which the donor bone marrow or stem cells attack the recipient.
“Imagine going through a transplant and then being told you have a moderate to severe chronic disease that can sometimes also be life-threatening,” commented Paul A. Carpenter, MD, attending physician at Seattle Children’s Hospital. “If these children were between 1 and 12 and didn’t respond to steroid treatment, we didn’t have any rigorously studied treatment options – until now.”
The new indication was approved by the U.S. Food and Drug Administration on the basis of results from the iMAGINE trial, for which Dr. Carpenter was a principal investigator.
The phase 1/2 iMAGINE trial was an open-label, multicenter, single-arm trial conducted with 47 patients (mean age, 13 years; range, 1-19 years) with relapsed/refractory cGVHD who had received at least one prior systemic therapy. Ibrutinib was given at a dose of 420 mg orally once daily to patients aged 12 and older and at a dose of 240 mg/m2 orally once daily to patients who were younger than 12 years.
The overall response rate through week 25 was 60% (confidence interval, 95%, 44%-74%). The median duration of response was 5.3 months (95% CI, 2.8-8.8).
The safety profile was consistent with the established profile for ibrutinib. Observed adverse events in pediatric patients were consistent with those observed in adult patients with moderate to severe cGVHD, the companies noted.
The FDA noted that the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.
Full prescribing information for ibrutinib is available here.
A version of this article first appeared on Medscape.com.
Specifically, the indication is for pediatric patients with cGVHD who have already been treated with one or more lines of systemic therapy. The manufacturers have also launched a new oral suspension formulation, in addition to capsules and tablets, which were already available.
Ibrutinib is already approved for use in adults with cGVHD.
The drug is also approved for use in several blood cancers, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia. All these approvals are for adult patients.
This is the first pediatric indication for the product and is “incredibly meaningful,” said Gauri Sunkersett, DO, associate medical director at AbbVie, which markets the drug together with Jansen. “As a pediatric oncologist, when my patients describe the physical pain they experience from simply hugging their parents, due to their cGVHD, the importance of researching alternative treatment options in this patient population is further validated.”
These children have already been through a lot, having been diagnosed with a leukemia or lymphoma and then undergoing chemotherapy and/or radiotherapy for a stem cell transplant. Just over half (52%-65%) of children who receive allogeneic transplants go on to develop cGVHD, in which the donor bone marrow or stem cells attack the recipient.
“Imagine going through a transplant and then being told you have a moderate to severe chronic disease that can sometimes also be life-threatening,” commented Paul A. Carpenter, MD, attending physician at Seattle Children’s Hospital. “If these children were between 1 and 12 and didn’t respond to steroid treatment, we didn’t have any rigorously studied treatment options – until now.”
The new indication was approved by the U.S. Food and Drug Administration on the basis of results from the iMAGINE trial, for which Dr. Carpenter was a principal investigator.
The phase 1/2 iMAGINE trial was an open-label, multicenter, single-arm trial conducted with 47 patients (mean age, 13 years; range, 1-19 years) with relapsed/refractory cGVHD who had received at least one prior systemic therapy. Ibrutinib was given at a dose of 420 mg orally once daily to patients aged 12 and older and at a dose of 240 mg/m2 orally once daily to patients who were younger than 12 years.
The overall response rate through week 25 was 60% (confidence interval, 95%, 44%-74%). The median duration of response was 5.3 months (95% CI, 2.8-8.8).
The safety profile was consistent with the established profile for ibrutinib. Observed adverse events in pediatric patients were consistent with those observed in adult patients with moderate to severe cGVHD, the companies noted.
The FDA noted that the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.
Full prescribing information for ibrutinib is available here.
A version of this article first appeared on Medscape.com.
NSAIDs linked to heart failure risk in diabetes
People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.
“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.
“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.
Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.
“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.
The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.
“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”
The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.
Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.
The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”
Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).
In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.
“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.
“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”
The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”
The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.
People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.
“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.
“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.
Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.
“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.
The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.
“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”
The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.
Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.
The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”
Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).
In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.
“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.
“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”
The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”
The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.
People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.
“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.
“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.
Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.
“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.
The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.
“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”
The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.
Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.
The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”
Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).
In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.
“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.
“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”
The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”
The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.
FROM ESC CONGRESS 2022
Metformin fails as early COVID-19 treatment but shows potential
Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.
However, metformin showed some potential in a secondary analysis.
Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.
“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”
In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.
A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.
The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).
The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.
The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.
Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.
The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.
However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.
“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.
The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.
“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”
Ineffective drugs are inefficient use of resources
“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.
At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.
The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.
“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”
The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.
However, metformin showed some potential in a secondary analysis.
Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.
“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”
In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.
A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.
The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).
The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.
The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.
Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.
The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.
However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.
“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.
The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.
“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”
Ineffective drugs are inefficient use of resources
“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.
At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.
The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.
“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”
The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.
However, metformin showed some potential in a secondary analysis.
Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.
“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”
In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.
A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.
The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).
The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.
The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.
Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.
The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.
However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.
“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.
The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.
“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”
Ineffective drugs are inefficient use of resources
“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.
At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.
The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.
“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”
The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Large genetic study links 72 genes to autism spectrum disorders
according to a study published in Nature Genetics. The findings, based on analysis of more than 150,000 people’s genetics, arose from a collaboration of five research groups whose work included comparisons of ASD cohorts with separate cohorts of individuals with developmental delay or schizophrenia.
“We know that many genes, when mutated, contribute to autism,” and this study brought together “multiple types of mutations in a wide array of samples to get a much richer sense of the genes and genetic architecture involved in autism and other neurodevelopmental conditions,” co–senior author Joseph D. Buxbaum, PhD, director of the Seaver Autism Center for Research and Treatment at Mount Sinai and a professor at the Icahn School of Medicine at Mount Sinai, both in New York, said in a prepared statement. “This is significant in that we now have more insights as to the biology of the brain changes that underlie autism and more potential targets for treatment.”
Glen Elliott, PhD, MD, a clinical professor of psychiatry at Stanford (Calif.) University who was not involved in the study, said the paper is important paper for informing clinicians of where the basic research is headed. “We’re still in for a long road” before it bears fruit in terms of therapeutics. The value of studies like these, that investigate which genes are most associated with ASD, is that they may lead toward understanding the pathways in the brain that give rise to certain symptoms of ASD, which can then become therapeutic targets, Dr. Elliott said.
Investigating large cohorts
The researchers analyzed genetic exome sequencing data from 33 ASD cohorts with a total of 63,237 people and then compared these data with another cohort of people with developmental delay and a cohort of people with schizophrenia. The combined ASD cohorts included 15,036 individuals with ASD, 28,522 parents, and 5,492 unaffected siblings. The remaining participants were 5,591 people with ASD and 8,597 matched controls from case control studies.
In the ASD cohorts, the researchers identified 72 genes that were associated with ASD. De novo variants were eight times more likely in cases (4%) than in controls (0.5%). Ten genes occurred at least twice in ASD cases but never occurred in unaffected siblings.
Then the researchers integrated these ASD genetic data with a cohort of 91,605 people that included 31,058 people with developmental delay and their parents. Substantial overlap with gene mutations existed between these two cohorts: 70.1% of the genes related to developmental delay appeared linked to risk for ASD, and 86.6% of genes associated with ASD risk also had associations with developmental delay. Overall, the researchers identified 373 genes strongly associated with ASD and/or developmental delay and 664 genes with a likely association.
“Isolating genes that exert a greater effect on ASD than they do on other developmental delays has remained challenging due to the frequent comorbidity of these phenotypes,” wrote lead author Jack M. Fu, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues. “Still, an estimated 13.4% of the transmission and de novo association–ASD genes show little evidence for association in the developmental delay cohort.”
ASD, developmental delay, and schizophrenia
When the researchers compared the cells where the genetic mutations occurred in fetal brains, they found that genes associated with developmental delay more often occurred in less differentiated cell types – less mature cells in the developmental process. Gene mutations associated with ASD, on the other hand, occurred in more mature cell types, particularly in maturing excitatory neurons and related cells.
”Our results are consistent with developmental delay-predominant genes being expressed earlier in development and in less differentiated cells than ASD-predominant genes,” they wrote.
The researchers also compared the specific gene mutations found in these two cohorts with a previously published set of 244 genes associated with schizophrenia. Of these, 234 genes are among those with a transmission and de novo association to ASD and/or developmental delay. Of the 72 genes linked to ASD, eight appear in the set of genes linked to schizophrenia, and 61 were associated with developmental delay, though these two subsets do not overlap each other much.
“The ASD-schizophrenia overlap was significantly enriched, while the developmental delay-schizophrenia overlap was not,” they reported. ”Together, these data suggest that one subset of ASD risk genes may overlap developmental delay while a different subset overlaps schizophrenia.”
Chasing therapy targets by backtracking through genes
The findings are a substantial step forward in understanding the potential genetic contribution to ASD, but they also highlight the challenges of eventually trying to use this information in a clinically meaningful way.
