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Inhaled, systemic steroids linked to changes in brain structure
New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.
Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.
Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.
The findings should encourage clinicians to consider whether doses they are prescribing are too high, said Dr. Meijer. He added that the negative effect of glucocorticoids on the brain was also found in those using inhalers, such as patients with asthma.
The findings were published online in the BMJ Open.
Serious side effects
Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.
However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.
About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.
Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.
The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.
The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).
Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.
The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).
In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
Imaging analyses
Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.
Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.
Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.
The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”
He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.
Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.
Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.
In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
Move away from ‘one dose for all’?
Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.
The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.
He added that longer use or higher doses may be necessary to also induce volumetric changes.
Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.
The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.
In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.
In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
Impressive, but several limitations
Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”
In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.
That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.
He noted that cognitive differences were also only observed with systemic corticosteroids.
Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.
However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.
Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.
No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.
A version of this article first appeared on Medscape.com.
New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.
Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.
Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.
The findings should encourage clinicians to consider whether doses they are prescribing are too high, said Dr. Meijer. He added that the negative effect of glucocorticoids on the brain was also found in those using inhalers, such as patients with asthma.
The findings were published online in the BMJ Open.
Serious side effects
Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.
However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.
About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.
Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.
The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.
The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).
Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.
The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).
In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
Imaging analyses
Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.
Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.
Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.
The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”
He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.
Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.
Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.
In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
Move away from ‘one dose for all’?
Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.
The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.
He added that longer use or higher doses may be necessary to also induce volumetric changes.
Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.
The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.
In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.
In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
Impressive, but several limitations
Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”
In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.
That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.
He noted that cognitive differences were also only observed with systemic corticosteroids.
Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.
However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.
Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.
No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.
A version of this article first appeared on Medscape.com.
New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.
Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.
Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.
The findings should encourage clinicians to consider whether doses they are prescribing are too high, said Dr. Meijer. He added that the negative effect of glucocorticoids on the brain was also found in those using inhalers, such as patients with asthma.
The findings were published online in the BMJ Open.
Serious side effects
Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.
However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.
About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.
Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.
The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.
The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).
Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.
The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).
In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
Imaging analyses
Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.
Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.
Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.
The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”
He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.
Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.
Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.
In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
Move away from ‘one dose for all’?
Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.
The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.
He added that longer use or higher doses may be necessary to also induce volumetric changes.
Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.
The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.
In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.
In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
Impressive, but several limitations
Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”
In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.
That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.
He noted that cognitive differences were also only observed with systemic corticosteroids.
Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.
However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.
Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.
No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.
A version of this article first appeared on Medscape.com.
FROM BMJ OPEN
Majority of muscle symptoms with statins not caused by treatment
In the vast majority of people who experience muscle pain or weakness while taking a statin, those symptoms are not related to the statin, a new individual patient data meta-analysis of randomized controlled trials shows.
The Cholesterol Trialists Collaboration meta-analysis examined 19 large randomized double-blind trials that compared statin therapy with placebo and involved almost 124,000 patients.
“Our results show that, in people who experience muscle symptoms in the first year of taking a statin, those symptoms are actually due to the statin in only 1 of 15 of those people. For the other 14 of the 15 people who experience muscle symptoms in the first year of taking a statin, that muscle pain is not due to the statin,” lead investigator Colin Baigent, MD, said.
After the first year, there was no difference in muscle symptoms between patients taking a statin or those taking placebo.
Dr. Baigent, who is director of the Population Health Research Unit at the University of Oxford (England), presented the data on Aug. 29 at the European Society of Cardiology 2022 Congress.
It was also simultaneously published online in The Lancet.
Dr. Baigent explained that statins very rarely cause serious muscle adverse effects with biochemical evidence of cellular damage, such as myopathy (which occurs in less than 1 in 10,000 patients per year) and rhabdomyolysis (which occurs in about 0.2 per 10,000 patients per year).
The effect of statins on other less serious muscle symptoms without biochemical evidence of cellular damage is less clear, but misinformation about the risks have arisen from nonrandomized studies, with social media and press reports suggesting that the risk for muscle symptoms with statins is extremely common, Dr. Baigent said.
In response to this, the Cholesterol Trialists Collaboration put together a new program of data collection, validation, and analysis to provide reliable information from large double-blind randomized trials that are free from bias and confounding.
“Overall, when we look at all these data, we find there is about a 3% relative increase in the risks of experiencing muscle pain or weakness with a statin versus with placebo,” Dr. Baigent reported.
Muscle pain or weakness was reported by 16,835 of 62,028 patients taking a statin, (27.1%), compared with 16,446 of 61,912 patients taking placebo (26.6%), for a rate ratio of 1.03 (95% confidence interval, 1.01-1.06).
In absolute terms, the results show a rate of 166 reports of muscle symptoms per 1,000 patient-years in those taking a statin, compared with 155 per 1,000-patient-years in those taking placebo in the first year. This gives a rate ratio of 1.07 and an excess of 11 cases of muscle pain or weakness per 1,000 patients in the first year of statin therapy.
“The very small excess of muscle symptoms in the statin patients were generally mild, with most patients able to continue treatment,” Dr. Baigent added.
After the first year, the rate of muscle pain or weakness was exactly the same in the statin and placebo groups, at 50 per 1,000 patient-years.
“Therefore, for the vast majority of people who experience muscle pain or weakness on a statin, those symptoms are not due to the statin itself. It is due to something else, which could be ageing, thyroid disease, or exercise,” Dr. Baigent said. “After the first year of taking a statin, there is no excess risk of muscle pain or weakness at all.”
“To summarize, the excess risk of muscle pain or weakness with statin use is tiny, and almost nonexistent after the first year,” he added.
“Muscle pain is very common in the general population, and it was very common in both patients taking a statin and those given placebo in these randomized trials. We can only detect a difference by looking at all the data combined in this enormous study. And we now know for sure that over 90% of cases of muscle symptoms experienced by people taking a statin are not due to the statin.”
The researchers also looked at statin intensity and found that the more intense statins tend to cause slightly more muscle pain. “There was also some evidence, although this was not very clear, that the muscle pain with the more intensive statins may persist for longer than 1 year,” Dr. Baigent said.
But in terms of different moderate-intensity and high-intensity statins, there was no evidence of differences in muscle pain between the individual statin brands, he added.
Better patient information needed
Dr. Baigent called for better information in statin package inserts about the real risk for muscle symptoms with these drugs.
“We need to do a better job of communicating the real risk of muscle symptom to patients who are taking statins and to their doctors. At the moment, doctors often stop statins if patients complain of muscle pain, but our data show that in 14 out of 15 times, they would be wrong for doing that. Stopping the statin is nearly always a mistake,” he commented.
“At present, the package inserts include a whole load of rubbish from observational studies, which are completely unreliable,” he added. “This is of no value to patients. They go through this information and find several symptoms they are experiencing, which they attribute to the drugs. We really need to divide up the information into the evidence that we really know for sure and then the more speculative stuff.”
Dr. Baigent also highlighted the large benefits of statins, compared with the small risk for muscle symptoms.
“While statins may cause 11 patients per 1,000 to experience some mild muscle pain in the first year of taking these drugs, and this was reduced to none in subsequent years, statins, when used for the primary prevention of cardiovascular disease, prevent 25 cardiovascular events per 1,000 patients every year they are taken. And for secondary prevention this rises to 50 events prevented per 1,000 patients each year,” he noted.
The individual participant data meta-analysis involved 23 trials with information on almost 155,000 patients. All trials included at least 1,000 patients and at least 2 years of scheduled treatment. Adverse-event data were collected for all individual participants in 19 large randomized double-blind trials comparing statin therapy with placebo (123,940 patients) and in four randomized double-blind trials comparing more-intensive with less-intensive statin therapy (30,724 patients).
In the four trials of more-intensive versus less-intensive statin therapy, high-intensity regimens (atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily) resulted in a larger relative increase in the rate of muscle pain or weakness than moderate-intensity regimens, with rate ratios of 1.08 (95% CI, 1.04-1.13) and 1.02 (95% CI, 1.00-1.05), respectively.
‘Reassuring information’
Discussant of the study at the ESC Hotline session, Erin Bohula, MD, Brigham and Women’s Hospital, Boston, said this new analysis had many strengths and used a rigorous approach to look at the issue of muscle symptoms with statins.
She pointed out some challenges, including the fact that the definition of adverse muscle events has changed over time and differed in the various trials, with heterogeneous data capture across trials. “So, this was a Herculean task to harmonize this very complicated dataset.”
Dr. Bohula concluded: “I think this is a very significant undertaking, resulting in a rich dataset that enhances our understanding of muscle symptoms related to statin use. The take-home for me is that muscle symptoms are a common complaint in the general population but are very rarely attributable to statins. This is very reassuring to me, and I hope it is reassuring to patients and can help us encourage them with adherence, given the clear cardiovascular benefits of statins.”
Chair of the ESC Hotline session at which the study was presented, Gabriel Steg, MD, Hôpital Bichat, Paris, asked whether some statin patients who experienced muscle symptoms with the drugs in active run-in periods in the trials may have been excluded from the main trials, so that this information might not have been captured, but Dr. Baigent replied that they also examined those data, which had been accounted for in the analysis.
“That’s really good news,” Dr. Steg commented. “This study is going to be one more tool in our response to statin skeptics and I think, as such, this work is a really a service to public health.”
The meta-analysis was funded by the British Heart Foundation, the U.K. Medical Research Council, and the Australian National Health and Medical Research Council.
A version of this article first appeared on Medscape.com.
In the vast majority of people who experience muscle pain or weakness while taking a statin, those symptoms are not related to the statin, a new individual patient data meta-analysis of randomized controlled trials shows.
The Cholesterol Trialists Collaboration meta-analysis examined 19 large randomized double-blind trials that compared statin therapy with placebo and involved almost 124,000 patients.
“Our results show that, in people who experience muscle symptoms in the first year of taking a statin, those symptoms are actually due to the statin in only 1 of 15 of those people. For the other 14 of the 15 people who experience muscle symptoms in the first year of taking a statin, that muscle pain is not due to the statin,” lead investigator Colin Baigent, MD, said.
After the first year, there was no difference in muscle symptoms between patients taking a statin or those taking placebo.
Dr. Baigent, who is director of the Population Health Research Unit at the University of Oxford (England), presented the data on Aug. 29 at the European Society of Cardiology 2022 Congress.
It was also simultaneously published online in The Lancet.
Dr. Baigent explained that statins very rarely cause serious muscle adverse effects with biochemical evidence of cellular damage, such as myopathy (which occurs in less than 1 in 10,000 patients per year) and rhabdomyolysis (which occurs in about 0.2 per 10,000 patients per year).
The effect of statins on other less serious muscle symptoms without biochemical evidence of cellular damage is less clear, but misinformation about the risks have arisen from nonrandomized studies, with social media and press reports suggesting that the risk for muscle symptoms with statins is extremely common, Dr. Baigent said.
In response to this, the Cholesterol Trialists Collaboration put together a new program of data collection, validation, and analysis to provide reliable information from large double-blind randomized trials that are free from bias and confounding.
“Overall, when we look at all these data, we find there is about a 3% relative increase in the risks of experiencing muscle pain or weakness with a statin versus with placebo,” Dr. Baigent reported.
Muscle pain or weakness was reported by 16,835 of 62,028 patients taking a statin, (27.1%), compared with 16,446 of 61,912 patients taking placebo (26.6%), for a rate ratio of 1.03 (95% confidence interval, 1.01-1.06).
In absolute terms, the results show a rate of 166 reports of muscle symptoms per 1,000 patient-years in those taking a statin, compared with 155 per 1,000-patient-years in those taking placebo in the first year. This gives a rate ratio of 1.07 and an excess of 11 cases of muscle pain or weakness per 1,000 patients in the first year of statin therapy.
“The very small excess of muscle symptoms in the statin patients were generally mild, with most patients able to continue treatment,” Dr. Baigent added.
After the first year, the rate of muscle pain or weakness was exactly the same in the statin and placebo groups, at 50 per 1,000 patient-years.
