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extacy
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A peer-reviewed clinical journal serving healthcare professionals working with the Department of Veterans Affairs, the Department of Defense, and the Public Health Service.
Nondiabetes hospitalization is wrong time to up diabetes meds
“Short-term hospitalization [for reasons other than diabetes] may not be the time to intervene in long-term diabetes management,” researchers conclude.
They found that, in a national cohort of older almost entirely male veterans with non–insulin-treated type 2 diabetes who were hospitalized for non–diabetes-related common medical conditions, intensified diabetes treatment on hospital discharge was linked to an increased risk of severe hypoglycemia in the immediate postdischarge period.
However, diabetes treatment intensification – that is, receiving a prescription for a new or higher dose of diabetes medicine – was not associated with decreased risks of severe hyperglycemia or with improved glycemic (hemoglobin A1c) control at 30 days or 1 year, according to study results, published in JAMA Network Open.
“We didn’t see a reduction in diabetes emergencies in more intensively treated patients,” lead investigator Timothy S. Anderson, MD, said in an interview.
Also, importantly, there was a low rate of persistence with the new treatment. “Half of the patients were no longer taking these [intensified diabetes medicines] at 1 year, which tells me that context is key,” he pointed out. “If a patient is in the hospital for diabetes [unlike the patients in this study], I think it makes a lot of sense to modify and adjust their regimen to try to help them right then and there.”
The overall risk of severe hyperglycemia or severe hypoglycemia was pretty small in the overall cohort, Dr. Anderson noted, “but we do put people at risk of leaving the hospital and ending up back in the hospital with low blood sugar when we intensify medications, and there’s not necessarily a good signal to suggest that it’s all that urgent to change these medicines.”
Instead, the “safer path” may be to make recommendations to the patient’s outpatient physician and also inform the patient – for example, “We saw some concerns about your diabetes while you were in the hospital, and this is really something that should be looked at when you’re recovered and feeling better from the rest of your health standpoint” – rather than making a diabetes medication change while the person is acutely ill or recovering from illness, said Dr. Anderson, from Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.
The researchers also found an “unexpected” significant decrease in 30-day mortality in the patients with intensified diabetes treatment, which was probably because of confounding that was not accounted for, Dr. Anderson speculated, since clinical trials have consistently shown that benefits from diabetes medications take a longer time to show an effect.
‘Important study,’ but lacked newer meds
This is an “important” study for primary care and in-hospital physicians that shows that “hospitalization is really not the time and the place” to intensify diabetes medication, Rozalina G. McCoy, MD, coauthor of an invited commentary, told this news organization in an interview.
“While overcoming treatment inertia is important, [it should be] done appropriately, so that we don’t overtreat patients,” Dr. McCoy, of the Mayo Clinic in Rochester, Minn., stressed.
The very low rate of persistence of taking intensified medications is a major finding, she agreed. Hospitalized patients “are not in their usual state of health, so if we make long-term treatment decisions based on their acute abnormal situation, that may not be appropriate.”
However, patients with high A1c may benefit from a change at hospital discharge rather than when they see their primary care provider, with the caveat that they need close follow-up as an outpatient.
The study emphasizes the “need for longitudinal patient care rather than episodic patches,” according to Dr. McCoy.
For example, a patient who is hospitalized for a chronic obstructive pulmonary disease or asthma exacerbation may be receiving steroids that cause high blood glucose levels but as soon as they’re done with their steroid course, blood glucose will decrease, so the “need for close outpatient follow-up is very important.”
One limitation of the current work is that an earlier study in the same population by the research group showed that 49% of patients whose treatment regimens were intensified had limited life expectancy or were at or below their A1c goal, so they would not have benefited from the stepped-up treatment, she noted.
Another limitation is that the findings cannot be generalized to women or younger patients, or to patients treated with glucagonlike peptide 1 (GLP-1)–receptor agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors.
The study patients were seen in the U.S. Veterans Health Administration health system when these newer agents were not used. Three-quarters of patients received intensified treatment with sulfonylurea or insulin, and only one patient received a new GLP-1–receptor agonist.