“Given the substantial overlap between the genes implicated in neurodevelopmental disorders writ large and those implicated directly in ASD, disentangling the relative impact of individual genes on neurodevelopment and phenotypic spectra is a daunting yet important challenge,” the researchers wrote. “To identify the key neurobiological features of ASD will likely require convergence of evidence from many ASD genes and studies.”
Dr. Elliott said the biggest takeaway from this study is a better understanding of how the paradigm has shifted away from finding “one gene” for autism or a cure based on genetics and more toward understanding the pathophysiology of symptoms that can point to therapies for better management of the condition.
“Basic researchers have completely changed the strategy for trying to understand the biology of major disorders,” including, in this case, autism, Dr. Elliott said. “The intent is to try to find the underlying systems [in the brain] by backtracking through genes. Meanwhile, given that scientists have made substantial progress in identifying genes that have specific effects on brain development, “the hope is that will mesh with this kind of research, to begin to identify systems that might ultimately be targets for treating.”
The end goal is to be able to offer targeted approaches, based on the pathways causing a symptom, which can be linked backward to a gene.
”So this is not going to offer an immediate cure – it’s probably not going to offer a cure at all – but it may actually lead to much more targeted medications than we currently have for specific types of symptoms within the autism spectrum,” Dr. Elliott said. “What they’re trying to do, ultimately, is to say, when this system is really badly affected because of a genetic abnormality, even though that genetic abnormality is very rare, it leads to these specific kinds of symptoms. If we can find out the neuroregulators underlying that change, then that would be the target, even if that gene were not present.”
The research was funded by the Simons Foundation for Autism Research Initiative, the SPARK project, the National Human Genome Research Institute Home, the National Institute of Mental Health, the National Institute of Child Health and Development, AMED, and the Beatrice and Samuel Seaver Foundation. Five authors reported financial disclosures linked to Desitin, Roche, BioMarin, BrigeBio Pharma, Illumina, Levo Therapeutics, and Microsoft.
according to a study published in Nature Genetics. The findings, based on analysis of more than 150,000 people’s genetics, arose from a collaboration of five research groups whose work included comparisons of ASD cohorts with separate cohorts of individuals with developmental delay or schizophrenia.
“We know that many genes, when mutated, contribute to autism,” and this study brought together “multiple types of mutations in a wide array of samples to get a much richer sense of the genes and genetic architecture involved in autism and other neurodevelopmental conditions,” co–senior author Joseph D. Buxbaum, PhD, director of the Seaver Autism Center for Research and Treatment at Mount Sinai and a professor at the Icahn School of Medicine at Mount Sinai, both in New York, said in a prepared statement. “This is significant in that we now have more insights as to the biology of the brain changes that underlie autism and more potential targets for treatment.”
Glen Elliott, PhD, MD, a clinical professor of psychiatry at Stanford (Calif.) University who was not involved in the study, said the paper is important paper for informing clinicians of where the basic research is headed. “We’re still in for a long road” before it bears fruit in terms of therapeutics. The value of studies like these, that investigate which genes are most associated with ASD, is that they may lead toward understanding the pathways in the brain that give rise to certain symptoms of ASD, which can then become therapeutic targets, Dr. Elliott said.
Investigating large cohorts
The researchers analyzed genetic exome sequencing data from 33 ASD cohorts with a total of 63,237 people and then compared these data with another cohort of people with developmental delay and a cohort of people with schizophrenia. The combined ASD cohorts included 15,036 individuals with ASD, 28,522 parents, and 5,492 unaffected siblings. The remaining participants were 5,591 people with ASD and 8,597 matched controls from case control studies.
In the ASD cohorts, the researchers identified 72 genes that were associated with ASD. De novo variants were eight times more likely in cases (4%) than in controls (0.5%). Ten genes occurred at least twice in ASD cases but never occurred in unaffected siblings.
Then the researchers integrated these ASD genetic data with a cohort of 91,605 people that included 31,058 people with developmental delay and their parents. Substantial overlap with gene mutations existed between these two cohorts: 70.1% of the genes related to developmental delay appeared linked to risk for ASD, and 86.6% of genes associated with ASD risk also had associations with developmental delay. Overall, the researchers identified 373 genes strongly associated with ASD and/or developmental delay and 664 genes with a likely association.
“Isolating genes that exert a greater effect on ASD than they do on other developmental delays has remained challenging due to the frequent comorbidity of these phenotypes,” wrote lead author Jack M. Fu, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues. “Still, an estimated 13.4% of the transmission and de novo association–ASD genes show little evidence for association in the developmental delay cohort.”
ASD, developmental delay, and schizophrenia
When the researchers compared the cells where the genetic mutations occurred in fetal brains, they found that genes associated with developmental delay more often occurred in less differentiated cell types – less mature cells in the developmental process. Gene mutations associated with ASD, on the other hand, occurred in more mature cell types, particularly in maturing excitatory neurons and related cells.
”Our results are consistent with developmental delay-predominant genes being expressed earlier in development and in less differentiated cells than ASD-predominant genes,” they wrote.
The researchers also compared the specific gene mutations found in these two cohorts with a previously published set of 244 genes associated with schizophrenia. Of these, 234 genes are among those with a transmission and de novo association to ASD and/or developmental delay. Of the 72 genes linked to ASD, eight appear in the set of genes linked to schizophrenia, and 61 were associated with developmental delay, though these two subsets do not overlap each other much.
“The ASD-schizophrenia overlap was significantly enriched, while the developmental delay-schizophrenia overlap was not,” they reported. ”Together, these data suggest that one subset of ASD risk genes may overlap developmental delay while a different subset overlaps schizophrenia.”
Chasing therapy targets by backtracking through genes
The findings are a substantial step forward in understanding the potential genetic contribution to ASD, but they also highlight the challenges of eventually trying to use this information in a clinically meaningful way.
“Given the substantial overlap between the genes implicated in neurodevelopmental disorders writ large and those implicated directly in ASD, disentangling the relative impact of individual genes on neurodevelopment and phenotypic spectra is a daunting yet important challenge,” the researchers wrote. “To identify the key neurobiological features of ASD will likely require convergence of evidence from many ASD genes and studies.”
Dr. Elliott said the biggest takeaway from this study is a better understanding of how the paradigm has shifted away from finding “one gene” for autism or a cure based on genetics and more toward understanding the pathophysiology of symptoms that can point to therapies for better management of the condition.
“Basic researchers have completely changed the strategy for trying to understand the biology of major disorders,” including, in this case, autism, Dr. Elliott said. “The intent is to try to find the underlying systems [in the brain] by backtracking through genes. Meanwhile, given that scientists have made substantial progress in identifying genes that have specific effects on brain development, “the hope is that will mesh with this kind of research, to begin to identify systems that might ultimately be targets for treating.”
The end goal is to be able to offer targeted approaches, based on the pathways causing a symptom, which can be linked backward to a gene.
”So this is not going to offer an immediate cure – it’s probably not going to offer a cure at all – but it may actually lead to much more targeted medications than we currently have for specific types of symptoms within the autism spectrum,” Dr. Elliott said. “What they’re trying to do, ultimately, is to say, when this system is really badly affected because of a genetic abnormality, even though that genetic abnormality is very rare, it leads to these specific kinds of symptoms. If we can find out the neuroregulators underlying that change, then that would be the target, even if that gene were not present.”
The research was funded by the Simons Foundation for Autism Research Initiative, the SPARK project, the National Human Genome Research Institute Home, the National Institute of Mental Health, the National Institute of Child Health and Development, AMED, and the Beatrice and Samuel Seaver Foundation. Five authors reported financial disclosures linked to Desitin, Roche, BioMarin, BrigeBio Pharma, Illumina, Levo Therapeutics, and Microsoft.
according to a study published in Nature Genetics. The findings, based on analysis of more than 150,000 people’s genetics, arose from a collaboration of five research groups whose work included comparisons of ASD cohorts with separate cohorts of individuals with developmental delay or schizophrenia.
“We know that many genes, when mutated, contribute to autism,” and this study brought together “multiple types of mutations in a wide array of samples to get a much richer sense of the genes and genetic architecture involved in autism and other neurodevelopmental conditions,” co–senior author Joseph D. Buxbaum, PhD, director of the Seaver Autism Center for Research and Treatment at Mount Sinai and a professor at the Icahn School of Medicine at Mount Sinai, both in New York, said in a prepared statement. “This is significant in that we now have more insights as to the biology of the brain changes that underlie autism and more potential targets for treatment.”
Glen Elliott, PhD, MD, a clinical professor of psychiatry at Stanford (Calif.) University who was not involved in the study, said the paper is important paper for informing clinicians of where the basic research is headed. “We’re still in for a long road” before it bears fruit in terms of therapeutics. The value of studies like these, that investigate which genes are most associated with ASD, is that they may lead toward understanding the pathways in the brain that give rise to certain symptoms of ASD, which can then become therapeutic targets, Dr. Elliott said.