“Therefore, for the vast majority of people who experience muscle pain or weakness on a statin, those symptoms are not due to the statin itself. It is due to something else, which could be ageing, thyroid disease, or exercise,” Dr. Baigent said. “After the first year of taking a statin, there is no excess risk of muscle pain or weakness at all.”
“To summarize, the excess risk of muscle pain or weakness with statin use is tiny, and almost nonexistent after the first year,” he added.
“Muscle pain is very common in the general population, and it was very common in both patients taking a statin and those given placebo in these randomized trials. We can only detect a difference by looking at all the data combined in this enormous study. And we now know for sure that over 90% of cases of muscle symptoms experienced by people taking a statin are not due to the statin.”
The researchers also looked at statin intensity and found that the more intense statins tend to cause slightly more muscle pain. “There was also some evidence, although this was not very clear, that the muscle pain with the more intensive statins may persist for longer than 1 year,” Dr. Baigent said.
But in terms of different moderate-intensity and high-intensity statins, there was no evidence of differences in muscle pain between the individual statin brands, he added.
Better patient information needed
Dr. Baigent called for better information in statin package inserts about the real risk for muscle symptoms with these drugs.
“We need to do a better job of communicating the real risk of muscle symptom to patients who are taking statins and to their doctors. At the moment, doctors often stop statins if patients complain of muscle pain, but our data show that in 14 out of 15 times, they would be wrong for doing that. Stopping the statin is nearly always a mistake,” he commented.
“At present, the package inserts include a whole load of rubbish from observational studies, which are completely unreliable,” he added. “This is of no value to patients. They go through this information and find several symptoms they are experiencing, which they attribute to the drugs. We really need to divide up the information into the evidence that we really know for sure and then the more speculative stuff.”
Dr. Baigent also highlighted the large benefits of statins, compared with the small risk for muscle symptoms.
“While statins may cause 11 patients per 1,000 to experience some mild muscle pain in the first year of taking these drugs, and this was reduced to none in subsequent years, statins, when used for the primary prevention of cardiovascular disease, prevent 25 cardiovascular events per 1,000 patients every year they are taken. And for secondary prevention this rises to 50 events prevented per 1,000 patients each year,” he noted.
The individual participant data meta-analysis involved 23 trials with information on almost 155,000 patients. All trials included at least 1,000 patients and at least 2 years of scheduled treatment. Adverse-event data were collected for all individual participants in 19 large randomized double-blind trials comparing statin therapy with placebo (123,940 patients) and in four randomized double-blind trials comparing more-intensive with less-intensive statin therapy (30,724 patients).
In the four trials of more-intensive versus less-intensive statin therapy, high-intensity regimens (atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily) resulted in a larger relative increase in the rate of muscle pain or weakness than moderate-intensity regimens, with rate ratios of 1.08 (95% CI, 1.04-1.13) and 1.02 (95% CI, 1.00-1.05), respectively.
‘Reassuring information’
Discussant of the study at the ESC Hotline session, Erin Bohula, MD, Brigham and Women’s Hospital, Boston, said this new analysis had many strengths and used a rigorous approach to look at the issue of muscle symptoms with statins.
She pointed out some challenges, including the fact that the definition of adverse muscle events has changed over time and differed in the various trials, with heterogeneous data capture across trials. “So, this was a Herculean task to harmonize this very complicated dataset.”
Dr. Bohula concluded: “I think this is a very significant undertaking, resulting in a rich dataset that enhances our understanding of muscle symptoms related to statin use. The take-home for me is that muscle symptoms are a common complaint in the general population but are very rarely attributable to statins. This is very reassuring to me, and I hope it is reassuring to patients and can help us encourage them with adherence, given the clear cardiovascular benefits of statins.”
Chair of the ESC Hotline session at which the study was presented, Gabriel Steg, MD, Hôpital Bichat, Paris, asked whether some statin patients who experienced muscle symptoms with the drugs in active run-in periods in the trials may have been excluded from the main trials, so that this information might not have been captured, but Dr. Baigent replied that they also examined those data, which had been accounted for in the analysis.
“That’s really good news,” Dr. Steg commented. “This study is going to be one more tool in our response to statin skeptics and I think, as such, this work is a really a service to public health.”
The meta-analysis was funded by the British Heart Foundation, the U.K. Medical Research Council, and the Australian National Health and Medical Research Council.
A version of this article first appeared on Medscape.com.
In the vast majority of people who experience muscle pain or weakness while taking a statin, those symptoms are not related to the statin, a new individual patient data meta-analysis of randomized controlled trials shows.
The Cholesterol Trialists Collaboration meta-analysis examined 19 large randomized double-blind trials that compared statin therapy with placebo and involved almost 124,000 patients.
“Our results show that, in people who experience muscle symptoms in the first year of taking a statin, those symptoms are actually due to the statin in only 1 of 15 of those people. For the other 14 of the 15 people who experience muscle symptoms in the first year of taking a statin, that muscle pain is not due to the statin,” lead investigator Colin Baigent, MD, said.
After the first year, there was no difference in muscle symptoms between patients taking a statin or those taking placebo.
Dr. Baigent, who is director of the Population Health Research Unit at the University of Oxford (England), presented the data on Aug. 29 at the European Society of Cardiology 2022 Congress.
It was also simultaneously published online in The Lancet.
Dr. Baigent explained that statins very rarely cause serious muscle adverse effects with biochemical evidence of cellular damage, such as myopathy (which occurs in less than 1 in 10,000 patients per year) and rhabdomyolysis (which occurs in about 0.2 per 10,000 patients per year).
The effect of statins on other less serious muscle symptoms without biochemical evidence of cellular damage is less clear, but misinformation about the risks have arisen from nonrandomized studies, with social media and press reports suggesting that the risk for muscle symptoms with statins is extremely common, Dr. Baigent said.
In response to this, the Cholesterol Trialists Collaboration put together a new program of data collection, validation, and analysis to provide reliable information from large double-blind randomized trials that are free from bias and confounding.
“Overall, when we look at all these data, we find there is about a 3% relative increase in the risks of experiencing muscle pain or weakness with a statin versus with placebo,” Dr. Baigent reported.
Muscle pain or weakness was reported by 16,835 of 62,028 patients taking a statin, (27.1%), compared with 16,446 of 61,912 patients taking placebo (26.6%), for a rate ratio of 1.03 (95% confidence interval, 1.01-1.06).
In absolute terms, the results show a rate of 166 reports of muscle symptoms per 1,000 patient-years in those taking a statin, compared with 155 per 1,000-patient-years in those taking placebo in the first year. This gives a rate ratio of 1.07 and an excess of 11 cases of muscle pain or weakness per 1,000 patients in the first year of statin therapy.
“The very small excess of muscle symptoms in the statin patients were generally mild, with most patients able to continue treatment,” Dr. Baigent added.
After the first year, the rate of muscle pain or weakness was exactly the same in the statin and placebo groups, at 50 per 1,000 patient-years.
“Therefore, for the vast majority of people who experience muscle pain or weakness on a statin, those symptoms are not due to the statin itself. It is due to something else, which could be ageing, thyroid disease, or exercise,” Dr. Baigent said. “After the first year of taking a statin, there is no excess risk of muscle pain or weakness at all.”
“To summarize, the excess risk of muscle pain or weakness with statin use is tiny, and almost nonexistent after the first year,” he added.
“Muscle pain is very common in the general population, and it was very common in both patients taking a statin and those given placebo in these randomized trials. We can only detect a difference by looking at all the data combined in this enormous study. And we now know for sure that over 90% of cases of muscle symptoms experienced by people taking a statin are not due to the statin.”
The researchers also looked at statin intensity and found that the more intense statins tend to cause slightly more muscle pain. “There was also some evidence, although this was not very clear, that the muscle pain with the more intensive statins may persist for longer than 1 year,” Dr. Baigent said.
But in terms of different moderate-intensity and high-intensity statins, there was no evidence of differences in muscle pain between the individual statin brands, he added.
Better patient information needed
Dr. Baigent called for better information in statin package inserts about the real risk for muscle symptoms with these drugs.
“We need to do a better job of communicating the real risk of muscle symptom to patients who are taking statins and to their doctors. At the moment, doctors often stop statins if patients complain of muscle pain, but our data show that in 14 out of 15 times, they would be wrong for doing that. Stopping the statin is nearly always a mistake,” he commented.
“At present, the package inserts include a whole load of rubbish from observational studies, which are completely unreliable,” he added. “This is of no value to patients. They go through this information and find several symptoms they are experiencing, which they attribute to the drugs. We really need to divide up the information into the evidence that we really know for sure and then the more speculative stuff.”
Dr. Baigent also highlighted the large benefits of statins, compared with the small risk for muscle symptoms.
“While statins may cause 11 patients per 1,000 to experience some mild muscle pain in the first year of taking these drugs, and this was reduced to none in subsequent years, statins, when used for the primary prevention of cardiovascular disease, prevent 25 cardiovascular events per 1,000 patients every year they are taken. And for secondary prevention this rises to 50 events prevented per 1,000 patients each year,” he noted.
The individual participant data meta-analysis involved 23 trials with information on almost 155,000 patients. All trials included at least 1,000 patients and at least 2 years of scheduled treatment. Adverse-event data were collected for all individual participants in 19 large randomized double-blind trials comparing statin therapy with placebo (123,940 patients) and in four randomized double-blind trials comparing more-intensive with less-intensive statin therapy (30,724 patients).
In the four trials of more-intensive versus less-intensive statin therapy, high-intensity regimens (atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily) resulted in a larger relative increase in the rate of muscle pain or weakness than moderate-intensity regimens, with rate ratios of 1.08 (95% CI, 1.04-1.13) and 1.02 (95% CI, 1.00-1.05), respectively.
‘Reassuring information’
Discussant of the study at the ESC Hotline session, Erin Bohula, MD, Brigham and Women’s Hospital, Boston, said this new analysis had many strengths and used a rigorous approach to look at the issue of muscle symptoms with statins.
She pointed out some challenges, including the fact that the definition of adverse muscle events has changed over time and differed in the various trials, with heterogeneous data capture across trials. “So, this was a Herculean task to harmonize this very complicated dataset.”
Dr. Bohula concluded: “I think this is a very significant undertaking, resulting in a rich dataset that enhances our understanding of muscle symptoms related to statin use. The take-home for me is that muscle symptoms are a common complaint in the general population but are very rarely attributable to statins. This is very reassuring to me, and I hope it is reassuring to patients and can help us encourage them with adherence, given the clear cardiovascular benefits of statins.”
Chair of the ESC Hotline session at which the study was presented, Gabriel Steg, MD, Hôpital Bichat, Paris, asked whether some statin patients who experienced muscle symptoms with the drugs in active run-in periods in the trials may have been excluded from the main trials, so that this information might not have been captured, but Dr. Baigent replied that they also examined those data, which had been accounted for in the analysis.
“That’s really good news,” Dr. Steg commented. “This study is going to be one more tool in our response to statin skeptics and I think, as such, this work is a really a service to public health.”
The meta-analysis was funded by the British Heart Foundation, the U.K. Medical Research Council, and the Australian National Health and Medical Research Council.
A version of this article first appeared on Medscape.com.
FROM ESC CONGRESS 2022
Hydroquinone, found in skin-lightening agents worldwide, linked with increased skin cancer risk
an analysis of records from a large research database suggests.
In the study, hydroquinone use was associated with an approximately threefold increase for skin cancer risk, coauthor Brittany Miles, a fourth-year medical student at the University of Texas Medical Branch at Galveston’s John Sealy School of Medicine, told this news organization. “The magnitude of the risk was surprising. Increased risk should be disclosed to patients considering hydroquinone treatment.”
The results of the study were presented in a poster at the annual meeting of the Society for Investigative Dermatology.
Hydroquinone (multiple brand names), a tyrosinase inhibitor used worldwide for skin lightening because of its inhibition of melanin production, was once considered “generally safe and effective” by the Food and Drug Administration, the authors wrote.