Ideally, Dr. McCoy said, patients should have been prescribed a GLP-1–receptor agonist if they had atherosclerotic cardiovascular disease or kidney disease, or an SGLT2 inhibitor if they had kidney disease or heart failure, which may have led to different results, and would need to be determined in further study.
Dr. Anderson agreed that “SGLT2 inhibitors and GLP1 agonists are broadly much safer than the older diabetes medicines, at least when it comes to risk of hypoglycemia, and may have more clear benefits in heart disease and mortality. So I would not want to extrapolate our findings to those new classes,” he said. “A similar set of studies would need to be done.”
Study rationale and findings
Hospitalized older adults with diabetes commonly have transiently elevated blood glucose levels that might lead clinicians to discharge them from hospital with a prescription for more intensive diabetes medications than they were on before they were hospitalized, but it is not clear if these diabetes medication changes would improve outcomes.
To investigate this, the researchers analyzed data from patients with diabetes who were 65 and older and hospitalized for common medical conditions in VHA hospitals during January 2011–September 2016, and then discharged to the community.
They excluded patients who were hospitalized for things that require immediate change in diabetes treatment and patients who were using insulin before their hospitalization (because instructions to modify insulin dosing frequently don’t have a new prescription).
The researchers identified 28,198 adults with diabetes who were not on insulin and were hospitalized in the VHA health system for heart failure (18%), coronary artery disease (13%), chronic obstructive pulmonary disease (10%), pneumonia (9.6%), and urinary tract infection (7.5%), and less often and not in decreasing order, for acute coronary syndrome, arrhythmia, asthma, chest pain, conduction disorders, heart valve disorders, sepsis, skin infection, stroke, and transient ischemic attack.
Of these patients, 2,768 patients (9.8%) received diabetes medication intensification, and the researchers matched 2,648 of these patients with an equal number of patients who did not receive this treatment intensification.
The patients in each group had a mean age of 73 and 98.5% were male; 78% were White.
They had a mean A1c of 7.9%. Most were receiving sulfonylurea (43%) or metformin (39%), and few were receiving thiazolidinediones (4.1%), alpha-glucosidase inhibitors (2.7%), dipeptidyl peptidase 4 inhibitors (2.0%), or other types of diabetes drugs (0.1%).
Of the 2,768 patients who received intensified diabetes medication, most received a prescription for insulin (51%) or sulfonylurea (23%).
In the propensity-matched cohort, patients with intensified diabetes medication had a higher rate of severe hypoglycemia at 30 days (1% vs. 0.5%), which translated into a significant twofold higher risk (hazard ratio, 2.17).
The rates of severe hypoglycemia at 1 year were similar in both groups (3.1% and 2.9%).
The incidence of severe hyperglycemia was the same in both groups at 30 days (0.3%) and 1 year (1.3%).
In secondary outcomes, at 1 year, 48% of new oral diabetes medications and 39% of new insulin prescriptions were no longer being filled.
Overall, patients who were discharged with intensified diabetes medication were significantly less likely to die within 30 days than the other patients (1.3% vs. 2.4%; HR, 0.55).
However, this mortality benefit was found only in the subgroup of 2,524 patients who had uncontrolled diabetes when they were admitted to hospital (A1c >7.5%; mean A1c, 9.1%), and not in the propensity-matched subgroup of 2,672 patients who had controlled diabetes then (A1c up to 7.5%; mean A1c, 6.8%).
There was no significant difference in 1-year mortality in patients with versus without intensified treatment (15.8% vs. 17.8%).
There were also no significant between-group difference in rates of hospital readmission at 30 days (roughly 17%) or 1 year (roughly 51%).
The decreases in mean A1c from hospital discharge to 1 year later were also the same in both groups (going from 7.9% to 7.7%).
The study was funded by grants from the National Institute on Aging and the American College of Cardiology. Dr. Anderson has no relevant financial disclosures. Dr. McCoy reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases, AARP, and the Patient-Centered Outcomes Research Institute outside the submitted work. The disclosures of the other authors and the editorial coauthor are available with the article and commentary.