Investigating large cohorts
The researchers analyzed genetic exome sequencing data from 33 ASD cohorts with a total of 63,237 people and then compared these data with another cohort of people with developmental delay and a cohort of people with schizophrenia. The combined ASD cohorts included 15,036 individuals with ASD, 28,522 parents, and 5,492 unaffected siblings. The remaining participants were 5,591 people with ASD and 8,597 matched controls from case control studies.
In the ASD cohorts, the researchers identified 72 genes that were associated with ASD. De novo variants were eight times more likely in cases (4%) than in controls (0.5%). Ten genes occurred at least twice in ASD cases but never occurred in unaffected siblings.
Then the researchers integrated these ASD genetic data with a cohort of 91,605 people that included 31,058 people with developmental delay and their parents. Substantial overlap with gene mutations existed between these two cohorts: 70.1% of the genes related to developmental delay appeared linked to risk for ASD, and 86.6% of genes associated with ASD risk also had associations with developmental delay. Overall, the researchers identified 373 genes strongly associated with ASD and/or developmental delay and 664 genes with a likely association.
“Isolating genes that exert a greater effect on ASD than they do on other developmental delays has remained challenging due to the frequent comorbidity of these phenotypes,” wrote lead author Jack M. Fu, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues. “Still, an estimated 13.4% of the transmission and de novo association–ASD genes show little evidence for association in the developmental delay cohort.”
ASD, developmental delay, and schizophrenia
When the researchers compared the cells where the genetic mutations occurred in fetal brains, they found that genes associated with developmental delay more often occurred in less differentiated cell types – less mature cells in the developmental process. Gene mutations associated with ASD, on the other hand, occurred in more mature cell types, particularly in maturing excitatory neurons and related cells.
”Our results are consistent with developmental delay-predominant genes being expressed earlier in development and in less differentiated cells than ASD-predominant genes,” they wrote.
The researchers also compared the specific gene mutations found in these two cohorts with a previously published set of 244 genes associated with schizophrenia. Of these, 234 genes are among those with a transmission and de novo association to ASD and/or developmental delay. Of the 72 genes linked to ASD, eight appear in the set of genes linked to schizophrenia, and 61 were associated with developmental delay, though these two subsets do not overlap each other much.
“The ASD-schizophrenia overlap was significantly enriched, while the developmental delay-schizophrenia overlap was not,” they reported. ”Together, these data suggest that one subset of ASD risk genes may overlap developmental delay while a different subset overlaps schizophrenia.”
Chasing therapy targets by backtracking through genes
The findings are a substantial step forward in understanding the potential genetic contribution to ASD, but they also highlight the challenges of eventually trying to use this information in a clinically meaningful way.
“Given the substantial overlap between the genes implicated in neurodevelopmental disorders writ large and those implicated directly in ASD, disentangling the relative impact of individual genes on neurodevelopment and phenotypic spectra is a daunting yet important challenge,” the researchers wrote. “To identify the key neurobiological features of ASD will likely require convergence of evidence from many ASD genes and studies.”
Dr. Elliott said the biggest takeaway from this study is a better understanding of how the paradigm has shifted away from finding “one gene” for autism or a cure based on genetics and more toward understanding the pathophysiology of symptoms that can point to therapies for better management of the condition.
“Basic researchers have completely changed the strategy for trying to understand the biology of major disorders,” including, in this case, autism, Dr. Elliott said. “The intent is to try to find the underlying systems [in the brain] by backtracking through genes. Meanwhile, given that scientists have made substantial progress in identifying genes that have specific effects on brain development, “the hope is that will mesh with this kind of research, to begin to identify systems that might ultimately be targets for treating.”
The end goal is to be able to offer targeted approaches, based on the pathways causing a symptom, which can be linked backward to a gene.
”So this is not going to offer an immediate cure – it’s probably not going to offer a cure at all – but it may actually lead to much more targeted medications than we currently have for specific types of symptoms within the autism spectrum,” Dr. Elliott said. “What they’re trying to do, ultimately, is to say, when this system is really badly affected because of a genetic abnormality, even though that genetic abnormality is very rare, it leads to these specific kinds of symptoms. If we can find out the neuroregulators underlying that change, then that would be the target, even if that gene were not present.”
The research was funded by the Simons Foundation for Autism Research Initiative, the SPARK project, the National Human Genome Research Institute Home, the National Institute of Mental Health, the National Institute of Child Health and Development, AMED, and the Beatrice and Samuel Seaver Foundation. Five authors reported financial disclosures linked to Desitin, Roche, BioMarin, BrigeBio Pharma, Illumina, Levo Therapeutics, and Microsoft.
FROM NATURE GENETICS
‘Conservative’ USPSTF primary prevention statin guidance finalized
Questions about how to prescribe statins for primary prevention abound more than 3 decades after the drugs swept into clinical practice to become a first-line medical approach to cutting cardiovascular (CV) risk. Statin usage recommendations from different bodies can vary in ways both limited and fundamental, spurring the kind of debate that accompanies such a document newly issued by the United States Preventive Services Task Force.
The document, little changed from the draft guidance released for public comment in February, was published online Aug. 23 in JAMA and the USPSTF website. It replaces a similar document issued by the task force in 2016.
The guidance has much in common with, but also sharp differences from, the influential 2018 guidelines on blood cholesterol management developed by the American College of Cardiology, American Heart Association, and 10 other medical societies.
And it is provocative enough to elicit at least four editorials issued the same day across the JAMA family of journals. They highlight key differences between the two documents, among them the USPSTF guidance’s consistent, narrow reliance on 7.5% and 10% cut points for 10-year risk levels as estimated from the ACC/AHA pooled cohort equations (PCE).
The guidance pairs the 10-year risk metric with at least one of only four prescribed CV risk factors to arrive at a limited choice of statin therapy recommendations. But its decision process isn’t bolstered by coronary artery calcium (CAC) scores or the prespecified “risk enhancers” that allowed the ACC/AHA-multisociety guidelines to be applied broadly and still be closely personalized. Those guidelines provide more PCE-based risk tiers for greater discrimination of risk and allow statins to be considered across a broader age group.
The USPSTF guidance’s evidence base consists of 23 clinical trials and three observational studies that directly compared a statin to either placebo or no statin, task force member John B. Wong, MD, Tufts University School of Medicine, Boston, told this news organization.
“In either kind of study, we found that the vast majority of patients had one or more of four risk factors – dyslipidemia, hypertension, diabetes, or smoking. So, when we categorized high risk or increased risk, we included the presence of one or more of those risk factors,” said Dr. Wong, who is director of comparative effectiveness research at Tufts Clinical Translational Science Institute.
‘Sensible and practical’
The USPSTF guidance applies only to adults aged 40-75 without CV signs or symptoms and recommends a statin prescription for persons at “high risk,” that is with an estimated 10-year PCE-based risk for death or CV events of 10% or higher plus at least one of the four risk factors, a level B recommendation.
It recommends that “clinicians selectively offer a statin” to such persons at “increased risk,” who have at least one of the risk factors and an estimated 10-year risk for death or CV events of 7.5% to less than 10%, a level C recommendation. “The likelihood of benefit is smaller in this group” than in persons at high risk, the document states.
“These recommendations from the USPSTF are sensible and practical,” states Salim S. Virani, MD, PhD, DeBakey Veterans Affairs Medical Center, Houston, in a related editorial published the same day in JAMA Network Open. He calls the former B-level recommendation “a conservative approach” and the latter C-level recommendation a “nuanced approach.”
Both are “understandable” given that some studies suggest that the PCE may overestimate the CV risk, Dr. Virani observes. “On the other hand, statin therapy has been shown to be efficacious” at 10-year CV-risk levels down to about 5%.
The USPSTF document “I think is going to perpetuate a problem that we have in this country, which is vast undertreatment of lipids,” Eric D. Peterson, MD, MPH, University of Texas Southwestern Medical Center, Dallas, said in an interview.
“We have a ton of good drugs that can lower cholesterol like crazy. If you lower cholesterol a lot, you improve outcomes,” he said. Dyslipidemia needs to be more widely and consistently treated, but “right now we have a pool of people in primary prevention who undertreat lipids and wait until disease happens – and then cardiologists get engaged. That’s an avoidable miss,” Dr. Peterson adds. He and JAMA Cardiology associate editor Ann Marie Navar, MD, PhD, provided JAMA with an editorial that accompanies the USPSTF guidance.
“My own personal bias would be that the [ACC/AHA-multisociety guidelines] are closer to being right,” Dr. Peterson said. They – unlike the USPSTF guidance – cover people with risk levels below 7.5%, down to at least 5%. They allow risk enhancers like metabolic syndrome, inflammatory diseases, or family history into the decision process. “And they’re more aggressive in diabetes and more aggressive in older people,” he said.