The compound’s use in over-the-counter products in the United States has been restricted based on suspicion of carcinogenicity, but few human studies have been conducted. In April, the FDA issued warning letters to 12 companies that sold hydroquinone in concentrations not generally recognized as safe and effective, because of other concerns including rashes, facial swelling, and ochronosis (skin discoloration).
Ms. Miles and her coauthor, Michael Wilkerson, MD, professor and chair of the department of dermatology at UTMB, analyzed data from TriNetX, the medical research database of anonymized medical record information from 61 million patients in 57 large health care organizations, almost all of them in the United States.
The researchers created two cohorts of patients aged 15 years and older with no prior diagnosis of skin cancer: one group had been treated with hydroquinone (medication code 5509 in the TriNetX system), and the other had not been exposed to the drug. Using ICD-10 codes for melanoma, nonmelanoma skin cancer, and all skin cancers, they investigated which groups of people were likely to develop these cancers.
They found that hydroquinone exposure was linked with a significant increase in melanoma (relative risk, 3.0; 95% confidence interval, 1.704-5.281; P < .0001), nonmelanoma skin cancers (RR, 3.6; 95%; CI, 2.815-4.561; P < .0001), and all reported skin cancers combined (relative risk, 3.4; 95% CI, 2.731-4.268; P < .0001)
While “the source of the data and the number of patients in the study are significant strengths,” Ms. Miles said, “the inability to determine how long and how consistently the patients used hydroquinone is likely the biggest weakness.”
Skin lightening is big business and more research is needed
“The U.S. market for skin-lightening agents was approximately 330 million dollars in 2021, and 330,000 prescriptions containing hydroquinone were dispensed in 2019,” Ms. Miles said.
Valencia D. Thomas, MD, professor in the department of dermatology of the University of Texas MD Anderson Cancer Center, Houston, said in an email that over-the-counter skin-lightening products containing low-concentration hydroquinone are in widespread use and are commonly used in populations of color.
“Hydroquinone preparations in higher concentrations are unfortunately also available in the United States,” added Dr. Thomas, who was not involved in the study and referred to the FDA warning letter issued in April.
Only one hydroquinone-containing medication – Tri-Luma at 4% concentration, used to treat melasma – is currently FDA-approved, she said.
The data in the study do not show an increased risk for skin cancer with hydroquinone exposure, but do show “an increased risk of cancer in the TriNetX medication code 5509 hydroquinone exposure group, which does not prove causation,” Dr. Thomas commented.
“Because ‘hydroquinone exposure’ is not defined, it is unclear how TriNetX identified the hydroquinone exposure cohort,” she noted. “Does ‘exposure’ count prescriptions written and potentially not used, the use of hydroquinone products of high concentration not approved by the FDA, or the use of over-the-counter hydroquinone products?
“The strength of this study is its size,” Dr. Thomas acknowledged. “This study is a wonderful starting point to further investigate the ‘hydroquinone exposure’ cohort to determine if hydroquinone is a driver of cancer, or if hydroquinone is itself a confounder.”
These results highlight the need to examine the social determinants of health that may explain increased risk for cancer, including race, geography, and poverty, she added.
“Given the global consumption of hydroquinone, multinational collaboration investigating hydroquinone and cancer data will likely be needed to provide insight into this continuing question,” Dr. Thomas advised.
Christiane Querfeld, MD, PhD, associate professor of dermatology and dermatopathology at City of Hope in Duarte, Calif., agreed that the occurrence of skin cancer following use of hydroquinone is largely understudied.
“The findings have a huge impact on how we counsel and monitor future patients,” Dr. Querfeld, who also was not involved in the study, said in an email. “There may be a trade-off at the start of treatment: Get rid of melasma but develop a skin cancer or melanoma with potentially severe outcomes.
“It remains to be seen if there is a higher incidence of skin cancer following use of hydroquinone or other voluntary bleaching and depigmentation remedies in ethnic groups such as African American or Hispanic patient populations, who have historically been at low risk of developing skin cancer,” she added. “It also remains to be seen if increased risk is due to direct effects or to indirect effects on already-photodamaged skin.
“These data are critical, and I am sure this will open further investigations to study effects in more detail,” Dr. Querfeld said.
The study authors, Dr. Thomas, and Dr. Querfeld reported no relevant financial relationships. The study did not receive external funding.
A version of this article first appeared on Medscape.com.
an analysis of records from a large research database suggests.
In the study, hydroquinone use was associated with an approximately threefold increase for skin cancer risk, coauthor Brittany Miles, a fourth-year medical student at the University of Texas Medical Branch at Galveston’s John Sealy School of Medicine, told this news organization. “The magnitude of the risk was surprising. Increased risk should be disclosed to patients considering hydroquinone treatment.”
The results of the study were presented in a poster at the annual meeting of the Society for Investigative Dermatology.
Hydroquinone (multiple brand names), a tyrosinase inhibitor used worldwide for skin lightening because of its inhibition of melanin production, was once considered “generally safe and effective” by the Food and Drug Administration, the authors wrote.
The compound’s use in over-the-counter products in the United States has been restricted based on suspicion of carcinogenicity, but few human studies have been conducted. In April, the FDA issued warning letters to 12 companies that sold hydroquinone in concentrations not generally recognized as safe and effective, because of other concerns including rashes, facial swelling, and ochronosis (skin discoloration).
Ms. Miles and her coauthor, Michael Wilkerson, MD, professor and chair of the department of dermatology at UTMB, analyzed data from TriNetX, the medical research database of anonymized medical record information from 61 million patients in 57 large health care organizations, almost all of them in the United States.
The researchers created two cohorts of patients aged 15 years and older with no prior diagnosis of skin cancer: one group had been treated with hydroquinone (medication code 5509 in the TriNetX system), and the other had not been exposed to the drug. Using ICD-10 codes for melanoma, nonmelanoma skin cancer, and all skin cancers, they investigated which groups of people were likely to develop these cancers.
They found that hydroquinone exposure was linked with a significant increase in melanoma (relative risk, 3.0; 95% confidence interval, 1.704-5.281; P < .0001), nonmelanoma skin cancers (RR, 3.6; 95%; CI, 2.815-4.561; P < .0001), and all reported skin cancers combined (relative risk, 3.4; 95% CI, 2.731-4.268; P < .0001)
While “the source of the data and the number of patients in the study are significant strengths,” Ms. Miles said, “the inability to determine how long and how consistently the patients used hydroquinone is likely the biggest weakness.”
Skin lightening is big business and more research is needed
“The U.S. market for skin-lightening agents was approximately 330 million dollars in 2021, and 330,000 prescriptions containing hydroquinone were dispensed in 2019,” Ms. Miles said.
Valencia D. Thomas, MD, professor in the department of dermatology of the University of Texas MD Anderson Cancer Center, Houston, said in an email that over-the-counter skin-lightening products containing low-concentration hydroquinone are in widespread use and are commonly used in populations of color.
“Hydroquinone preparations in higher concentrations are unfortunately also available in the United States,” added Dr. Thomas, who was not involved in the study and referred to the FDA warning letter issued in April.
Only one hydroquinone-containing medication – Tri-Luma at 4% concentration, used to treat melasma – is currently FDA-approved, she said.
The data in the study do not show an increased risk for skin cancer with hydroquinone exposure, but do show “an increased risk of cancer in the TriNetX medication code 5509 hydroquinone exposure group, which does not prove causation,” Dr. Thomas commented.
“Because ‘hydroquinone exposure’ is not defined, it is unclear how TriNetX identified the hydroquinone exposure cohort,” she noted. “Does ‘exposure’ count prescriptions written and potentially not used, the use of hydroquinone products of high concentration not approved by the FDA, or the use of over-the-counter hydroquinone products?
“The strength of this study is its size,” Dr. Thomas acknowledged. “This study is a wonderful starting point to further investigate the ‘hydroquinone exposure’ cohort to determine if hydroquinone is a driver of cancer, or if hydroquinone is itself a confounder.”
These results highlight the need to examine the social determinants of health that may explain increased risk for cancer, including race, geography, and poverty, she added.
“Given the global consumption of hydroquinone, multinational collaboration investigating hydroquinone and cancer data will likely be needed to provide insight into this continuing question,” Dr. Thomas advised.
Christiane Querfeld, MD, PhD, associate professor of dermatology and dermatopathology at City of Hope in Duarte, Calif., agreed that the occurrence of skin cancer following use of hydroquinone is largely understudied.
“The findings have a huge impact on how we counsel and monitor future patients,” Dr. Querfeld, who also was not involved in the study, said in an email. “There may be a trade-off at the start of treatment: Get rid of melasma but develop a skin cancer or melanoma with potentially severe outcomes.
“It remains to be seen if there is a higher incidence of skin cancer following use of hydroquinone or other voluntary bleaching and depigmentation remedies in ethnic groups such as African American or Hispanic patient populations, who have historically been at low risk of developing skin cancer,” she added. “It also remains to be seen if increased risk is due to direct effects or to indirect effects on already-photodamaged skin.
“These data are critical, and I am sure this will open further investigations to study effects in more detail,” Dr. Querfeld said.
The study authors, Dr. Thomas, and Dr. Querfeld reported no relevant financial relationships. The study did not receive external funding.
A version of this article first appeared on Medscape.com.
an analysis of records from a large research database suggests.
In the study, hydroquinone use was associated with an approximately threefold increase for skin cancer risk, coauthor Brittany Miles, a fourth-year medical student at the University of Texas Medical Branch at Galveston’s John Sealy School of Medicine, told this news organization. “The magnitude of the risk was surprising. Increased risk should be disclosed to patients considering hydroquinone treatment.”
The results of the study were presented in a poster at the annual meeting of the Society for Investigative Dermatology.
Hydroquinone (multiple brand names), a tyrosinase inhibitor used worldwide for skin lightening because of its inhibition of melanin production, was once considered “generally safe and effective” by the Food and Drug Administration, the authors wrote.
The compound’s use in over-the-counter products in the United States has been restricted based on suspicion of carcinogenicity, but few human studies have been conducted. In April, the FDA issued warning letters to 12 companies that sold hydroquinone in concentrations not generally recognized as safe and effective, because of other concerns including rashes, facial swelling, and ochronosis (skin discoloration).
Ms. Miles and her coauthor, Michael Wilkerson, MD, professor and chair of the department of dermatology at UTMB, analyzed data from TriNetX, the medical research database of anonymized medical record information from 61 million patients in 57 large health care organizations, almost all of them in the United States.
The researchers created two cohorts of patients aged 15 years and older with no prior diagnosis of skin cancer: one group had been treated with hydroquinone (medication code 5509 in the TriNetX system), and the other had not been exposed to the drug. Using ICD-10 codes for melanoma, nonmelanoma skin cancer, and all skin cancers, they investigated which groups of people were likely to develop these cancers.
They found that hydroquinone exposure was linked with a significant increase in melanoma (relative risk, 3.0; 95% confidence interval, 1.704-5.281; P < .0001), nonmelanoma skin cancers (RR, 3.6; 95%; CI, 2.815-4.561; P < .0001), and all reported skin cancers combined (relative risk, 3.4; 95% CI, 2.731-4.268; P < .0001)
While “the source of the data and the number of patients in the study are significant strengths,” Ms. Miles said, “the inability to determine how long and how consistently the patients used hydroquinone is likely the biggest weakness.”
Skin lightening is big business and more research is needed
“The U.S. market for skin-lightening agents was approximately 330 million dollars in 2021, and 330,000 prescriptions containing hydroquinone were dispensed in 2019,” Ms. Miles said.
Valencia D. Thomas, MD, professor in the department of dermatology of the University of Texas MD Anderson Cancer Center, Houston, said in an email that over-the-counter skin-lightening products containing low-concentration hydroquinone are in widespread use and are commonly used in populations of color.
“Hydroquinone preparations in higher concentrations are unfortunately also available in the United States,” added Dr. Thomas, who was not involved in the study and referred to the FDA warning letter issued in April.