“Short-term hospitalization [for reasons other than diabetes] may not be the time to intervene in long-term diabetes management,” researchers conclude.
They found that, in a national cohort of older almost entirely male veterans with non–insulin-treated type 2 diabetes who were hospitalized for non–diabetes-related common medical conditions, intensified diabetes treatment on hospital discharge was linked to an increased risk of severe hypoglycemia in the immediate postdischarge period.
However, diabetes treatment intensification – that is, receiving a prescription for a new or higher dose of diabetes medicine – was not associated with decreased risks of severe hyperglycemia or with improved glycemic (hemoglobin A1c) control at 30 days or 1 year, according to study results, published in JAMA Network Open.
“We didn’t see a reduction in diabetes emergencies in more intensively treated patients,” lead investigator Timothy S. Anderson, MD, said in an interview.
Also, importantly, there was a low rate of persistence with the new treatment. “Half of the patients were no longer taking these [intensified diabetes medicines] at 1 year, which tells me that context is key,” he pointed out. “If a patient is in the hospital for diabetes [unlike the patients in this study], I think it makes a lot of sense to modify and adjust their regimen to try to help them right then and there.”
The overall risk of severe hyperglycemia or severe hypoglycemia was pretty small in the overall cohort, Dr. Anderson noted, “but we do put people at risk of leaving the hospital and ending up back in the hospital with low blood sugar when we intensify medications, and there’s not necessarily a good signal to suggest that it’s all that urgent to change these medicines.”
Instead, the “safer path” may be to make recommendations to the patient’s outpatient physician and also inform the patient – for example, “We saw some concerns about your diabetes while you were in the hospital, and this is really something that should be looked at when you’re recovered and feeling better from the rest of your health standpoint” – rather than making a diabetes medication change while the person is acutely ill or recovering from illness, said Dr. Anderson, from Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.
The researchers also found an “unexpected” significant decrease in 30-day mortality in the patients with intensified diabetes treatment, which was probably because of confounding that was not accounted for, Dr. Anderson speculated, since clinical trials have consistently shown that benefits from diabetes medications take a longer time to show an effect.
‘Important study,’ but lacked newer meds
This is an “important” study for primary care and in-hospital physicians that shows that “hospitalization is really not the time and the place” to intensify diabetes medication, Rozalina G. McCoy, MD, coauthor of an invited commentary, told this news organization in an interview.
“While overcoming treatment inertia is important, [it should be] done appropriately, so that we don’t overtreat patients,” Dr. McCoy, of the Mayo Clinic in Rochester, Minn., stressed.
The very low rate of persistence of taking intensified medications is a major finding, she agreed. Hospitalized patients “are not in their usual state of health, so if we make long-term treatment decisions based on their acute abnormal situation, that may not be appropriate.”
However, patients with high A1c may benefit from a change at hospital discharge rather than when they see their primary care provider, with the caveat that they need close follow-up as an outpatient.
The study emphasizes the “need for longitudinal patient care rather than episodic patches,” according to Dr. McCoy.
For example, a patient who is hospitalized for a chronic obstructive pulmonary disease or asthma exacerbation may be receiving steroids that cause high blood glucose levels but as soon as they’re done with their steroid course, blood glucose will decrease, so the “need for close outpatient follow-up is very important.”
One limitation of the current work is that an earlier study in the same population by the research group showed that 49% of patients whose treatment regimens were intensified had limited life expectancy or were at or below their A1c goal, so they would not have benefited from the stepped-up treatment, she noted.
Another limitation is that the findings cannot be generalized to women or younger patients, or to patients treated with glucagonlike peptide 1 (GLP-1)–receptor agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors.
The study patients were seen in the U.S. Veterans Health Administration health system when these newer agents were not used. Three-quarters of patients received intensified treatment with sulfonylurea or insulin, and only one patient received a new GLP-1–receptor agonist.
Ideally, Dr. McCoy said, patients should have been prescribed a GLP-1–receptor agonist if they had atherosclerotic cardiovascular disease or kidney disease, or an SGLT2 inhibitor if they had kidney disease or heart failure, which may have led to different results, and would need to be determined in further study.