Higher threshold for therapy
The USPSTF guidance also explicitly omits some high-risk groups and makes little accommodation for others who might especially benefit from statins, several of the editorials contend. For example, states a related JAMA Cardiology editorial published the same day, “The USPSTF does not comment on familial hypercholesterolemia or an LDL-C level of 190 mg/dL or higher,” yet they are covered by the ACC/AHA-multispecialty guidelines.
In addition, write the editorialists, led by Neil J. Stone, MD, Northwestern University, Chicago, “the USPSTF uses a slightly higher threshold for initiation of statin therapy” than was used in the ACC/AHA-multisociety guidelines. USPSTF, for example, calls for 10-year risk to reach 10% before recommending a statin prescription.
“One concern about the USPSTF setting the bar higher for statin initiation is that it reduces the number of young patients (age 40-50 years) at risk for premature myocardial infarction considered for treatment,” write Dr. Stone and colleagues.
That may be related to a weakness of the PCE-based decision process. “Because the PCE estimates of 10-year CV disease risk rely so heavily on age, sex, and race, use of these estimates to identify candidates for statins results in significant skewing of the population recommended for statins,” write Dr. Navar and Dr. Peterson in their JAMA editorial.
The risk enhancers in the ACC/AHA-multispecialty guidelines, about a dozen of them, compensate for that limitation to some extent. But the PCE-dominated USPSTF risk estimates will likely miss some groups that could potentially benefit from statin therapy, Dr. Peterson agreed in an interview.
For example, younger adults facing years of high LDL-cholesterol levels could easily have PCE-based 10-year risk below 10%. “Having a high LDL over a lifetime puts you at really high risk,” he said. “Young people are missed even though their longitudinal risk is high.” So, by waiting for the lofty 10% level of risk over 10 years, “we limit the use of medicine that’s pretty cheap and highly effective.”
Dose intensity, adverse events
Also at variance from the ACC/AHA-multispecialty guidelines, the USPSTF states that, “Based on available evidence, use of moderate-intensity statin therapy seems reasonable for the primary prevention of CV disease in most persons.”
The task force specifically explored whether evidence supports some use of high-intensity vs. moderate-intensity statins, Tufts University’s Dr. Wong said. “We found only one study that looked at that particular question, and it didn’t give us a strong answer.” An elevated rosuvastatin-related diabetes risk was apparent in the JUPITER trial, “but for the other studies, we did not find that association.”
Most of the studies that explored statins for reducing risk for a first stroke or myocardial infarction used a moderate-dose statin, Dr. Wong said. “So that’s what we would usually recommend.”
But, Dr. Virani writes, consistent with the ACC/AHA-multispecialty guidelines, “clinicians should consider titrating the intensity of therapy to the risk of the individual.” Persons in certain high-risk primary prevention groups, such as those with end-organ injury from diabetes or LDL cholesterol at least 190 mg/dL, “may derive further benefit from the use of high-intensity statin therapy.”
Low-intensity statins are another potential option, but “in contrast with its 2016 recommendations, the USPSTF no longer recommends use of low-intensity statins in certain situations,” observes a fourth editorial published the same day in JAMA Internal Medicine, with lead author Anand R. Habib, MD, MPhil, and senior author Rita F. Redberg, MD, MSc, both of the University of California, San Francisco. Dr. Redberg is the journal’s editor and has long expressed cautions about statin safety.
“While it is understandable that the Task Force was limited by lack of data on dosing, this change is unfortunate for patients because the frequency of adverse effects increases as the statin dose increases,” the editorial states. Although USPSTF did not find statistically significant harm from the drugs, “in clinical practice, adverse events are commonly reported with use of statins.”
It continues: “At present, there are further reasons to curb our enthusiasm about the use of statins for primary prevention of CV disease.” To illustrate, the editorial questioned primary-prevention statins’ balance of risk vs. clinically meaningful benefit, not benefit that is merely statistically significant.
“The purported benefits of statins in terms of relative risk reduction are fairly constant across baseline lipid levels and cardiovascular risk score categories for primary prevention,” the editorial states.
“Therefore, the absolute benefit for those in lower-risk categories is likely small given that their baseline absolute risk is low, while the chance of adverse effects is constant across risk categories.”
However, USPSTF states, “In pooled analyses of trial data, statin therapy was not associated with increased risk of study withdrawal due to adverse events or serious adverse events.” Nor did it find significant associations with cancers, liver enzyme abnormalities, or diabetes, including new-onset diabetes.
And, the USPSTF adds, “Evidence on the association between statins and renal or cognitive harms is very limited but does not indicate increased risk.”
USPSTF is supported by the U.S. Agency for Healthcare Research and Quality. Dr. Virani discloses receiving grants from the Department of Veterans Affairs, National Institutes of Health, and the World Heart Federation; and personal fees from the American College of Cardiology. Dr. Peterson discloses serving on the JAMA editorial board and receiving research support to his institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and consulting fees from Novo Nordisk, Bayer, and Novartis. Dr. Navar discloses receiving research support to her institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and receiving honoraria and consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Lilly, Novo Nordisk, Novartis, New Amsterdam, and Pfizer. Dr. Stone discloses receiving an honorarium from Knowledge to Practice, an educational company not associated with the pharmaceutical industry; disclosures for the other authors are in the report. Dr. Redberg discloses receiving research funding from the Arnold Ventures Foundation and the Greenwall Foundation.
A version of this article first appeared on Medscape.com.
Questions about how to prescribe statins for primary prevention abound more than 3 decades after the drugs swept into clinical practice to become a first-line medical approach to cutting cardiovascular (CV) risk. Statin usage recommendations from different bodies can vary in ways both limited and fundamental, spurring the kind of debate that accompanies such a document newly issued by the United States Preventive Services Task Force.
The document, little changed from the draft guidance released for public comment in February, was published online Aug. 23 in JAMA and the USPSTF website. It replaces a similar document issued by the task force in 2016.
The guidance has much in common with, but also sharp differences from, the influential 2018 guidelines on blood cholesterol management developed by the American College of Cardiology, American Heart Association, and 10 other medical societies.
And it is provocative enough to elicit at least four editorials issued the same day across the JAMA family of journals. They highlight key differences between the two documents, among them the USPSTF guidance’s consistent, narrow reliance on 7.5% and 10% cut points for 10-year risk levels as estimated from the ACC/AHA pooled cohort equations (PCE).
The guidance pairs the 10-year risk metric with at least one of only four prescribed CV risk factors to arrive at a limited choice of statin therapy recommendations. But its decision process isn’t bolstered by coronary artery calcium (CAC) scores or the prespecified “risk enhancers” that allowed the ACC/AHA-multisociety guidelines to be applied broadly and still be closely personalized. Those guidelines provide more PCE-based risk tiers for greater discrimination of risk and allow statins to be considered across a broader age group.
The USPSTF guidance’s evidence base consists of 23 clinical trials and three observational studies that directly compared a statin to either placebo or no statin, task force member John B. Wong, MD, Tufts University School of Medicine, Boston, told this news organization.
“In either kind of study, we found that the vast majority of patients had one or more of four risk factors – dyslipidemia, hypertension, diabetes, or smoking. So, when we categorized high risk or increased risk, we included the presence of one or more of those risk factors,” said Dr. Wong, who is director of comparative effectiveness research at Tufts Clinical Translational Science Institute.
‘Sensible and practical’
The USPSTF guidance applies only to adults aged 40-75 without CV signs or symptoms and recommends a statin prescription for persons at “high risk,” that is with an estimated 10-year PCE-based risk for death or CV events of 10% or higher plus at least one of the four risk factors, a level B recommendation.
It recommends that “clinicians selectively offer a statin” to such persons at “increased risk,” who have at least one of the risk factors and an estimated 10-year risk for death or CV events of 7.5% to less than 10%, a level C recommendation. “The likelihood of benefit is smaller in this group” than in persons at high risk, the document states.
“These recommendations from the USPSTF are sensible and practical,” states Salim S. Virani, MD, PhD, DeBakey Veterans Affairs Medical Center, Houston, in a related editorial published the same day in JAMA Network Open. He calls the former B-level recommendation “a conservative approach” and the latter C-level recommendation a “nuanced approach.”
Both are “understandable” given that some studies suggest that the PCE may overestimate the CV risk, Dr. Virani observes. “On the other hand, statin therapy has been shown to be efficacious” at 10-year CV-risk levels down to about 5%.
The USPSTF document “I think is going to perpetuate a problem that we have in this country, which is vast undertreatment of lipids,” Eric D. Peterson, MD, MPH, University of Texas Southwestern Medical Center, Dallas, said in an interview.
“We have a ton of good drugs that can lower cholesterol like crazy. If you lower cholesterol a lot, you improve outcomes,” he said. Dyslipidemia needs to be more widely and consistently treated, but “right now we have a pool of people in primary prevention who undertreat lipids and wait until disease happens – and then cardiologists get engaged. That’s an avoidable miss,” Dr. Peterson adds. He and JAMA Cardiology associate editor Ann Marie Navar, MD, PhD, provided JAMA with an editorial that accompanies the USPSTF guidance.