Only one hydroquinone-containing medication – Tri-Luma at 4% concentration, used to treat melasma – is currently FDA-approved, she said.
The data in the study do not show an increased risk for skin cancer with hydroquinone exposure, but do show “an increased risk of cancer in the TriNetX medication code 5509 hydroquinone exposure group, which does not prove causation,” Dr. Thomas commented.
“Because ‘hydroquinone exposure’ is not defined, it is unclear how TriNetX identified the hydroquinone exposure cohort,” she noted. “Does ‘exposure’ count prescriptions written and potentially not used, the use of hydroquinone products of high concentration not approved by the FDA, or the use of over-the-counter hydroquinone products?
“The strength of this study is its size,” Dr. Thomas acknowledged. “This study is a wonderful starting point to further investigate the ‘hydroquinone exposure’ cohort to determine if hydroquinone is a driver of cancer, or if hydroquinone is itself a confounder.”
These results highlight the need to examine the social determinants of health that may explain increased risk for cancer, including race, geography, and poverty, she added.
“Given the global consumption of hydroquinone, multinational collaboration investigating hydroquinone and cancer data will likely be needed to provide insight into this continuing question,” Dr. Thomas advised.
Christiane Querfeld, MD, PhD, associate professor of dermatology and dermatopathology at City of Hope in Duarte, Calif., agreed that the occurrence of skin cancer following use of hydroquinone is largely understudied.
“The findings have a huge impact on how we counsel and monitor future patients,” Dr. Querfeld, who also was not involved in the study, said in an email. “There may be a trade-off at the start of treatment: Get rid of melasma but develop a skin cancer or melanoma with potentially severe outcomes.
“It remains to be seen if there is a higher incidence of skin cancer following use of hydroquinone or other voluntary bleaching and depigmentation remedies in ethnic groups such as African American or Hispanic patient populations, who have historically been at low risk of developing skin cancer,” she added. “It also remains to be seen if increased risk is due to direct effects or to indirect effects on already-photodamaged skin.
“These data are critical, and I am sure this will open further investigations to study effects in more detail,” Dr. Querfeld said.
The study authors, Dr. Thomas, and Dr. Querfeld reported no relevant financial relationships. The study did not receive external funding.
A version of this article first appeared on Medscape.com.
FROM SID 2022
Abbott to start making Similac baby formula again
Abbott Nutrition is resuming production of Similac, its leading baby formula, at a Michigan plant that was shut down earlier in 2022 because of contamination concerns.
The company closed the plant in February, which triggered a national shortage of baby formula amid pandemic-related supply chain issues that created a lack of formula ingredients.
“We know that the nationwide infant formula shortage has been difficult for the families we serve, and while restarting Similac production in Michigan is an important milestone, we won’t rest until this product is back on shelves,” Robert Ford, chairman and CEO of Abbott, said in a statement on Aug. 26.
“Making infant formula is a responsibility we take very seriously, and parents can feel confident in the quality and safety of Similac and other Abbott formulas,” he said. “We are committed to re-earning the trust parents and health care providers have placed in us for decades.”
Abbott estimated that it will take about 6 weeks for Similac products to ship to stores. Production has restarted, which will be followed by “enhanced” testing before and after the formula is made.
In February, Abbott voluntarily recalled batches of three formulas after the Food and Drug Administration received consumer complaints about infants becoming sick. Four babies who consumed formulas from the Michigan plant got bacterial infections, and at least two babies died.
The illnesses were linked to Cronobacter sakazakii – bacteria that can lead to life-threatening infections and inflammation of the brain and spine.
After investigations at the plant, Abbott said there is no conclusive evidence to link the formula to the illnesses. No samples of the recalled product tested positive for the bacteria, and in all four cases, unopened containers of formula in the infants’ homes tested negative for the bacteria.
At the same time, FDA officials said in May that the Michigan plant had a leaking roof, water pooling on the floor, and cracks in production equipment that could allow bacteria to grow, according to The New York Times.
Abbott agreed with the federal government to create new safeguards, such as hiring a qualified expert to oversee improvements at the plant and notify the FDA if any issues were identified, the newspaper reported.
On July 1, the company restarted production of EleCare, a specialty formula, and later resumed production of some metabolic formulas. These products will begin to ship in coming weeks, the company said.
Since July, C. sakazakii has been found in a couple of batches of formula.
“In those cases, we found the issue, addressed it and no affected product has been or will be distributed,” Abbott said in the statement. “This confirms our quality systems work.”
In August, Abbott will supply the United States with more than 8 million pounds of infant formula, which is higher than the levels in August 2021, the company said. To ensure that people in the federal Special Supplemental Nutrition Program for Women, Infants and Children have access to formula, the company is extending rebates until the end of October.
“Restarting a large manufacturing facility after a several-month shutdown is a complex process, and it takes time to ensure that equipment, processes and production are functioning smoothly and sustainably,” the company said in the statement. “There have been – and likely will be – stops and starts from time to time. We’ve experienced events like severe weather, we’ve had to make mechanical adjustments, and we’ve had to discard some early production batches that didn’t meet our standards.”
A version of this article first appeared on WebMD.com.
Abbott Nutrition is resuming production of Similac, its leading baby formula, at a Michigan plant that was shut down earlier in 2022 because of contamination concerns.
The company closed the plant in February, which triggered a national shortage of baby formula amid pandemic-related supply chain issues that created a lack of formula ingredients.
“We know that the nationwide infant formula shortage has been difficult for the families we serve, and while restarting Similac production in Michigan is an important milestone, we won’t rest until this product is back on shelves,” Robert Ford, chairman and CEO of Abbott, said in a statement on Aug. 26.
“Making infant formula is a responsibility we take very seriously, and parents can feel confident in the quality and safety of Similac and other Abbott formulas,” he said. “We are committed to re-earning the trust parents and health care providers have placed in us for decades.”
Abbott estimated that it will take about 6 weeks for Similac products to ship to stores. Production has restarted, which will be followed by “enhanced” testing before and after the formula is made.
In February, Abbott voluntarily recalled batches of three formulas after the Food and Drug Administration received consumer complaints about infants becoming sick. Four babies who consumed formulas from the Michigan plant got bacterial infections, and at least two babies died.
The illnesses were linked to Cronobacter sakazakii – bacteria that can lead to life-threatening infections and inflammation of the brain and spine.
After investigations at the plant, Abbott said there is no conclusive evidence to link the formula to the illnesses. No samples of the recalled product tested positive for the bacteria, and in all four cases, unopened containers of formula in the infants’ homes tested negative for the bacteria.
At the same time, FDA officials said in May that the Michigan plant had a leaking roof, water pooling on the floor, and cracks in production equipment that could allow bacteria to grow, according to The New York Times.
Abbott agreed with the federal government to create new safeguards, such as hiring a qualified expert to oversee improvements at the plant and notify the FDA if any issues were identified, the newspaper reported.
On July 1, the company restarted production of EleCare, a specialty formula, and later resumed production of some metabolic formulas. These products will begin to ship in coming weeks, the company said.
Since July, C. sakazakii has been found in a couple of batches of formula.
“In those cases, we found the issue, addressed it and no affected product has been or will be distributed,” Abbott said in the statement. “This confirms our quality systems work.”
In August, Abbott will supply the United States with more than 8 million pounds of infant formula, which is higher than the levels in August 2021, the company said. To ensure that people in the federal Special Supplemental Nutrition Program for Women, Infants and Children have access to formula, the company is extending rebates until the end of October.
“Restarting a large manufacturing facility after a several-month shutdown is a complex process, and it takes time to ensure that equipment, processes and production are functioning smoothly and sustainably,” the company said in the statement. “There have been – and likely will be – stops and starts from time to time. We’ve experienced events like severe weather, we’ve had to make mechanical adjustments, and we’ve had to discard some early production batches that didn’t meet our standards.”
A version of this article first appeared on WebMD.com.
Abbott Nutrition is resuming production of Similac, its leading baby formula, at a Michigan plant that was shut down earlier in 2022 because of contamination concerns.
The company closed the plant in February, which triggered a national shortage of baby formula amid pandemic-related supply chain issues that created a lack of formula ingredients.
“We know that the nationwide infant formula shortage has been difficult for the families we serve, and while restarting Similac production in Michigan is an important milestone, we won’t rest until this product is back on shelves,” Robert Ford, chairman and CEO of Abbott, said in a statement on Aug. 26.
“Making infant formula is a responsibility we take very seriously, and parents can feel confident in the quality and safety of Similac and other Abbott formulas,” he said. “We are committed to re-earning the trust parents and health care providers have placed in us for decades.”
Abbott estimated that it will take about 6 weeks for Similac products to ship to stores. Production has restarted, which will be followed by “enhanced” testing before and after the formula is made.
In February, Abbott voluntarily recalled batches of three formulas after the Food and Drug Administration received consumer complaints about infants becoming sick. Four babies who consumed formulas from the Michigan plant got bacterial infections, and at least two babies died.
The illnesses were linked to Cronobacter sakazakii – bacteria that can lead to life-threatening infections and inflammation of the brain and spine.
After investigations at the plant, Abbott said there is no conclusive evidence to link the formula to the illnesses. No samples of the recalled product tested positive for the bacteria, and in all four cases, unopened containers of formula in the infants’ homes tested negative for the bacteria.
At the same time, FDA officials said in May that the Michigan plant had a leaking roof, water pooling on the floor, and cracks in production equipment that could allow bacteria to grow, according to The New York Times.
Abbott agreed with the federal government to create new safeguards, such as hiring a qualified expert to oversee improvements at the plant and notify the FDA if any issues were identified, the newspaper reported.
On July 1, the company restarted production of EleCare, a specialty formula, and later resumed production of some metabolic formulas. These products will begin to ship in coming weeks, the company said.
Since July, C. sakazakii has been found in a couple of batches of formula.
“In those cases, we found the issue, addressed it and no affected product has been or will be distributed,” Abbott said in the statement. “This confirms our quality systems work.”
In August, Abbott will supply the United States with more than 8 million pounds of infant formula, which is higher than the levels in August 2021, the company said. To ensure that people in the federal Special Supplemental Nutrition Program for Women, Infants and Children have access to formula, the company is extending rebates until the end of October.
“Restarting a large manufacturing facility after a several-month shutdown is a complex process, and it takes time to ensure that equipment, processes and production are functioning smoothly and sustainably,” the company said in the statement. “There have been – and likely will be – stops and starts from time to time. We’ve experienced events like severe weather, we’ve had to make mechanical adjustments, and we’ve had to discard some early production batches that didn’t meet our standards.”
A version of this article first appeared on WebMD.com.
Checkpoint inhibitor combos show promise in advanced RCC
A systematic review of immune checkpoint inhibitor (ICI) combinations suggests that they have a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib and should be made generally available to patients with advanced renal cell carcinoma (RCC).
Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.
. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials that have examined ICIs in combination with VEGF-directed therapies.
In a study published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and one each tested an ICI/anti-VEGF antibody and dual ICIs.
After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared with sunitinib. Final survival analyses from one of the trials have not been reported yet.
PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate/poor-risk patients, compared with sunitinib, but the combination led to more frequent discontinuation because of toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation because of toxicity were similar to sunitinib.
Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation because of toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).
Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggested that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.
The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.
Safety concerns associated with dual-ICI combination therapy was similar to that seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.
The authors note that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, IMDC risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.
Four of the authors reported receiving honoraria, research funding, or consulting for a variety of pharmaceutical companies, including AbbVie, Astellas, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche, and TerSera.
A systematic review of immune checkpoint inhibitor (ICI) combinations suggests that they have a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib and should be made generally available to patients with advanced renal cell carcinoma (RCC).
Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.
. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials that have examined ICIs in combination with VEGF-directed therapies.
In a study published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and one each tested an ICI/anti-VEGF antibody and dual ICIs.
After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared with sunitinib. Final survival analyses from one of the trials have not been reported yet.
PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate/poor-risk patients, compared with sunitinib, but the combination led to more frequent discontinuation because of toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation because of toxicity were similar to sunitinib.
Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation because of toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).
Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggested that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.
The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.
Safety concerns associated with dual-ICI combination therapy was similar to that seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.
The authors note that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, IMDC risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.
Four of the authors reported receiving honoraria, research funding, or consulting for a variety of pharmaceutical companies, including AbbVie, Astellas, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche, and TerSera.
A systematic review of immune checkpoint inhibitor (ICI) combinations suggests that they have a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib and should be made generally available to patients with advanced renal cell carcinoma (RCC).
Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.
. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials that have examined ICIs in combination with VEGF-directed therapies.
In a study published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and one each tested an ICI/anti-VEGF antibody and dual ICIs.
After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared with sunitinib. Final survival analyses from one of the trials have not been reported yet.
PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate/poor-risk patients, compared with sunitinib, but the combination led to more frequent discontinuation because of toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation because of toxicity were similar to sunitinib.
Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation because of toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).
Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggested that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.
The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.
Safety concerns associated with dual-ICI combination therapy was similar to that seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.
The authors note that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, IMDC risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.
Four of the authors reported receiving honoraria, research funding, or consulting for a variety of pharmaceutical companies, including AbbVie, Astellas, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche, and TerSera.
FROM THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
Online tool IDs people with genetic mutations linked to cancer
(PGVs) in a diverse spectrum of cancer susceptibility genes.
The PREMMplus online tool was developed and validated by researchers at the Dana-Farber Cancer Institute, Boston using three cohorts involving more than 30,000 individuals who had undergone multigene hereditary cancer risk testing.
The study was published online in the Journal of Clinical Oncology.
“Our findings show that PREMMplus has the potential to change the model by which patients and family members are referred for genetic testing and counseling,” senior author Sapna Syngal, MD, MPH, with Dana-Farber/Brigham and Women’s Hospital, Boston, said in an institution news release.
Traditionally, when there is concern about a family cancer history, the individual is referred to a genetics clinic, where a counselor takes a complete family history.
“At a time when there’s a shortage of genetic counselors, PREMMplus can help streamline risk assessment and ensure that their time can be focused on where they’re most needed – helping people understand the results of genetic testing and the options available when a cancer-susceptibility gene is found,” Dr. Syngal says.
Online tool
The tool uses clinical data (age, sex, ethnicity, and personal/family history of 18 cancers) to determine an individual’s likelihood of harboring a PGV in 19 cancer susceptibility genes.
A PREMMplus score of 2.5% or greater had a 89%-94% sensitivity and > 97% negative predictive value (NPV) for identifying individuals with PGVs in 11 well-defined “category A” high-penetrance cancer risk genes: APC, BRCA1, BRCA2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53.
These PGVs “represent diverse types of inherited cancer risk for which there are established risk-reduction guidelines,” the study team says. Cancers associated with these PGVs include breast, ovarian, colorectal, pancreatic, and prostate cancer, as well as those that make up Lynch syndrome.
The ability of PREMMplus to identify individuals with PGVs in “moderate-penetrance” cancer risk genes (such as CHEK2 and ATM) was somewhat reduced but was still “quite strong” (84%-90% sensitivity and > 93% NPV), the study team reports.
In an interview, Dr. Syngal said her ultimate vision of this online tool is that it will be adapted into the electronic medical record (EMR).
“Through the EMR, it might somehow get pushed out to people before an oncology or primary care appointment or before a mammography or colonoscopy. Then by the time they come in, the doctor or nurse practitioner has the information and can refer them for genetic testing if appropriate,” Dr. Syngal explained.
The tool is not currently available for routine clinical use. The goal is to make it available online in a couple of months.
Dr. Syngal said two versions will be available. One will be a user-friendly version that can be filled out directly by patients and that will tell whether someone passes the threshold of needing genetic testing. The patient would then take that information to their primary care doctor.
With the second version, the doctor and patient would fill out the information together during an office visit.
PREMMplus would be free for the individual patient or provider.
“What we hope is that hospital systems will use it and that insurance companies will also use it as a way to say who needs testing and who to approve for testing,” Dr. Syngal told this news organization.
“For a hospital system or a genetic testing company, for example, that wants to integrate it into their direct-to-consumer platform, they would have to take out a license from Dana-Farber, and cost would be negotiated with each entity based on how they’re going to use it,” Dr. Syngal said.
Funding for the research was provided by the National Institutes of Health. A complete list of author disclosures is available with the original article.
A version of this article first appeared on Medscape.com.
(PGVs) in a diverse spectrum of cancer susceptibility genes.
The PREMMplus online tool was developed and validated by researchers at the Dana-Farber Cancer Institute, Boston using three cohorts involving more than 30,000 individuals who had undergone multigene hereditary cancer risk testing.
The study was published online in the Journal of Clinical Oncology.
“Our findings show that PREMMplus has the potential to change the model by which patients and family members are referred for genetic testing and counseling,” senior author Sapna Syngal, MD, MPH, with Dana-Farber/Brigham and Women’s Hospital, Boston, said in an institution news release.
Traditionally, when there is concern about a family cancer history, the individual is referred to a genetics clinic, where a counselor takes a complete family history.
“At a time when there’s a shortage of genetic counselors, PREMMplus can help streamline risk assessment and ensure that their time can be focused on where they’re most needed – helping people understand the results of genetic testing and the options available when a cancer-susceptibility gene is found,” Dr. Syngal says.
Online tool
The tool uses clinical data (age, sex, ethnicity, and personal/family history of 18 cancers) to determine an individual’s likelihood of harboring a PGV in 19 cancer susceptibility genes.
A PREMMplus score of 2.5% or greater had a 89%-94% sensitivity and > 97% negative predictive value (NPV) for identifying individuals with PGVs in 11 well-defined “category A” high-penetrance cancer risk genes: APC, BRCA1, BRCA2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53.
These PGVs “represent diverse types of inherited cancer risk for which there are established risk-reduction guidelines,” the study team says. Cancers associated with these PGVs include breast, ovarian, colorectal, pancreatic, and prostate cancer, as well as those that make up Lynch syndrome.
The ability of PREMMplus to identify individuals with PGVs in “moderate-penetrance” cancer risk genes (such as CHEK2 and ATM) was somewhat reduced but was still “quite strong” (84%-90% sensitivity and > 93% NPV), the study team reports.
In an interview, Dr. Syngal said her ultimate vision of this online tool is that it will be adapted into the electronic medical record (EMR).
“Through the EMR, it might somehow get pushed out to people before an oncology or primary care appointment or before a mammography or colonoscopy. Then by the time they come in, the doctor or nurse practitioner has the information and can refer them for genetic testing if appropriate,” Dr. Syngal explained.
The tool is not currently available for routine clinical use. The goal is to make it available online in a couple of months.
Dr. Syngal said two versions will be available. One will be a user-friendly version that can be filled out directly by patients and that will tell whether someone passes the threshold of needing genetic testing. The patient would then take that information to their primary care doctor.
With the second version, the doctor and patient would fill out the information together during an office visit.
PREMMplus would be free for the individual patient or provider.
“What we hope is that hospital systems will use it and that insurance companies will also use it as a way to say who needs testing and who to approve for testing,” Dr. Syngal told this news organization.
“For a hospital system or a genetic testing company, for example, that wants to integrate it into their direct-to-consumer platform, they would have to take out a license from Dana-Farber, and cost would be negotiated with each entity based on how they’re going to use it,” Dr. Syngal said.
Funding for the research was provided by the National Institutes of Health. A complete list of author disclosures is available with the original article.
A version of this article first appeared on Medscape.com.
(PGVs) in a diverse spectrum of cancer susceptibility genes.
The PREMMplus online tool was developed and validated by researchers at the Dana-Farber Cancer Institute, Boston using three cohorts involving more than 30,000 individuals who had undergone multigene hereditary cancer risk testing.
The study was published online in the Journal of Clinical Oncology.
“Our findings show that PREMMplus has the potential to change the model by which patients and family members are referred for genetic testing and counseling,” senior author Sapna Syngal, MD, MPH, with Dana-Farber/Brigham and Women’s Hospital, Boston, said in an institution news release.
Traditionally, when there is concern about a family cancer history, the individual is referred to a genetics clinic, where a counselor takes a complete family history.
“At a time when there’s a shortage of genetic counselors, PREMMplus can help streamline risk assessment and ensure that their time can be focused on where they’re most needed – helping people understand the results of genetic testing and the options available when a cancer-susceptibility gene is found,” Dr. Syngal says.
Online tool
The tool uses clinical data (age, sex, ethnicity, and personal/family history of 18 cancers) to determine an individual’s likelihood of harboring a PGV in 19 cancer susceptibility genes.
A PREMMplus score of 2.5% or greater had a 89%-94% sensitivity and > 97% negative predictive value (NPV) for identifying individuals with PGVs in 11 well-defined “category A” high-penetrance cancer risk genes: APC, BRCA1, BRCA2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53.
These PGVs “represent diverse types of inherited cancer risk for which there are established risk-reduction guidelines,” the study team says. Cancers associated with these PGVs include breast, ovarian, colorectal, pancreatic, and prostate cancer, as well as those that make up Lynch syndrome.
The ability of PREMMplus to identify individuals with PGVs in “moderate-penetrance” cancer risk genes (such as CHEK2 and ATM) was somewhat reduced but was still “quite strong” (84%-90% sensitivity and > 93% NPV), the study team reports.
In an interview, Dr. Syngal said her ultimate vision of this online tool is that it will be adapted into the electronic medical record (EMR).
“Through the EMR, it might somehow get pushed out to people before an oncology or primary care appointment or before a mammography or colonoscopy. Then by the time they come in, the doctor or nurse practitioner has the information and can refer them for genetic testing if appropriate,” Dr. Syngal explained.
The tool is not currently available for routine clinical use. The goal is to make it available online in a couple of months.
Dr. Syngal said two versions will be available. One will be a user-friendly version that can be filled out directly by patients and that will tell whether someone passes the threshold of needing genetic testing. The patient would then take that information to their primary care doctor.
With the second version, the doctor and patient would fill out the information together during an office visit.
PREMMplus would be free for the individual patient or provider.
“What we hope is that hospital systems will use it and that insurance companies will also use it as a way to say who needs testing and who to approve for testing,” Dr. Syngal told this news organization.
“For a hospital system or a genetic testing company, for example, that wants to integrate it into their direct-to-consumer platform, they would have to take out a license from Dana-Farber, and cost would be negotiated with each entity based on how they’re going to use it,” Dr. Syngal said.
Funding for the research was provided by the National Institutes of Health. A complete list of author disclosures is available with the original article.
A version of this article first appeared on Medscape.com.
Intera Oncology recalls hepatic artery infusion pumps for possible life-threatening issue
Although no injuries or deaths related to the pump malfunction have been reported yet, the U.S. Food and Drug Administration has deemed the recall Class I, the most serious category that indicates the device could cause injury or death.
Intera Oncology initiated the recall in July following reports from clinicians that the pumps, which are implanted to deliver chemotherapy to treat liver tumors, were delivering medications faster than expected. A fast flow rate can lead to life-threatening hematologic toxicity, neurotoxicity, or death. It also means patients will run out of medication too soon, potentially leading to disease progression or death.
The FDA notice states the company has advised customers to continue to monitor flow rate as per standard refill procedure as well as monitor for liver toxicity to adjust dosing as per standard protocols.
The company also said to consider pump replacement if altered flow can’t be adequately managed by dosing adjustments or having patients come in for medication refills and to verify the flow rate sooner than every 2 weeks if the pump appears to be flowing more than 15% outside its labeled specification.
Questions about the recall can be directed to Intera Oncology at (800) 660-2660 or support@interaoncol.
A version of this article first appeared on Medscape.com.