Dr. Anderson agreed that “SGLT2 inhibitors and GLP1 agonists are broadly much safer than the older diabetes medicines, at least when it comes to risk of hypoglycemia, and may have more clear benefits in heart disease and mortality. So I would not want to extrapolate our findings to those new classes,” he said. “A similar set of studies would need to be done.”
Study rationale and findings
Hospitalized older adults with diabetes commonly have transiently elevated blood glucose levels that might lead clinicians to discharge them from hospital with a prescription for more intensive diabetes medications than they were on before they were hospitalized, but it is not clear if these diabetes medication changes would improve outcomes.
To investigate this, the researchers analyzed data from patients with diabetes who were 65 and older and hospitalized for common medical conditions in VHA hospitals during January 2011–September 2016, and then discharged to the community.
They excluded patients who were hospitalized for things that require immediate change in diabetes treatment and patients who were using insulin before their hospitalization (because instructions to modify insulin dosing frequently don’t have a new prescription).
The researchers identified 28,198 adults with diabetes who were not on insulin and were hospitalized in the VHA health system for heart failure (18%), coronary artery disease (13%), chronic obstructive pulmonary disease (10%), pneumonia (9.6%), and urinary tract infection (7.5%), and less often and not in decreasing order, for acute coronary syndrome, arrhythmia, asthma, chest pain, conduction disorders, heart valve disorders, sepsis, skin infection, stroke, and transient ischemic attack.
Of these patients, 2,768 patients (9.8%) received diabetes medication intensification, and the researchers matched 2,648 of these patients with an equal number of patients who did not receive this treatment intensification.
The patients in each group had a mean age of 73 and 98.5% were male; 78% were White.
They had a mean A1c of 7.9%. Most were receiving sulfonylurea (43%) or metformin (39%), and few were receiving thiazolidinediones (4.1%), alpha-glucosidase inhibitors (2.7%), dipeptidyl peptidase 4 inhibitors (2.0%), or other types of diabetes drugs (0.1%).
Of the 2,768 patients who received intensified diabetes medication, most received a prescription for insulin (51%) or sulfonylurea (23%).
In the propensity-matched cohort, patients with intensified diabetes medication had a higher rate of severe hypoglycemia at 30 days (1% vs. 0.5%), which translated into a significant twofold higher risk (hazard ratio, 2.17).
The rates of severe hypoglycemia at 1 year were similar in both groups (3.1% and 2.9%).
The incidence of severe hyperglycemia was the same in both groups at 30 days (0.3%) and 1 year (1.3%).
In secondary outcomes, at 1 year, 48% of new oral diabetes medications and 39% of new insulin prescriptions were no longer being filled.
Overall, patients who were discharged with intensified diabetes medication were significantly less likely to die within 30 days than the other patients (1.3% vs. 2.4%; HR, 0.55).
However, this mortality benefit was found only in the subgroup of 2,524 patients who had uncontrolled diabetes when they were admitted to hospital (A1c >7.5%; mean A1c, 9.1%), and not in the propensity-matched subgroup of 2,672 patients who had controlled diabetes then (A1c up to 7.5%; mean A1c, 6.8%).
There was no significant difference in 1-year mortality in patients with versus without intensified treatment (15.8% vs. 17.8%).
There were also no significant between-group difference in rates of hospital readmission at 30 days (roughly 17%) or 1 year (roughly 51%).
The decreases in mean A1c from hospital discharge to 1 year later were also the same in both groups (going from 7.9% to 7.7%).
The study was funded by grants from the National Institute on Aging and the American College of Cardiology. Dr. Anderson has no relevant financial disclosures. Dr. McCoy reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases, AARP, and the Patient-Centered Outcomes Research Institute outside the submitted work. The disclosures of the other authors and the editorial coauthor are available with the article and commentary.
“Short-term hospitalization [for reasons other than diabetes] may not be the time to intervene in long-term diabetes management,” researchers conclude.