“My own personal bias would be that the [ACC/AHA-multisociety guidelines] are closer to being right,” Dr. Peterson said. They – unlike the USPSTF guidance – cover people with risk levels below 7.5%, down to at least 5%. They allow risk enhancers like metabolic syndrome, inflammatory diseases, or family history into the decision process. “And they’re more aggressive in diabetes and more aggressive in older people,” he said.
Higher threshold for therapy
The USPSTF guidance also explicitly omits some high-risk groups and makes little accommodation for others who might especially benefit from statins, several of the editorials contend. For example, states a related JAMA Cardiology editorial published the same day, “The USPSTF does not comment on familial hypercholesterolemia or an LDL-C level of 190 mg/dL or higher,” yet they are covered by the ACC/AHA-multispecialty guidelines.
In addition, write the editorialists, led by Neil J. Stone, MD, Northwestern University, Chicago, “the USPSTF uses a slightly higher threshold for initiation of statin therapy” than was used in the ACC/AHA-multisociety guidelines. USPSTF, for example, calls for 10-year risk to reach 10% before recommending a statin prescription.
“One concern about the USPSTF setting the bar higher for statin initiation is that it reduces the number of young patients (age 40-50 years) at risk for premature myocardial infarction considered for treatment,” write Dr. Stone and colleagues.
That may be related to a weakness of the PCE-based decision process. “Because the PCE estimates of 10-year CV disease risk rely so heavily on age, sex, and race, use of these estimates to identify candidates for statins results in significant skewing of the population recommended for statins,” write Dr. Navar and Dr. Peterson in their JAMA editorial.
The risk enhancers in the ACC/AHA-multispecialty guidelines, about a dozen of them, compensate for that limitation to some extent. But the PCE-dominated USPSTF risk estimates will likely miss some groups that could potentially benefit from statin therapy, Dr. Peterson agreed in an interview.
For example, younger adults facing years of high LDL-cholesterol levels could easily have PCE-based 10-year risk below 10%. “Having a high LDL over a lifetime puts you at really high risk,” he said. “Young people are missed even though their longitudinal risk is high.” So, by waiting for the lofty 10% level of risk over 10 years, “we limit the use of medicine that’s pretty cheap and highly effective.”
Dose intensity, adverse events
Also at variance from the ACC/AHA-multispecialty guidelines, the USPSTF states that, “Based on available evidence, use of moderate-intensity statin therapy seems reasonable for the primary prevention of CV disease in most persons.”
The task force specifically explored whether evidence supports some use of high-intensity vs. moderate-intensity statins, Tufts University’s Dr. Wong said. “We found only one study that looked at that particular question, and it didn’t give us a strong answer.” An elevated rosuvastatin-related diabetes risk was apparent in the JUPITER trial, “but for the other studies, we did not find that association.”
Most of the studies that explored statins for reducing risk for a first stroke or myocardial infarction used a moderate-dose statin, Dr. Wong said. “So that’s what we would usually recommend.”
But, Dr. Virani writes, consistent with the ACC/AHA-multispecialty guidelines, “clinicians should consider titrating the intensity of therapy to the risk of the individual.” Persons in certain high-risk primary prevention groups, such as those with end-organ injury from diabetes or LDL cholesterol at least 190 mg/dL, “may derive further benefit from the use of high-intensity statin therapy.”
Low-intensity statins are another potential option, but “in contrast with its 2016 recommendations, the USPSTF no longer recommends use of low-intensity statins in certain situations,” observes a fourth editorial published the same day in JAMA Internal Medicine, with lead author Anand R. Habib, MD, MPhil, and senior author Rita F. Redberg, MD, MSc, both of the University of California, San Francisco. Dr. Redberg is the journal’s editor and has long expressed cautions about statin safety.
“While it is understandable that the Task Force was limited by lack of data on dosing, this change is unfortunate for patients because the frequency of adverse effects increases as the statin dose increases,” the editorial states. Although USPSTF did not find statistically significant harm from the drugs, “in clinical practice, adverse events are commonly reported with use of statins.”
It continues: “At present, there are further reasons to curb our enthusiasm about the use of statins for primary prevention of CV disease.” To illustrate, the editorial questioned primary-prevention statins’ balance of risk vs. clinically meaningful benefit, not benefit that is merely statistically significant.
“The purported benefits of statins in terms of relative risk reduction are fairly constant across baseline lipid levels and cardiovascular risk score categories for primary prevention,” the editorial states.
“Therefore, the absolute benefit for those in lower-risk categories is likely small given that their baseline absolute risk is low, while the chance of adverse effects is constant across risk categories.”
However, USPSTF states, “In pooled analyses of trial data, statin therapy was not associated with increased risk of study withdrawal due to adverse events or serious adverse events.” Nor did it find significant associations with cancers, liver enzyme abnormalities, or diabetes, including new-onset diabetes.
And, the USPSTF adds, “Evidence on the association between statins and renal or cognitive harms is very limited but does not indicate increased risk.”
USPSTF is supported by the U.S. Agency for Healthcare Research and Quality. Dr. Virani discloses receiving grants from the Department of Veterans Affairs, National Institutes of Health, and the World Heart Federation; and personal fees from the American College of Cardiology. Dr. Peterson discloses serving on the JAMA editorial board and receiving research support to his institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and consulting fees from Novo Nordisk, Bayer, and Novartis. Dr. Navar discloses receiving research support to her institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and receiving honoraria and consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Lilly, Novo Nordisk, Novartis, New Amsterdam, and Pfizer. Dr. Stone discloses receiving an honorarium from Knowledge to Practice, an educational company not associated with the pharmaceutical industry; disclosures for the other authors are in the report. Dr. Redberg discloses receiving research funding from the Arnold Ventures Foundation and the Greenwall Foundation.
A version of this article first appeared on Medscape.com.
Questions about how to prescribe statins for primary prevention abound more than 3 decades after the drugs swept into clinical practice to become a first-line medical approach to cutting cardiovascular (CV) risk. Statin usage recommendations from different bodies can vary in ways both limited and fundamental, spurring the kind of debate that accompanies such a document newly issued by the United States Preventive Services Task Force.
The document, little changed from the draft guidance released for public comment in February, was published online Aug. 23 in JAMA and the USPSTF website. It replaces a similar document issued by the task force in 2016.
The guidance has much in common with, but also sharp differences from, the influential 2018 guidelines on blood cholesterol management developed by the American College of Cardiology, American Heart Association, and 10 other medical societies.
And it is provocative enough to elicit at least four editorials issued the same day across the JAMA family of journals. They highlight key differences between the two documents, among them the USPSTF guidance’s consistent, narrow reliance on 7.5% and 10% cut points for 10-year risk levels as estimated from the ACC/AHA pooled cohort equations (PCE).
The guidance pairs the 10-year risk metric with at least one of only four prescribed CV risk factors to arrive at a limited choice of statin therapy recommendations. But its decision process isn’t bolstered by coronary artery calcium (CAC) scores or the prespecified “risk enhancers” that allowed the ACC/AHA-multisociety guidelines to be applied broadly and still be closely personalized. Those guidelines provide more PCE-based risk tiers for greater discrimination of risk and allow statins to be considered across a broader age group.
The USPSTF guidance’s evidence base consists of 23 clinical trials and three observational studies that directly compared a statin to either placebo or no statin, task force member John B. Wong, MD, Tufts University School of Medicine, Boston, told this news organization.
“In either kind of study, we found that the vast majority of patients had one or more of four risk factors – dyslipidemia, hypertension, diabetes, or smoking. So, when we categorized high risk or increased risk, we included the presence of one or more of those risk factors,” said Dr. Wong, who is director of comparative effectiveness research at Tufts Clinical Translational Science Institute.
‘Sensible and practical’
The USPSTF guidance applies only to adults aged 40-75 without CV signs or symptoms and recommends a statin prescription for persons at “high risk,” that is with an estimated 10-year PCE-based risk for death or CV events of 10% or higher plus at least one of the four risk factors, a level B recommendation.
It recommends that “clinicians selectively offer a statin” to such persons at “increased risk,” who have at least one of the risk factors and an estimated 10-year risk for death or CV events of 7.5% to less than 10%, a level C recommendation. “The likelihood of benefit is smaller in this group” than in persons at high risk, the document states.
“These recommendations from the USPSTF are sensible and practical,” states Salim S. Virani, MD, PhD, DeBakey Veterans Affairs Medical Center, Houston, in a related editorial published the same day in JAMA Network Open. He calls the former B-level recommendation “a conservative approach” and the latter C-level recommendation a “nuanced approach.”