Although no injuries or deaths related to the pump malfunction have been reported yet, the U.S. Food and Drug Administration has deemed the recall Class I, the most serious category that indicates the device could cause injury or death.
Intera Oncology initiated the recall in July following reports from clinicians that the pumps, which are implanted to deliver chemotherapy to treat liver tumors, were delivering medications faster than expected. A fast flow rate can lead to life-threatening hematologic toxicity, neurotoxicity, or death. It also means patients will run out of medication too soon, potentially leading to disease progression or death.
The FDA notice states the company has advised customers to continue to monitor flow rate as per standard refill procedure as well as monitor for liver toxicity to adjust dosing as per standard protocols.
The company also said to consider pump replacement if altered flow can’t be adequately managed by dosing adjustments or having patients come in for medication refills and to verify the flow rate sooner than every 2 weeks if the pump appears to be flowing more than 15% outside its labeled specification.
Questions about the recall can be directed to Intera Oncology at (800) 660-2660 or support@interaoncol.
A version of this article first appeared on Medscape.com.
Although no injuries or deaths related to the pump malfunction have been reported yet, the U.S. Food and Drug Administration has deemed the recall Class I, the most serious category that indicates the device could cause injury or death.
Intera Oncology initiated the recall in July following reports from clinicians that the pumps, which are implanted to deliver chemotherapy to treat liver tumors, were delivering medications faster than expected. A fast flow rate can lead to life-threatening hematologic toxicity, neurotoxicity, or death. It also means patients will run out of medication too soon, potentially leading to disease progression or death.
The FDA notice states the company has advised customers to continue to monitor flow rate as per standard refill procedure as well as monitor for liver toxicity to adjust dosing as per standard protocols.
The company also said to consider pump replacement if altered flow can’t be adequately managed by dosing adjustments or having patients come in for medication refills and to verify the flow rate sooner than every 2 weeks if the pump appears to be flowing more than 15% outside its labeled specification.
Questions about the recall can be directed to Intera Oncology at (800) 660-2660 or support@interaoncol.
A version of this article first appeared on Medscape.com.
Medicare drug changes ought to benefit rheumatology patients
Changes in Medicare law will help some patients who need costly rheumatology treatments, including several medicines for which competition has been kept in check for many years.
In fact, this field of medicine includes prime examples of the kinds of products that drove Congress to give the giant federal health program leverage to try to restrain rising pharmaceutical costs through negotiations. The Inflation Reduction Act, signed into law by President Joe Biden on Aug. 16, also provides some fairly quick aid for people enrolled in Medicare who struggle with pharmacy bills.
As described in an official summary from the Congressional Research Service, the law establishes:
- A cap on annual Medicare Part D out-of-pocket spending that starts in 2025 at $2,000, with planned annual adjustments thereafter.
- A limit on cost-sharing under Medicare Part D for a month’s supply of covered insulin products at $35 for 2023 through 2025, with plans for continued limits on this cost in the years after pegged to negotiated prices.
- A program under which drug manufacturers provide discounts to beneficiaries who have incurred costs above the annual deductible beginning in 2025.
- A requirement that drugmakers issue rebates to Medicare for certain brand-name drugs covered without generic equivalents for which prices increase faster than inflation.
- An obligation for Medicare Part D plans to pay for adult vaccines that are recommended by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices without requiring cost sharing.
The law’s marquee health provision sets the stage for Medicare, the nation’s largest purchaser of drugs, for the first time to leverage its clout directly in negotiating for lower costs for medicines. Democrats sought to build what amount to guardrails into this program, seeking to spare from competition new and innovative drugs and ones developed by smaller companies. Drugs likely to soon face competition from copycat versions also would fall outside of the pool for negotiations.
In effect, the design of the program would allow Medicare to negotiate in the future in cases such as those seen in recent years with blockbuster medicines often in rheumatology. That’s due in a large part to legal challenges that have helped thwart the introduction of copycat versions of these kinds of products known as biosimilars.
Etanercept (Enbrel) has been sold in the United States since 1998 and adalimumab (Humira) since 2003. Both products face competition from copycat versions called biosimilars in other nations, but the introductions of these products have been delayed in the United States until 2029 for etanercept and 2023 for adalimumab, the Office of Inspector General for the Department of Health & Human Services said in a March 2022 report. The OIG said in the report that the combined 2019 Medicare Part D tab for the two biologics was more than $5 billion.
Rheumatology drugs rival cancer medicines for dominance among the most expensive drugs for people enrolled in Medicare. The average 2020 spending for the most widely used forms of adalimumab by people in Medicare’s Part D pharmacy program topped $51,000, according to federal data. The price per dosage-unit for the drug rose about 7% from 2019 to 2020.
The pharmaceutical industry defends the high introductory costs of medicines and subsequent rising prices as necessary payback for research on products sold and the ones still in development. Since the initial Food and Drug Administration approval of adalimumab on Dec. 31, 2002, Abbott Laboratories and its AbbVie spin-off have made changes to the drug’s administration and paid for studies to expand its approved indications.
Still, the investment in adalimumab appears to have been paid well.
Abbott Labs acquired adalimumab as part of its purchase of BASF’s pharmaceutical operations in 2001, a purchase that also included the thyroid drug Synthroid. Abbott paid $7.2 billion, or roughly $12 billion in current dollars. In 2021 alone, Humira sales were $20.7 billion, with the United States accounting for $17.3 billion of the product’s revenue.
Losing access to treatment when moving to Medicare
Sue Lee of Crestwood, Ky., is among the patients waiting to see if the changes in Medicare law might allow her to again afford adalimumab. For now, Ms. Lee said she is hoping her plaque psoriasis stays manageable with the topical ointments and moisturizers she has been using since losing access to adalimumab. Ms. Lee, 80, took the medicine during her working years for her plaque psoriasis.
“I told people: ‘I’m on the wonder drug. Look at me. I can show my skin now. I don’t have all of these sores,’ ” she said in an interview.
But after she retired at 75, she was shocked at the tab she faced after switching from private insurance to Medicare. She said it could have cost her close to $10,000 a year to take Humira. Ms. Lee’s Social Security earnings make her ineligible for certain assistance with drug costs.
“I cried a lot,” she said about the loss of affordable access to the drug.
What’s the path ahead?
The American College of Rheumatology and the Coalition of State Rheumatology Organizations are among the physician groups that pressed Congress for years for action to lower drug costs. Their members have been on the frontline of the crisis in the United States among patients unable to afford medicines.
“The financial burden of skyrocketing drug prices has forced many of our patients to spread their treatment out longer than prescribed, delay care, abandon prescriptions, or forgo treatment entirely – all of which risks flare-ups, disease regression, permanent disability, and even premature death,” said Blair Solow, MD, chair of the ACR’s Government Affairs Committee, in a statement on the new Medicare provisions.
In an interview, Dr. Solow, an assistant professor of medicine in the division of rheumatic diseases at University of Texas Southwestern Medical Center, Dallas, noted that there are concerns about how changes in Medicare drug pricing might affect future development of medicines. This has been a chief criticism of the pharmaceutical industry of efforts to allow Medicare to negotiate for lower prices.
“Of note, drug companies research, create, and produce medications that will perform well in the market, not necessarily those that may be most needed,” Dr. Solow wrote. “We can hope the new medications put forth by manufacturers are those that improve the lives of patients.”
In July, the Congressional Budget Office released a report on an earlier version of the Democrats’ plans for Medicare drug negotiations that suggested the potential loss to drugmakers’ productivity may be relatively small. The CBO expects that about 1,300 drugs will be approved over the next 30 years. The legislation as proposed in July might reduce the tally by 15 drugs. The CBO said these estimates fell in the middle of the distribution of possible outcomes and are subject to uncertainty, and it is still working on an estimate of the expects effects of the final version of the law.
“CBO did not predict what kind of drugs would be affected or analyze the effects of forgone innovation on public health,” the agency said.
Dr. Solow also said there may be some challenges for physicians in explaining to patients the timeline for the new law’s Medicare provisions. People need to be aware of how long it will take to implement the plan and the potential for changes or delays.
“I think this is important, because the interpretation of the law can be done in a way that was not necessarily what Congress intended, and depending on the control of Congress and the Administration, this could impact downstream effects in how this law plays out,” she said in an interview.
CMS has substantial work ahead of it in choosing the drugs for which there will be subject to negotiations. The new law limits the number of drugs that can be negotiated to 10 annually in 2026, increasing to 20 drugs annually by 2029. Drugs would be eligible for negotiated prices from 9 years after drug approval or 13 years for biologics, until entry of a generic or biosimilar competitor.
The new law calls for taxes and other penalties for companies that refuse to negotiate or offer the agreed price, Thomas J. Hwang, MD; Aaron S. Kesselheim, MD, JD, MPH; and Benjamin N. Rome, MD, MPH, all of Harvard Medical School, Boston, wrote in an Aug. 19 viewpoint article in JAMA. U.S. lawmakers took a different approach to negotiations about drug prices than those used in other countries, they wrote.
“Notably, the Inflation Reduction Act shields new drugs from negotiated prices for the first 9-13 years on the market,” they wrote. “In contrast, most other peer countries typically negotiate drug prices at the time of market entry, and no peer country limits the number of drugs negotiated.”
Missed opportunities
Madelaine Feldman, MD, president of the CSRO and a rheumatologist in private practice with The Rheumatology Group in New Orleans, said in an interview that she welcomes many of the provisions of the new law, as they will help her rheumatology patients afford their medicine.
But she considers one of the provisions of the law to be a disappointment. The law further delays the start date for a federal rule intended to allow people on Medicare Part D to directly benefit from discounts negotiated on drugs. This is a point often overlooked in news reports on the law.
Insurers use what are called pharmacy benefit manager (PBM) services to obtain rebates on medicines, but they don’t fully or directly share these price reductions with people enrolled in Part D plans. Instead, people in the Part D plans have their cost sharing pegged closer to listed prices, the ones set before the rebates obtained by PBMs. The PBM industry argues that the rebates, often based on the list price of the drug, serve to keep monthly insurance premiums low. But there’s been concern about perverse incentives in this approach, where more expensive drugs are preferred by PBMs, leading to higher rebates.
Congress had already delayed its implementation of the PBM rule, which would apply savings more directly to patients, until 2027 and did so again in the Inflation Reduction Act.
Implementing this rule on Medicare Part D prescription drug rebates would be a help for patients struggling to pay for costly drugs, such as those used in rheumatology, Dr. Feldman said.
“It just doesn’t make any sense to hold off on these changes if you really want to cut Medicare’s beneficiaries’ cost sharing and attempt to stop the perverse incentive that puts higher priced drugs on Part D formularies,” she said.
Changes in Medicare law will help some patients who need costly rheumatology treatments, including several medicines for which competition has been kept in check for many years.
In fact, this field of medicine includes prime examples of the kinds of products that drove Congress to give the giant federal health program leverage to try to restrain rising pharmaceutical costs through negotiations. The Inflation Reduction Act, signed into law by President Joe Biden on Aug. 16, also provides some fairly quick aid for people enrolled in Medicare who struggle with pharmacy bills.
As described in an official summary from the Congressional Research Service, the law establishes:
- A cap on annual Medicare Part D out-of-pocket spending that starts in 2025 at $2,000, with planned annual adjustments thereafter.
- A limit on cost-sharing under Medicare Part D for a month’s supply of covered insulin products at $35 for 2023 through 2025, with plans for continued limits on this cost in the years after pegged to negotiated prices.
- A program under which drug manufacturers provide discounts to beneficiaries who have incurred costs above the annual deductible beginning in 2025.
- A requirement that drugmakers issue rebates to Medicare for certain brand-name drugs covered without generic equivalents for which prices increase faster than inflation.
- An obligation for Medicare Part D plans to pay for adult vaccines that are recommended by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices without requiring cost sharing.
The law’s marquee health provision sets the stage for Medicare, the nation’s largest purchaser of drugs, for the first time to leverage its clout directly in negotiating for lower costs for medicines. Democrats sought to build what amount to guardrails into this program, seeking to spare from competition new and innovative drugs and ones developed by smaller companies. Drugs likely to soon face competition from copycat versions also would fall outside of the pool for negotiations.