They found that, in a national cohort of older almost entirely male veterans with non–insulin-treated type 2 diabetes who were hospitalized for non–diabetes-related common medical conditions, intensified diabetes treatment on hospital discharge was linked to an increased risk of severe hypoglycemia in the immediate postdischarge period.
However, diabetes treatment intensification – that is, receiving a prescription for a new or higher dose of diabetes medicine – was not associated with decreased risks of severe hyperglycemia or with improved glycemic (hemoglobin A1c) control at 30 days or 1 year, according to study results, published in JAMA Network Open.
“We didn’t see a reduction in diabetes emergencies in more intensively treated patients,” lead investigator Timothy S. Anderson, MD, said in an interview.
Also, importantly, there was a low rate of persistence with the new treatment. “Half of the patients were no longer taking these [intensified diabetes medicines] at 1 year, which tells me that context is key,” he pointed out. “If a patient is in the hospital for diabetes [unlike the patients in this study], I think it makes a lot of sense to modify and adjust their regimen to try to help them right then and there.”
The overall risk of severe hyperglycemia or severe hypoglycemia was pretty small in the overall cohort, Dr. Anderson noted, “but we do put people at risk of leaving the hospital and ending up back in the hospital with low blood sugar when we intensify medications, and there’s not necessarily a good signal to suggest that it’s all that urgent to change these medicines.”
Instead, the “safer path” may be to make recommendations to the patient’s outpatient physician and also inform the patient – for example, “We saw some concerns about your diabetes while you were in the hospital, and this is really something that should be looked at when you’re recovered and feeling better from the rest of your health standpoint” – rather than making a diabetes medication change while the person is acutely ill or recovering from illness, said Dr. Anderson, from Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.
The researchers also found an “unexpected” significant decrease in 30-day mortality in the patients with intensified diabetes treatment, which was probably because of confounding that was not accounted for, Dr. Anderson speculated, since clinical trials have consistently shown that benefits from diabetes medications take a longer time to show an effect.
‘Important study,’ but lacked newer meds
This is an “important” study for primary care and in-hospital physicians that shows that “hospitalization is really not the time and the place” to intensify diabetes medication, Rozalina G. McCoy, MD, coauthor of an invited commentary, told this news organization in an interview.
“While overcoming treatment inertia is important, [it should be] done appropriately, so that we don’t overtreat patients,” Dr. McCoy, of the Mayo Clinic in Rochester, Minn., stressed.
The very low rate of persistence of taking intensified medications is a major finding, she agreed. Hospitalized patients “are not in their usual state of health, so if we make long-term treatment decisions based on their acute abnormal situation, that may not be appropriate.”
However, patients with high A1c may benefit from a change at hospital discharge rather than when they see their primary care provider, with the caveat that they need close follow-up as an outpatient.
The study emphasizes the “need for longitudinal patient care rather than episodic patches,” according to Dr. McCoy.
For example, a patient who is hospitalized for a chronic obstructive pulmonary disease or asthma exacerbation may be receiving steroids that cause high blood glucose levels but as soon as they’re done with their steroid course, blood glucose will decrease, so the “need for close outpatient follow-up is very important.”
One limitation of the current work is that an earlier study in the same population by the research group showed that 49% of patients whose treatment regimens were intensified had limited life expectancy or were at or below their A1c goal, so they would not have benefited from the stepped-up treatment, she noted.
Another limitation is that the findings cannot be generalized to women or younger patients, or to patients treated with glucagonlike peptide 1 (GLP-1)–receptor agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors.
The study patients were seen in the U.S. Veterans Health Administration health system when these newer agents were not used. Three-quarters of patients received intensified treatment with sulfonylurea or insulin, and only one patient received a new GLP-1–receptor agonist.
Ideally, Dr. McCoy said, patients should have been prescribed a GLP-1–receptor agonist if they had atherosclerotic cardiovascular disease or kidney disease, or an SGLT2 inhibitor if they had kidney disease or heart failure, which may have led to different results, and would need to be determined in further study.
Dr. Anderson agreed that “SGLT2 inhibitors and GLP1 agonists are broadly much safer than the older diabetes medicines, at least when it comes to risk of hypoglycemia, and may have more clear benefits in heart disease and mortality. So I would not want to extrapolate our findings to those new classes,” he said. “A similar set of studies would need to be done.”