Both are “understandable” given that some studies suggest that the PCE may overestimate the CV risk, Dr. Virani observes. “On the other hand, statin therapy has been shown to be efficacious” at 10-year CV-risk levels down to about 5%.
The USPSTF document “I think is going to perpetuate a problem that we have in this country, which is vast undertreatment of lipids,” Eric D. Peterson, MD, MPH, University of Texas Southwestern Medical Center, Dallas, said in an interview.
“We have a ton of good drugs that can lower cholesterol like crazy. If you lower cholesterol a lot, you improve outcomes,” he said. Dyslipidemia needs to be more widely and consistently treated, but “right now we have a pool of people in primary prevention who undertreat lipids and wait until disease happens – and then cardiologists get engaged. That’s an avoidable miss,” Dr. Peterson adds. He and JAMA Cardiology associate editor Ann Marie Navar, MD, PhD, provided JAMA with an editorial that accompanies the USPSTF guidance.
“My own personal bias would be that the [ACC/AHA-multisociety guidelines] are closer to being right,” Dr. Peterson said. They – unlike the USPSTF guidance – cover people with risk levels below 7.5%, down to at least 5%. They allow risk enhancers like metabolic syndrome, inflammatory diseases, or family history into the decision process. “And they’re more aggressive in diabetes and more aggressive in older people,” he said.
Higher threshold for therapy
The USPSTF guidance also explicitly omits some high-risk groups and makes little accommodation for others who might especially benefit from statins, several of the editorials contend. For example, states a related JAMA Cardiology editorial published the same day, “The USPSTF does not comment on familial hypercholesterolemia or an LDL-C level of 190 mg/dL or higher,” yet they are covered by the ACC/AHA-multispecialty guidelines.
In addition, write the editorialists, led by Neil J. Stone, MD, Northwestern University, Chicago, “the USPSTF uses a slightly higher threshold for initiation of statin therapy” than was used in the ACC/AHA-multisociety guidelines. USPSTF, for example, calls for 10-year risk to reach 10% before recommending a statin prescription.
“One concern about the USPSTF setting the bar higher for statin initiation is that it reduces the number of young patients (age 40-50 years) at risk for premature myocardial infarction considered for treatment,” write Dr. Stone and colleagues.
That may be related to a weakness of the PCE-based decision process. “Because the PCE estimates of 10-year CV disease risk rely so heavily on age, sex, and race, use of these estimates to identify candidates for statins results in significant skewing of the population recommended for statins,” write Dr. Navar and Dr. Peterson in their JAMA editorial.
The risk enhancers in the ACC/AHA-multispecialty guidelines, about a dozen of them, compensate for that limitation to some extent. But the PCE-dominated USPSTF risk estimates will likely miss some groups that could potentially benefit from statin therapy, Dr. Peterson agreed in an interview.
For example, younger adults facing years of high LDL-cholesterol levels could easily have PCE-based 10-year risk below 10%. “Having a high LDL over a lifetime puts you at really high risk,” he said. “Young people are missed even though their longitudinal risk is high.” So, by waiting for the lofty 10% level of risk over 10 years, “we limit the use of medicine that’s pretty cheap and highly effective.”
Dose intensity, adverse events
Also at variance from the ACC/AHA-multispecialty guidelines, the USPSTF states that, “Based on available evidence, use of moderate-intensity statin therapy seems reasonable for the primary prevention of CV disease in most persons.”
The task force specifically explored whether evidence supports some use of high-intensity vs. moderate-intensity statins, Tufts University’s Dr. Wong said. “We found only one study that looked at that particular question, and it didn’t give us a strong answer.” An elevated rosuvastatin-related diabetes risk was apparent in the JUPITER trial, “but for the other studies, we did not find that association.”
Most of the studies that explored statins for reducing risk for a first stroke or myocardial infarction used a moderate-dose statin, Dr. Wong said. “So that’s what we would usually recommend.”
But, Dr. Virani writes, consistent with the ACC/AHA-multispecialty guidelines, “clinicians should consider titrating the intensity of therapy to the risk of the individual.” Persons in certain high-risk primary prevention groups, such as those with end-organ injury from diabetes or LDL cholesterol at least 190 mg/dL, “may derive further benefit from the use of high-intensity statin therapy.”
Low-intensity statins are another potential option, but “in contrast with its 2016 recommendations, the USPSTF no longer recommends use of low-intensity statins in certain situations,” observes a fourth editorial published the same day in JAMA Internal Medicine, with lead author Anand R. Habib, MD, MPhil, and senior author Rita F. Redberg, MD, MSc, both of the University of California, San Francisco. Dr. Redberg is the journal’s editor and has long expressed cautions about statin safety.
“While it is understandable that the Task Force was limited by lack of data on dosing, this change is unfortunate for patients because the frequency of adverse effects increases as the statin dose increases,” the editorial states. Although USPSTF did not find statistically significant harm from the drugs, “in clinical practice, adverse events are commonly reported with use of statins.”
It continues: “At present, there are further reasons to curb our enthusiasm about the use of statins for primary prevention of CV disease.” To illustrate, the editorial questioned primary-prevention statins’ balance of risk vs. clinically meaningful benefit, not benefit that is merely statistically significant.
“The purported benefits of statins in terms of relative risk reduction are fairly constant across baseline lipid levels and cardiovascular risk score categories for primary prevention,” the editorial states.
“Therefore, the absolute benefit for those in lower-risk categories is likely small given that their baseline absolute risk is low, while the chance of adverse effects is constant across risk categories.”
However, USPSTF states, “In pooled analyses of trial data, statin therapy was not associated with increased risk of study withdrawal due to adverse events or serious adverse events.” Nor did it find significant associations with cancers, liver enzyme abnormalities, or diabetes, including new-onset diabetes.
And, the USPSTF adds, “Evidence on the association between statins and renal or cognitive harms is very limited but does not indicate increased risk.”
USPSTF is supported by the U.S. Agency for Healthcare Research and Quality. Dr. Virani discloses receiving grants from the Department of Veterans Affairs, National Institutes of Health, and the World Heart Federation; and personal fees from the American College of Cardiology. Dr. Peterson discloses serving on the JAMA editorial board and receiving research support to his institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and consulting fees from Novo Nordisk, Bayer, and Novartis. Dr. Navar discloses receiving research support to her institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and receiving honoraria and consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Lilly, Novo Nordisk, Novartis, New Amsterdam, and Pfizer. Dr. Stone discloses receiving an honorarium from Knowledge to Practice, an educational company not associated with the pharmaceutical industry; disclosures for the other authors are in the report. Dr. Redberg discloses receiving research funding from the Arnold Ventures Foundation and the Greenwall Foundation.
A version of this article first appeared on Medscape.com.
FROM JAMA
Blood biomarkers predict TBI disability and mortality
, new research suggests.
In new data from the TRACK-TBI study group, high levels of glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) proteins found in glial cells and neurons, respectively, correlated with death and severe injury. Investigators note that measuring these biomarkers may give a more accurate assessment of a patient’s prognosis following TBI.
This study is the “first report of the accuracy of a blood test that can be obtained rapidly on the day of injury to predict neurological recovery at 6 months after injury,” lead author Frederick Korley, MD, PhD, associate professor of emergency medicine at the University of Michigan, Ann Arbor, said in a news release.
The findings were published online in the Lancet Neurology.
Added value
The researchers measured GFAP and UCH-L1 in blood samples taken from 1,696 patients with TBI on the day of their injury, and they assessed patient recovery 6 months later.
The markers were measured using the i-STAT TBI Plasma test (Abbott Labs). The test was approved in 2021 by the U.S. Food and Drug Administration to determine which patients with mild TBI should undergo computed tomography scans.
About two-thirds of the study population were men, and the average age was 39 years. All patients were evaluated at Level I trauma centers for injuries caused primarily by traffic accidents or falls.
Six months following injury, 7% of the patients had died and 14% had an unfavorable outcome, ranging from vegetative state to severe disability requiring daily support. In addition, 67% had incomplete recovery, ranging from moderate disabilities requiring assistance outside of the home to minor disabling neurological or psychological deficits.
Day-of-injury GFAP and UCH-L1 levels had a high probability of predicting death (87% for GFAP and 89% for UCH-L1) and severe disability (86% for both GFAP and UCH-L1) at 6 months, the investigators reported.
The biomarkers were less accurate in predicting incomplete recovery (62% for GFAP and 61% for UCH-L1).
The researchers also assessed the added value of combining the blood biomarkers to current TBI prognostic models that take into account variables such as age, motor score, pupil reactivity, and CT characteristics.
In patients with a Glasgow Coma Scale (GCS) score of 3-12, adding GFAP and UCH-L1 alone or combined to each of the three International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) models significantly increased their accuracy for predicting death (range, 90%-94%) and unfavorable outcome (range, 83%-89%).
In patients with milder TBI (GCS score, 13-15), adding GFAP and UCH-L1 to the UPFRONT prognostic model modestly increased accuracy for predicting incomplete recovery (69%).