In effect, the design of the program would allow Medicare to negotiate in the future in cases such as those seen in recent years with blockbuster medicines often in rheumatology. That’s due in a large part to legal challenges that have helped thwart the introduction of copycat versions of these kinds of products known as biosimilars.
Etanercept (Enbrel) has been sold in the United States since 1998 and adalimumab (Humira) since 2003. Both products face competition from copycat versions called biosimilars in other nations, but the introductions of these products have been delayed in the United States until 2029 for etanercept and 2023 for adalimumab, the Office of Inspector General for the Department of Health & Human Services said in a March 2022 report. The OIG said in the report that the combined 2019 Medicare Part D tab for the two biologics was more than $5 billion.
Rheumatology drugs rival cancer medicines for dominance among the most expensive drugs for people enrolled in Medicare. The average 2020 spending for the most widely used forms of adalimumab by people in Medicare’s Part D pharmacy program topped $51,000, according to federal data. The price per dosage-unit for the drug rose about 7% from 2019 to 2020.
The pharmaceutical industry defends the high introductory costs of medicines and subsequent rising prices as necessary payback for research on products sold and the ones still in development. Since the initial Food and Drug Administration approval of adalimumab on Dec. 31, 2002, Abbott Laboratories and its AbbVie spin-off have made changes to the drug’s administration and paid for studies to expand its approved indications.
Still, the investment in adalimumab appears to have been paid well.
Abbott Labs acquired adalimumab as part of its purchase of BASF’s pharmaceutical operations in 2001, a purchase that also included the thyroid drug Synthroid. Abbott paid $7.2 billion, or roughly $12 billion in current dollars. In 2021 alone, Humira sales were $20.7 billion, with the United States accounting for $17.3 billion of the product’s revenue.
Losing access to treatment when moving to Medicare
Sue Lee of Crestwood, Ky., is among the patients waiting to see if the changes in Medicare law might allow her to again afford adalimumab. For now, Ms. Lee said she is hoping her plaque psoriasis stays manageable with the topical ointments and moisturizers she has been using since losing access to adalimumab. Ms. Lee, 80, took the medicine during her working years for her plaque psoriasis.
“I told people: ‘I’m on the wonder drug. Look at me. I can show my skin now. I don’t have all of these sores,’ ” she said in an interview.
But after she retired at 75, she was shocked at the tab she faced after switching from private insurance to Medicare. She said it could have cost her close to $10,000 a year to take Humira. Ms. Lee’s Social Security earnings make her ineligible for certain assistance with drug costs.
“I cried a lot,” she said about the loss of affordable access to the drug.
What’s the path ahead?
The American College of Rheumatology and the Coalition of State Rheumatology Organizations are among the physician groups that pressed Congress for years for action to lower drug costs. Their members have been on the frontline of the crisis in the United States among patients unable to afford medicines.
“The financial burden of skyrocketing drug prices has forced many of our patients to spread their treatment out longer than prescribed, delay care, abandon prescriptions, or forgo treatment entirely – all of which risks flare-ups, disease regression, permanent disability, and even premature death,” said Blair Solow, MD, chair of the ACR’s Government Affairs Committee, in a statement on the new Medicare provisions.
In an interview, Dr. Solow, an assistant professor of medicine in the division of rheumatic diseases at University of Texas Southwestern Medical Center, Dallas, noted that there are concerns about how changes in Medicare drug pricing might affect future development of medicines. This has been a chief criticism of the pharmaceutical industry of efforts to allow Medicare to negotiate for lower prices.
“Of note, drug companies research, create, and produce medications that will perform well in the market, not necessarily those that may be most needed,” Dr. Solow wrote. “We can hope the new medications put forth by manufacturers are those that improve the lives of patients.”
In July, the Congressional Budget Office released a report on an earlier version of the Democrats’ plans for Medicare drug negotiations that suggested the potential loss to drugmakers’ productivity may be relatively small. The CBO expects that about 1,300 drugs will be approved over the next 30 years. The legislation as proposed in July might reduce the tally by 15 drugs. The CBO said these estimates fell in the middle of the distribution of possible outcomes and are subject to uncertainty, and it is still working on an estimate of the expects effects of the final version of the law.
“CBO did not predict what kind of drugs would be affected or analyze the effects of forgone innovation on public health,” the agency said.
Dr. Solow also said there may be some challenges for physicians in explaining to patients the timeline for the new law’s Medicare provisions. People need to be aware of how long it will take to implement the plan and the potential for changes or delays.
“I think this is important, because the interpretation of the law can be done in a way that was not necessarily what Congress intended, and depending on the control of Congress and the Administration, this could impact downstream effects in how this law plays out,” she said in an interview.
CMS has substantial work ahead of it in choosing the drugs for which there will be subject to negotiations. The new law limits the number of drugs that can be negotiated to 10 annually in 2026, increasing to 20 drugs annually by 2029. Drugs would be eligible for negotiated prices from 9 years after drug approval or 13 years for biologics, until entry of a generic or biosimilar competitor.
The new law calls for taxes and other penalties for companies that refuse to negotiate or offer the agreed price, Thomas J. Hwang, MD; Aaron S. Kesselheim, MD, JD, MPH; and Benjamin N. Rome, MD, MPH, all of Harvard Medical School, Boston, wrote in an Aug. 19 viewpoint article in JAMA. U.S. lawmakers took a different approach to negotiations about drug prices than those used in other countries, they wrote.
“Notably, the Inflation Reduction Act shields new drugs from negotiated prices for the first 9-13 years on the market,” they wrote. “In contrast, most other peer countries typically negotiate drug prices at the time of market entry, and no peer country limits the number of drugs negotiated.”
Missed opportunities
Madelaine Feldman, MD, president of the CSRO and a rheumatologist in private practice with The Rheumatology Group in New Orleans, said in an interview that she welcomes many of the provisions of the new law, as they will help her rheumatology patients afford their medicine.
But she considers one of the provisions of the law to be a disappointment. The law further delays the start date for a federal rule intended to allow people on Medicare Part D to directly benefit from discounts negotiated on drugs. This is a point often overlooked in news reports on the law.
Insurers use what are called pharmacy benefit manager (PBM) services to obtain rebates on medicines, but they don’t fully or directly share these price reductions with people enrolled in Part D plans. Instead, people in the Part D plans have their cost sharing pegged closer to listed prices, the ones set before the rebates obtained by PBMs. The PBM industry argues that the rebates, often based on the list price of the drug, serve to keep monthly insurance premiums low. But there’s been concern about perverse incentives in this approach, where more expensive drugs are preferred by PBMs, leading to higher rebates.
Congress had already delayed its implementation of the PBM rule, which would apply savings more directly to patients, until 2027 and did so again in the Inflation Reduction Act.
Implementing this rule on Medicare Part D prescription drug rebates would be a help for patients struggling to pay for costly drugs, such as those used in rheumatology, Dr. Feldman said.
“It just doesn’t make any sense to hold off on these changes if you really want to cut Medicare’s beneficiaries’ cost sharing and attempt to stop the perverse incentive that puts higher priced drugs on Part D formularies,” she said.
Changes in Medicare law will help some patients who need costly rheumatology treatments, including several medicines for which competition has been kept in check for many years.
In fact, this field of medicine includes prime examples of the kinds of products that drove Congress to give the giant federal health program leverage to try to restrain rising pharmaceutical costs through negotiations. The Inflation Reduction Act, signed into law by President Joe Biden on Aug. 16, also provides some fairly quick aid for people enrolled in Medicare who struggle with pharmacy bills.
As described in an official summary from the Congressional Research Service, the law establishes:
- A cap on annual Medicare Part D out-of-pocket spending that starts in 2025 at $2,000, with planned annual adjustments thereafter.
- A limit on cost-sharing under Medicare Part D for a month’s supply of covered insulin products at $35 for 2023 through 2025, with plans for continued limits on this cost in the years after pegged to negotiated prices.
- A program under which drug manufacturers provide discounts to beneficiaries who have incurred costs above the annual deductible beginning in 2025.
- A requirement that drugmakers issue rebates to Medicare for certain brand-name drugs covered without generic equivalents for which prices increase faster than inflation.
- An obligation for Medicare Part D plans to pay for adult vaccines that are recommended by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices without requiring cost sharing.
The law’s marquee health provision sets the stage for Medicare, the nation’s largest purchaser of drugs, for the first time to leverage its clout directly in negotiating for lower costs for medicines. Democrats sought to build what amount to guardrails into this program, seeking to spare from competition new and innovative drugs and ones developed by smaller companies. Drugs likely to soon face competition from copycat versions also would fall outside of the pool for negotiations.
In effect, the design of the program would allow Medicare to negotiate in the future in cases such as those seen in recent years with blockbuster medicines often in rheumatology. That’s due in a large part to legal challenges that have helped thwart the introduction of copycat versions of these kinds of products known as biosimilars.
Etanercept (Enbrel) has been sold in the United States since 1998 and adalimumab (Humira) since 2003. Both products face competition from copycat versions called biosimilars in other nations, but the introductions of these products have been delayed in the United States until 2029 for etanercept and 2023 for adalimumab, the Office of Inspector General for the Department of Health & Human Services said in a March 2022 report. The OIG said in the report that the combined 2019 Medicare Part D tab for the two biologics was more than $5 billion.
Rheumatology drugs rival cancer medicines for dominance among the most expensive drugs for people enrolled in Medicare. The average 2020 spending for the most widely used forms of adalimumab by people in Medicare’s Part D pharmacy program topped $51,000, according to federal data. The price per dosage-unit for the drug rose about 7% from 2019 to 2020.
The pharmaceutical industry defends the high introductory costs of medicines and subsequent rising prices as necessary payback for research on products sold and the ones still in development. Since the initial Food and Drug Administration approval of adalimumab on Dec. 31, 2002, Abbott Laboratories and its AbbVie spin-off have made changes to the drug’s administration and paid for studies to expand its approved indications.
Still, the investment in adalimumab appears to have been paid well.
Abbott Labs acquired adalimumab as part of its purchase of BASF’s pharmaceutical operations in 2001, a purchase that also included the thyroid drug Synthroid. Abbott paid $7.2 billion, or roughly $12 billion in current dollars. In 2021 alone, Humira sales were $20.7 billion, with the United States accounting for $17.3 billion of the product’s revenue.
Losing access to treatment when moving to Medicare
Sue Lee of Crestwood, Ky., is among the patients waiting to see if the changes in Medicare law might allow her to again afford adalimumab. For now, Ms. Lee said she is hoping her plaque psoriasis stays manageable with the topical ointments and moisturizers she has been using since losing access to adalimumab. Ms. Lee, 80, took the medicine during her working years for her plaque psoriasis.
“I told people: ‘I’m on the wonder drug. Look at me. I can show my skin now. I don’t have all of these sores,’ ” she said in an interview.
But after she retired at 75, she was shocked at the tab she faced after switching from private insurance to Medicare. She said it could have cost her close to $10,000 a year to take Humira. Ms. Lee’s Social Security earnings make her ineligible for certain assistance with drug costs.
“I cried a lot,” she said about the loss of affordable access to the drug.
What’s the path ahead?
The American College of Rheumatology and the Coalition of State Rheumatology Organizations are among the physician groups that pressed Congress for years for action to lower drug costs. Their members have been on the frontline of the crisis in the United States among patients unable to afford medicines.
“The financial burden of skyrocketing drug prices has forced many of our patients to spread their treatment out longer than prescribed, delay care, abandon prescriptions, or forgo treatment entirely – all of which risks flare-ups, disease regression, permanent disability, and even premature death,” said Blair Solow, MD, chair of the ACR’s Government Affairs Committee, in a statement on the new Medicare provisions.