Study rationale and findings
Hospitalized older adults with diabetes commonly have transiently elevated blood glucose levels that might lead clinicians to discharge them from hospital with a prescription for more intensive diabetes medications than they were on before they were hospitalized, but it is not clear if these diabetes medication changes would improve outcomes.
To investigate this, the researchers analyzed data from patients with diabetes who were 65 and older and hospitalized for common medical conditions in VHA hospitals during January 2011–September 2016, and then discharged to the community.
They excluded patients who were hospitalized for things that require immediate change in diabetes treatment and patients who were using insulin before their hospitalization (because instructions to modify insulin dosing frequently don’t have a new prescription).
The researchers identified 28,198 adults with diabetes who were not on insulin and were hospitalized in the VHA health system for heart failure (18%), coronary artery disease (13%), chronic obstructive pulmonary disease (10%), pneumonia (9.6%), and urinary tract infection (7.5%), and less often and not in decreasing order, for acute coronary syndrome, arrhythmia, asthma, chest pain, conduction disorders, heart valve disorders, sepsis, skin infection, stroke, and transient ischemic attack.
Of these patients, 2,768 patients (9.8%) received diabetes medication intensification, and the researchers matched 2,648 of these patients with an equal number of patients who did not receive this treatment intensification.
The patients in each group had a mean age of 73 and 98.5% were male; 78% were White.
They had a mean A1c of 7.9%. Most were receiving sulfonylurea (43%) or metformin (39%), and few were receiving thiazolidinediones (4.1%), alpha-glucosidase inhibitors (2.7%), dipeptidyl peptidase 4 inhibitors (2.0%), or other types of diabetes drugs (0.1%).
Of the 2,768 patients who received intensified diabetes medication, most received a prescription for insulin (51%) or sulfonylurea (23%).
In the propensity-matched cohort, patients with intensified diabetes medication had a higher rate of severe hypoglycemia at 30 days (1% vs. 0.5%), which translated into a significant twofold higher risk (hazard ratio, 2.17).
The rates of severe hypoglycemia at 1 year were similar in both groups (3.1% and 2.9%).
The incidence of severe hyperglycemia was the same in both groups at 30 days (0.3%) and 1 year (1.3%).
In secondary outcomes, at 1 year, 48% of new oral diabetes medications and 39% of new insulin prescriptions were no longer being filled.
Overall, patients who were discharged with intensified diabetes medication were significantly less likely to die within 30 days than the other patients (1.3% vs. 2.4%; HR, 0.55).
However, this mortality benefit was found only in the subgroup of 2,524 patients who had uncontrolled diabetes when they were admitted to hospital (A1c >7.5%; mean A1c, 9.1%), and not in the propensity-matched subgroup of 2,672 patients who had controlled diabetes then (A1c up to 7.5%; mean A1c, 6.8%).
There was no significant difference in 1-year mortality in patients with versus without intensified treatment (15.8% vs. 17.8%).
There were also no significant between-group difference in rates of hospital readmission at 30 days (roughly 17%) or 1 year (roughly 51%).
The decreases in mean A1c from hospital discharge to 1 year later were also the same in both groups (going from 7.9% to 7.7%).
The study was funded by grants from the National Institute on Aging and the American College of Cardiology. Dr. Anderson has no relevant financial disclosures. Dr. McCoy reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases, AARP, and the Patient-Centered Outcomes Research Institute outside the submitted work. The disclosures of the other authors and the editorial coauthor are available with the article and commentary.
FROM JAMA NETWORK OPEN
Lung cancer screening rates in U.S. nowhere near goal
according to a review and meta-analysis published in the Journal of Thoracic Oncology.
“Lung cancer screening is effective in reducing mortality, particularly when patients adhere to follow-up recommendations standardized by the Lung CT Screening Reporting & Data System (Lung-RADS),” Yannan Lin, MD, MPH, of the University of California, Los Angeles, and colleagues wrote. ”Patient adherence to Lung-RADS–recommended screening intervals is suboptimal across clinical lung cancer screening programs in the U.S., especially among patients with Lung-RADS category 1-2 results.”