‘Important’ findings
Commenting on the study, Cyrus A. Raji, MD, PhD, assistant professor of radiology and neurology, Washington University, St. Louis, said this “critical” study shows that these biomarkers can “predict key outcomes,” including mortality and severe disability. “Thus, in conjunction with clinical evaluations and related data such as neuroimaging, these tests may warrant translation to broader clinical practice, particularly in acute settings,” said Dr. Raji, who was not involved in the research.
Also weighing in, Heidi Fusco, MD, assistant director of the traumatic brain injury program at NYU Langone Rusk Rehabilitation, said the findings are “important.”
“Prognosis after brain injury often is based on the initial presentation, ongoing clinical exams, and neuroimaging; and the addition of biomarkers would contribute to creating a more objective prognostic model,” Dr. Fusco said.
She noted “it’s unclear” whether clinical hospital laboratories would be able to accommodate this type of laboratory drawing.
“It is imperative that clinicians still use the patient history [and] clinical and radiological exam when making clinical decisions for a patient and not just lab values. It would be best to incorporate the GFAP and UCH-L1 into a preexisting prognostic model,” Dr. Fusco said.
The study was funded by the U.S. National Institutes of Health, the National Institute of Neurologic Disorders and Stroke, the U.S. Department of Defense, One Mind, and U.S. Army Medical Research and Development Command. Dr. Korley reported having previously consulted for Abbott Laboratories and has received research funding from Abbott Laboratories, which makes the assays used in the study. Dr. Raji is a consultant for Brainreader ApS and Neurevolution. Dr. Fusco has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
In new data from the TRACK-TBI study group, high levels of glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) proteins found in glial cells and neurons, respectively, correlated with death and severe injury. Investigators note that measuring these biomarkers may give a more accurate assessment of a patient’s prognosis following TBI.
This study is the “first report of the accuracy of a blood test that can be obtained rapidly on the day of injury to predict neurological recovery at 6 months after injury,” lead author Frederick Korley, MD, PhD, associate professor of emergency medicine at the University of Michigan, Ann Arbor, said in a news release.
The findings were published online in the Lancet Neurology.
Added value
The researchers measured GFAP and UCH-L1 in blood samples taken from 1,696 patients with TBI on the day of their injury, and they assessed patient recovery 6 months later.
The markers were measured using the i-STAT TBI Plasma test (Abbott Labs). The test was approved in 2021 by the U.S. Food and Drug Administration to determine which patients with mild TBI should undergo computed tomography scans.
About two-thirds of the study population were men, and the average age was 39 years. All patients were evaluated at Level I trauma centers for injuries caused primarily by traffic accidents or falls.
Six months following injury, 7% of the patients had died and 14% had an unfavorable outcome, ranging from vegetative state to severe disability requiring daily support. In addition, 67% had incomplete recovery, ranging from moderate disabilities requiring assistance outside of the home to minor disabling neurological or psychological deficits.
Day-of-injury GFAP and UCH-L1 levels had a high probability of predicting death (87% for GFAP and 89% for UCH-L1) and severe disability (86% for both GFAP and UCH-L1) at 6 months, the investigators reported.
The biomarkers were less accurate in predicting incomplete recovery (62% for GFAP and 61% for UCH-L1).
The researchers also assessed the added value of combining the blood biomarkers to current TBI prognostic models that take into account variables such as age, motor score, pupil reactivity, and CT characteristics.
In patients with a Glasgow Coma Scale (GCS) score of 3-12, adding GFAP and UCH-L1 alone or combined to each of the three International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) models significantly increased their accuracy for predicting death (range, 90%-94%) and unfavorable outcome (range, 83%-89%).
In patients with milder TBI (GCS score, 13-15), adding GFAP and UCH-L1 to the UPFRONT prognostic model modestly increased accuracy for predicting incomplete recovery (69%).
‘Important’ findings
Commenting on the study, Cyrus A. Raji, MD, PhD, assistant professor of radiology and neurology, Washington University, St. Louis, said this “critical” study shows that these biomarkers can “predict key outcomes,” including mortality and severe disability. “Thus, in conjunction with clinical evaluations and related data such as neuroimaging, these tests may warrant translation to broader clinical practice, particularly in acute settings,” said Dr. Raji, who was not involved in the research.
Also weighing in, Heidi Fusco, MD, assistant director of the traumatic brain injury program at NYU Langone Rusk Rehabilitation, said the findings are “important.”
“Prognosis after brain injury often is based on the initial presentation, ongoing clinical exams, and neuroimaging; and the addition of biomarkers would contribute to creating a more objective prognostic model,” Dr. Fusco said.
She noted “it’s unclear” whether clinical hospital laboratories would be able to accommodate this type of laboratory drawing.
“It is imperative that clinicians still use the patient history [and] clinical and radiological exam when making clinical decisions for a patient and not just lab values. It would be best to incorporate the GFAP and UCH-L1 into a preexisting prognostic model,” Dr. Fusco said.
The study was funded by the U.S. National Institutes of Health, the National Institute of Neurologic Disorders and Stroke, the U.S. Department of Defense, One Mind, and U.S. Army Medical Research and Development Command. Dr. Korley reported having previously consulted for Abbott Laboratories and has received research funding from Abbott Laboratories, which makes the assays used in the study. Dr. Raji is a consultant for Brainreader ApS and Neurevolution. Dr. Fusco has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
In new data from the TRACK-TBI study group, high levels of glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) proteins found in glial cells and neurons, respectively, correlated with death and severe injury. Investigators note that measuring these biomarkers may give a more accurate assessment of a patient’s prognosis following TBI.
This study is the “first report of the accuracy of a blood test that can be obtained rapidly on the day of injury to predict neurological recovery at 6 months after injury,” lead author Frederick Korley, MD, PhD, associate professor of emergency medicine at the University of Michigan, Ann Arbor, said in a news release.
The findings were published online in the Lancet Neurology.
Added value
The researchers measured GFAP and UCH-L1 in blood samples taken from 1,696 patients with TBI on the day of their injury, and they assessed patient recovery 6 months later.
The markers were measured using the i-STAT TBI Plasma test (Abbott Labs). The test was approved in 2021 by the U.S. Food and Drug Administration to determine which patients with mild TBI should undergo computed tomography scans.
About two-thirds of the study population were men, and the average age was 39 years. All patients were evaluated at Level I trauma centers for injuries caused primarily by traffic accidents or falls.
Six months following injury, 7% of the patients had died and 14% had an unfavorable outcome, ranging from vegetative state to severe disability requiring daily support. In addition, 67% had incomplete recovery, ranging from moderate disabilities requiring assistance outside of the home to minor disabling neurological or psychological deficits.
Day-of-injury GFAP and UCH-L1 levels had a high probability of predicting death (87% for GFAP and 89% for UCH-L1) and severe disability (86% for both GFAP and UCH-L1) at 6 months, the investigators reported.
The biomarkers were less accurate in predicting incomplete recovery (62% for GFAP and 61% for UCH-L1).
The researchers also assessed the added value of combining the blood biomarkers to current TBI prognostic models that take into account variables such as age, motor score, pupil reactivity, and CT characteristics.
In patients with a Glasgow Coma Scale (GCS) score of 3-12, adding GFAP and UCH-L1 alone or combined to each of the three International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) models significantly increased their accuracy for predicting death (range, 90%-94%) and unfavorable outcome (range, 83%-89%).
In patients with milder TBI (GCS score, 13-15), adding GFAP and UCH-L1 to the UPFRONT prognostic model modestly increased accuracy for predicting incomplete recovery (69%).
‘Important’ findings
Commenting on the study, Cyrus A. Raji, MD, PhD, assistant professor of radiology and neurology, Washington University, St. Louis, said this “critical” study shows that these biomarkers can “predict key outcomes,” including mortality and severe disability. “Thus, in conjunction with clinical evaluations and related data such as neuroimaging, these tests may warrant translation to broader clinical practice, particularly in acute settings,” said Dr. Raji, who was not involved in the research.
Also weighing in, Heidi Fusco, MD, assistant director of the traumatic brain injury program at NYU Langone Rusk Rehabilitation, said the findings are “important.”
“Prognosis after brain injury often is based on the initial presentation, ongoing clinical exams, and neuroimaging; and the addition of biomarkers would contribute to creating a more objective prognostic model,” Dr. Fusco said.
She noted “it’s unclear” whether clinical hospital laboratories would be able to accommodate this type of laboratory drawing.
“It is imperative that clinicians still use the patient history [and] clinical and radiological exam when making clinical decisions for a patient and not just lab values. It would be best to incorporate the GFAP and UCH-L1 into a preexisting prognostic model,” Dr. Fusco said.