In an interview, Dr. Solow, an assistant professor of medicine in the division of rheumatic diseases at University of Texas Southwestern Medical Center, Dallas, noted that there are concerns about how changes in Medicare drug pricing might affect future development of medicines. This has been a chief criticism of the pharmaceutical industry of efforts to allow Medicare to negotiate for lower prices.
“Of note, drug companies research, create, and produce medications that will perform well in the market, not necessarily those that may be most needed,” Dr. Solow wrote. “We can hope the new medications put forth by manufacturers are those that improve the lives of patients.”
In July, the Congressional Budget Office released a report on an earlier version of the Democrats’ plans for Medicare drug negotiations that suggested the potential loss to drugmakers’ productivity may be relatively small. The CBO expects that about 1,300 drugs will be approved over the next 30 years. The legislation as proposed in July might reduce the tally by 15 drugs. The CBO said these estimates fell in the middle of the distribution of possible outcomes and are subject to uncertainty, and it is still working on an estimate of the expects effects of the final version of the law.
“CBO did not predict what kind of drugs would be affected or analyze the effects of forgone innovation on public health,” the agency said.
Dr. Solow also said there may be some challenges for physicians in explaining to patients the timeline for the new law’s Medicare provisions. People need to be aware of how long it will take to implement the plan and the potential for changes or delays.
“I think this is important, because the interpretation of the law can be done in a way that was not necessarily what Congress intended, and depending on the control of Congress and the Administration, this could impact downstream effects in how this law plays out,” she said in an interview.
CMS has substantial work ahead of it in choosing the drugs for which there will be subject to negotiations. The new law limits the number of drugs that can be negotiated to 10 annually in 2026, increasing to 20 drugs annually by 2029. Drugs would be eligible for negotiated prices from 9 years after drug approval or 13 years for biologics, until entry of a generic or biosimilar competitor.
The new law calls for taxes and other penalties for companies that refuse to negotiate or offer the agreed price, Thomas J. Hwang, MD; Aaron S. Kesselheim, MD, JD, MPH; and Benjamin N. Rome, MD, MPH, all of Harvard Medical School, Boston, wrote in an Aug. 19 viewpoint article in JAMA. U.S. lawmakers took a different approach to negotiations about drug prices than those used in other countries, they wrote.
“Notably, the Inflation Reduction Act shields new drugs from negotiated prices for the first 9-13 years on the market,” they wrote. “In contrast, most other peer countries typically negotiate drug prices at the time of market entry, and no peer country limits the number of drugs negotiated.”
Missed opportunities
Madelaine Feldman, MD, president of the CSRO and a rheumatologist in private practice with The Rheumatology Group in New Orleans, said in an interview that she welcomes many of the provisions of the new law, as they will help her rheumatology patients afford their medicine.
But she considers one of the provisions of the law to be a disappointment. The law further delays the start date for a federal rule intended to allow people on Medicare Part D to directly benefit from discounts negotiated on drugs. This is a point often overlooked in news reports on the law.
Insurers use what are called pharmacy benefit manager (PBM) services to obtain rebates on medicines, but they don’t fully or directly share these price reductions with people enrolled in Part D plans. Instead, people in the Part D plans have their cost sharing pegged closer to listed prices, the ones set before the rebates obtained by PBMs. The PBM industry argues that the rebates, often based on the list price of the drug, serve to keep monthly insurance premiums low. But there’s been concern about perverse incentives in this approach, where more expensive drugs are preferred by PBMs, leading to higher rebates.
Congress had already delayed its implementation of the PBM rule, which would apply savings more directly to patients, until 2027 and did so again in the Inflation Reduction Act.
Implementing this rule on Medicare Part D prescription drug rebates would be a help for patients struggling to pay for costly drugs, such as those used in rheumatology, Dr. Feldman said.
“It just doesn’t make any sense to hold off on these changes if you really want to cut Medicare’s beneficiaries’ cost sharing and attempt to stop the perverse incentive that puts higher priced drugs on Part D formularies,” she said.
Question 2
Q2. Correct answer: D. Treatment for recurrent or metastatic disease is imatinib.
Rationale
This patient has a gastrointestinal stromal tumor (GIST) of the stomach. GISTs are the most common mesenchymal tumor found in the stomach. Gastric GISTs have a better prognosis than those found in the small intestine. GISTs are often found incidentally but can cause symptoms such as bleeding due to ulceration. Pathology of a GIST shows spindle cells that stain positive for CD117 and harbor KIT mutations. Malignant potential and decreased survival are associated with size more than 2 cm and high mitotic index (more than 5/50 high power field). Endoscopic ultrasound with tissue sampling is the preferred diagnostic technique. High-risk features include lobulated or irregular borders, invasion into adjacent structures and heterogeneity. Fine needle aspirate may be suboptimal, and core biopsy is an acceptable alternative. Resection is indicated for lesions that are symptomatic, size more than 2 cm or high-risk EUS features. Lesions less than 2 cm without high-risk features can be surveyed by EUS annually. Endoscopic resection might be possible for small lesions but should be done in specialized centers. Metastatic or recurrent lesions are treated with imatinib.
Reference
ASGE Standards of Practice Committee. Gastrointest Endosc. 2015 Jul;82(1):1-8.
Q2. Correct answer: D. Treatment for recurrent or metastatic disease is imatinib.
Rationale
This patient has a gastrointestinal stromal tumor (GIST) of the stomach. GISTs are the most common mesenchymal tumor found in the stomach. Gastric GISTs have a better prognosis than those found in the small intestine. GISTs are often found incidentally but can cause symptoms such as bleeding due to ulceration. Pathology of a GIST shows spindle cells that stain positive for CD117 and harbor KIT mutations. Malignant potential and decreased survival are associated with size more than 2 cm and high mitotic index (more than 5/50 high power field). Endoscopic ultrasound with tissue sampling is the preferred diagnostic technique. High-risk features include lobulated or irregular borders, invasion into adjacent structures and heterogeneity. Fine needle aspirate may be suboptimal, and core biopsy is an acceptable alternative. Resection is indicated for lesions that are symptomatic, size more than 2 cm or high-risk EUS features. Lesions less than 2 cm without high-risk features can be surveyed by EUS annually. Endoscopic resection might be possible for small lesions but should be done in specialized centers. Metastatic or recurrent lesions are treated with imatinib.
Reference
ASGE Standards of Practice Committee. Gastrointest Endosc. 2015 Jul;82(1):1-8.
Q2. Correct answer: D. Treatment for recurrent or metastatic disease is imatinib.
Rationale
This patient has a gastrointestinal stromal tumor (GIST) of the stomach. GISTs are the most common mesenchymal tumor found in the stomach. Gastric GISTs have a better prognosis than those found in the small intestine. GISTs are often found incidentally but can cause symptoms such as bleeding due to ulceration. Pathology of a GIST shows spindle cells that stain positive for CD117 and harbor KIT mutations. Malignant potential and decreased survival are associated with size more than 2 cm and high mitotic index (more than 5/50 high power field). Endoscopic ultrasound with tissue sampling is the preferred diagnostic technique. High-risk features include lobulated or irregular borders, invasion into adjacent structures and heterogeneity. Fine needle aspirate may be suboptimal, and core biopsy is an acceptable alternative. Resection is indicated for lesions that are symptomatic, size more than 2 cm or high-risk EUS features. Lesions less than 2 cm without high-risk features can be surveyed by EUS annually. Endoscopic resection might be possible for small lesions but should be done in specialized centers. Metastatic or recurrent lesions are treated with imatinib.
Reference
ASGE Standards of Practice Committee. Gastrointest Endosc. 2015 Jul;82(1):1-8.
Q2. A 65-year-old man undergoes upper endoscopy for epigastric discomfort. The exam results are normal, except for a 3-cm submucosal mass in the body of the stomach. Endoscopic ultrasound shows that the mass arises from the fourth layer of the stomach wall. CT of the abdomen confirms the solid gastric mass with several small lesions in the liver concerning for metastatic disease. Biopsy of the mass shows CD117-positive spindle cells.
SGLT-2I may be preferred over DPP-4I for frail patients with T2D
Key clinical point: Sodium-glucose cotransporter-2 inhibitors (SGLT-2I) offered advantages over dipeptidyl peptidase-4 inhibitors (DPP-4I) for preventing major adverse cardiovascular events (MACE), heart failure (HF) hospitalizations, and all-cause mortality in frail patients with type 2 diabetes (T2D) who were recently hospitalized.
Major finding: The rates of MACE (subdistribution hazard ratio [sHR] 0.51; 95% CI 0.46-0.56), HF hospitalization (sHR 0.42; 95% CI 0.36-0.49), and all-cause mortality (HR 0.38; 95% CI 0.33-0.43) were significantly lower in patients receiving SGLT-2I vs DPP-4I.
Study details: The data come from a cohort study of 32,043 patients aged ≥30 years with T2D who were recently discharged from hospital, of which 5152 received SGLT-2I and 26,891 received DPP-4I.
Disclosures: This study received no specific funding. JS Bell, JE Shaw, J Ilomaki, and M Cesari declared receiving personal fees or research grants from various sources.
Source: Wood SJ et al. Effectiveness of sodium-glucose cotransporter-2 inhibitors vs. dipeptidyl peptidase-4 inhibitors in frail people with diabetes who were recently hospitalized. Front Pharmacol. 2022;13:886834 (Jul 12). Doi: 10.3389/fphar.2022.886834
Key clinical point: Sodium-glucose cotransporter-2 inhibitors (SGLT-2I) offered advantages over dipeptidyl peptidase-4 inhibitors (DPP-4I) for preventing major adverse cardiovascular events (MACE), heart failure (HF) hospitalizations, and all-cause mortality in frail patients with type 2 diabetes (T2D) who were recently hospitalized.
Major finding: The rates of MACE (subdistribution hazard ratio [sHR] 0.51; 95% CI 0.46-0.56), HF hospitalization (sHR 0.42; 95% CI 0.36-0.49), and all-cause mortality (HR 0.38; 95% CI 0.33-0.43) were significantly lower in patients receiving SGLT-2I vs DPP-4I.
Study details: The data come from a cohort study of 32,043 patients aged ≥30 years with T2D who were recently discharged from hospital, of which 5152 received SGLT-2I and 26,891 received DPP-4I.
Disclosures: This study received no specific funding. JS Bell, JE Shaw, J Ilomaki, and M Cesari declared receiving personal fees or research grants from various sources.
Source: Wood SJ et al. Effectiveness of sodium-glucose cotransporter-2 inhibitors vs. dipeptidyl peptidase-4 inhibitors in frail people with diabetes who were recently hospitalized. Front Pharmacol. 2022;13:886834 (Jul 12). Doi: 10.3389/fphar.2022.886834
Key clinical point: Sodium-glucose cotransporter-2 inhibitors (SGLT-2I) offered advantages over dipeptidyl peptidase-4 inhibitors (DPP-4I) for preventing major adverse cardiovascular events (MACE), heart failure (HF) hospitalizations, and all-cause mortality in frail patients with type 2 diabetes (T2D) who were recently hospitalized.
Major finding: The rates of MACE (subdistribution hazard ratio [sHR] 0.51; 95% CI 0.46-0.56), HF hospitalization (sHR 0.42; 95% CI 0.36-0.49), and all-cause mortality (HR 0.38; 95% CI 0.33-0.43) were significantly lower in patients receiving SGLT-2I vs DPP-4I.
Study details: The data come from a cohort study of 32,043 patients aged ≥30 years with T2D who were recently discharged from hospital, of which 5152 received SGLT-2I and 26,891 received DPP-4I.
Disclosures: This study received no specific funding. JS Bell, JE Shaw, J Ilomaki, and M Cesari declared receiving personal fees or research grants from various sources.
Source: Wood SJ et al. Effectiveness of sodium-glucose cotransporter-2 inhibitors vs. dipeptidyl peptidase-4 inhibitors in frail people with diabetes who were recently hospitalized. Front Pharmacol. 2022;13:886834 (Jul 12). Doi: 10.3389/fphar.2022.886834