The study was funded by the U.S. National Institutes of Health, the National Institute of Neurologic Disorders and Stroke, the U.S. Department of Defense, One Mind, and U.S. Army Medical Research and Development Command. Dr. Korley reported having previously consulted for Abbott Laboratories and has received research funding from Abbott Laboratories, which makes the assays used in the study. Dr. Raji is a consultant for Brainreader ApS and Neurevolution. Dr. Fusco has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE LANCET NEUROLOGY
Pfizer seeks approval for updated COVID booster
Pfizer has sent an application to the Food and Drug Administration for emergency use authorization of its updated COVID-19 booster vaccine for the fall of 2022, the company announced on Aug. 22.
The vaccine, which is adapted for the BA.4 and BA.5 Omicron variants, would be meant for ages 12 and older. If authorized by the FDA, the doses could ship as soon as September.
“Having rapidly scaled up production, we are positioned to immediately begin distribution of the bivalent Omicron BA.4/BA.5 boosters, if authorized, to help protect individuals and families as we prepare for potential fall and winter surges,” Albert Bourla, PhD, Pfizer’s chairman and CEO, said in the statement.
Earlier this year, the FDA ordered vaccine makers such as Pfizer and Moderna to update their shots to target BA.4 and BA.5, which are better at escaping immunity from earlier vaccines and previous infections.
The United States has a contract to buy 105 million of the Pfizer doses and 66 million of the Moderna doses, according to The Associated Press. Moderna is expected to file its FDA application soon as well.
The new shots target both the original spike protein on the coronavirus and the spike mutations carried by BA.4 and BA.5. For now, BA.5 is causing 89% of new infections in the United States, followed by BA.4.6 with 6.3% and BA.4 with 4.3%, according to the latest Centers for Disease Control and Prevention data.
There’s no way to tell if BA.5 will still be the dominant strain this winter or if new variant will replace it, the AP reported. But public health officials have supported the updated boosters as a way to target the most recent strains and increase immunity again.
On Aug. 15, Great Britain became the first country to authorize another one of Moderna’s updated vaccines, which adds protection against BA.1, or the original Omicron strain that became dominant in the winter of 2021-2022. European regulators are considering this shot, the AP reported, but the United States opted not to use this version since new Omicron variants have become dominant.
To approve the latest Pfizer shot, the FDA will rely on scientific testing of prior updates to the vaccine, rather than the newest boosters, to decide whether to fast-track the updated shots for fall, the AP reported. This method is like how flu vaccines are updated each year without large studies that take months.
Previously, Pfizer announced results from a study that found the earlier Omicron update significantly boosted antibodies capable of fighting the BA.1 variant and provided some protection against BA.4 and BA.5. The company’s latest FDA application contains that data and animal testing on the newest booster, the AP reported.
Pfizer will start a trial using the BA.4/BA.5 booster in coming weeks to get more data on how well the latest shot works. Moderna has begun a similar study.
The full results from these studies won’t be available before a fall booster campaign, which is why the FDA and public health officials have called for an updated shot to be ready for distribution in September.
“It’s clear that none of these vaccines are going to completely prevent infection,” Rachel Presti, MD, a researcher with the Moderna trial and an infectious diseases specialist at Washington University in St. Louis, told the AP.
But previous studies of variant booster candidates have shown that “you still get a broader immune response giving a variant booster than giving the same booster,” she said.
A version of this article first appeared on WebMD.com.
Pfizer has sent an application to the Food and Drug Administration for emergency use authorization of its updated COVID-19 booster vaccine for the fall of 2022, the company announced on Aug. 22.
The vaccine, which is adapted for the BA.4 and BA.5 Omicron variants, would be meant for ages 12 and older. If authorized by the FDA, the doses could ship as soon as September.
“Having rapidly scaled up production, we are positioned to immediately begin distribution of the bivalent Omicron BA.4/BA.5 boosters, if authorized, to help protect individuals and families as we prepare for potential fall and winter surges,” Albert Bourla, PhD, Pfizer’s chairman and CEO, said in the statement.
Earlier this year, the FDA ordered vaccine makers such as Pfizer and Moderna to update their shots to target BA.4 and BA.5, which are better at escaping immunity from earlier vaccines and previous infections.
The United States has a contract to buy 105 million of the Pfizer doses and 66 million of the Moderna doses, according to The Associated Press. Moderna is expected to file its FDA application soon as well.
The new shots target both the original spike protein on the coronavirus and the spike mutations carried by BA.4 and BA.5. For now, BA.5 is causing 89% of new infections in the United States, followed by BA.4.6 with 6.3% and BA.4 with 4.3%, according to the latest Centers for Disease Control and Prevention data.
There’s no way to tell if BA.5 will still be the dominant strain this winter or if new variant will replace it, the AP reported. But public health officials have supported the updated boosters as a way to target the most recent strains and increase immunity again.
On Aug. 15, Great Britain became the first country to authorize another one of Moderna’s updated vaccines, which adds protection against BA.1, or the original Omicron strain that became dominant in the winter of 2021-2022. European regulators are considering this shot, the AP reported, but the United States opted not to use this version since new Omicron variants have become dominant.
To approve the latest Pfizer shot, the FDA will rely on scientific testing of prior updates to the vaccine, rather than the newest boosters, to decide whether to fast-track the updated shots for fall, the AP reported. This method is like how flu vaccines are updated each year without large studies that take months.
Previously, Pfizer announced results from a study that found the earlier Omicron update significantly boosted antibodies capable of fighting the BA.1 variant and provided some protection against BA.4 and BA.5. The company’s latest FDA application contains that data and animal testing on the newest booster, the AP reported.
Pfizer will start a trial using the BA.4/BA.5 booster in coming weeks to get more data on how well the latest shot works. Moderna has begun a similar study.
The full results from these studies won’t be available before a fall booster campaign, which is why the FDA and public health officials have called for an updated shot to be ready for distribution in September.
“It’s clear that none of these vaccines are going to completely prevent infection,” Rachel Presti, MD, a researcher with the Moderna trial and an infectious diseases specialist at Washington University in St. Louis, told the AP.
But previous studies of variant booster candidates have shown that “you still get a broader immune response giving a variant booster than giving the same booster,” she said.
A version of this article first appeared on WebMD.com.
Pfizer has sent an application to the Food and Drug Administration for emergency use authorization of its updated COVID-19 booster vaccine for the fall of 2022, the company announced on Aug. 22.
The vaccine, which is adapted for the BA.4 and BA.5 Omicron variants, would be meant for ages 12 and older. If authorized by the FDA, the doses could ship as soon as September.
“Having rapidly scaled up production, we are positioned to immediately begin distribution of the bivalent Omicron BA.4/BA.5 boosters, if authorized, to help protect individuals and families as we prepare for potential fall and winter surges,” Albert Bourla, PhD, Pfizer’s chairman and CEO, said in the statement.
Earlier this year, the FDA ordered vaccine makers such as Pfizer and Moderna to update their shots to target BA.4 and BA.5, which are better at escaping immunity from earlier vaccines and previous infections.
The United States has a contract to buy 105 million of the Pfizer doses and 66 million of the Moderna doses, according to The Associated Press. Moderna is expected to file its FDA application soon as well.
The new shots target both the original spike protein on the coronavirus and the spike mutations carried by BA.4 and BA.5. For now, BA.5 is causing 89% of new infections in the United States, followed by BA.4.6 with 6.3% and BA.4 with 4.3%, according to the latest Centers for Disease Control and Prevention data.
There’s no way to tell if BA.5 will still be the dominant strain this winter or if new variant will replace it, the AP reported. But public health officials have supported the updated boosters as a way to target the most recent strains and increase immunity again.
On Aug. 15, Great Britain became the first country to authorize another one of Moderna’s updated vaccines, which adds protection against BA.1, or the original Omicron strain that became dominant in the winter of 2021-2022. European regulators are considering this shot, the AP reported, but the United States opted not to use this version since new Omicron variants have become dominant.
To approve the latest Pfizer shot, the FDA will rely on scientific testing of prior updates to the vaccine, rather than the newest boosters, to decide whether to fast-track the updated shots for fall, the AP reported. This method is like how flu vaccines are updated each year without large studies that take months.
Previously, Pfizer announced results from a study that found the earlier Omicron update significantly boosted antibodies capable of fighting the BA.1 variant and provided some protection against BA.4 and BA.5. The company’s latest FDA application contains that data and animal testing on the newest booster, the AP reported.
Pfizer will start a trial using the BA.4/BA.5 booster in coming weeks to get more data on how well the latest shot works. Moderna has begun a similar study.
The full results from these studies won’t be available before a fall booster campaign, which is why the FDA and public health officials have called for an updated shot to be ready for distribution in September.
“It’s clear that none of these vaccines are going to completely prevent infection,” Rachel Presti, MD, a researcher with the Moderna trial and an infectious diseases specialist at Washington University in St. Louis, told the AP.
But previous studies of variant booster candidates have shown that “you still get a broader immune response giving a variant booster than giving the same booster,” she said.
A version of this article first appeared on WebMD.com.