Lung cancer screening can identify tumors at earlier, more treatable stages, but patients with lung cancer diagnoses based on new nodules at incidence screening have shown shortened survivals. The National Lung Screening Trial (NLST) has shown a 20% relative reduction in lung cancer mortality with low-dose chest CT screening relative to chest radiography. The Lung-RADS guidelines to standardize the reporting of lung cancer screening were developed based on findings from the NLST and other screening studies, partly to reduce false-positive rates. Lung-RADS scores are based upon nodule size, characteristics and location, with management guidelines specific to Lung-RADS categories, ranging from low-dose chest CT in 12 months for Lung-RADS 1-2 to chest CT, PET/CT, or tissue sampling for Lung-RADS 4B/X.
The rate of adherence to lung cancer screening based on Lung-RADS guidelines is unclear. This systematic review and meta-analysis looked at patient adherence to Lung-RADS recommended screening intervals in clinical practice.
The meta-analysis included 21 studies. The pooled adherence rate was 57% for defined adherence, which included an annual incidence screen performed within 15 months, among 6,689 patients and 65% for anytime adherence among 5,085 patients. The authors noted that overall rates of adherence to Lung-RADS recommended screening intervals in clinical practices is low as compared with the over 90% adherence seen in the NLST, adversely affecting the mortality benefits of lung cancer screening.
Higher adherence rates were found in patients with Lung-RADS 3 (risk for lung cancer, 1%-2%) and 4 (risk, >5%) than Lung-RADS 1 and 2 (risk, <1%; P < .05), which the authors said suggests that tailored interventions based on Lung-RADS categories may be beneficial.
“It is likely that patients and referrers are more concerned about nodules at a higher risk for lung cancer, prompting greater adherence to recommended screening intervals in Lung-RADS 3-4,” the authors wrote. “It is crucial that patients and referrers alike understand that screening is most effective when performed regularly, including for those with negative baseline screens, as de novo nodules, those detected after a negative screen, are more aggressive than those detected at baseline screen.”
These low adherence rates seen in the clinical practices could be explained by patient characteristics, insurance coverage and interventions to ensure adherence, among other factors.
Further, inconsistent reporting of adherence rates was observed. Standardized reporting of adherence rates to lung cancer screening is needed to identify interventions to improve adherence, the authors wrote.
The authors of this study noted no conflicts of interest.
according to a review and meta-analysis published in the Journal of Thoracic Oncology.
“Lung cancer screening is effective in reducing mortality, particularly when patients adhere to follow-up recommendations standardized by the Lung CT Screening Reporting & Data System (Lung-RADS),” Yannan Lin, MD, MPH, of the University of California, Los Angeles, and colleagues wrote. ”Patient adherence to Lung-RADS–recommended screening intervals is suboptimal across clinical lung cancer screening programs in the U.S., especially among patients with Lung-RADS category 1-2 results.”
Lung cancer screening can identify tumors at earlier, more treatable stages, but patients with lung cancer diagnoses based on new nodules at incidence screening have shown shortened survivals. The National Lung Screening Trial (NLST) has shown a 20% relative reduction in lung cancer mortality with low-dose chest CT screening relative to chest radiography. The Lung-RADS guidelines to standardize the reporting of lung cancer screening were developed based on findings from the NLST and other screening studies, partly to reduce false-positive rates. Lung-RADS scores are based upon nodule size, characteristics and location, with management guidelines specific to Lung-RADS categories, ranging from low-dose chest CT in 12 months for Lung-RADS 1-2 to chest CT, PET/CT, or tissue sampling for Lung-RADS 4B/X.
The rate of adherence to lung cancer screening based on Lung-RADS guidelines is unclear. This systematic review and meta-analysis looked at patient adherence to Lung-RADS recommended screening intervals in clinical practice.
The meta-analysis included 21 studies. The pooled adherence rate was 57% for defined adherence, which included an annual incidence screen performed within 15 months, among 6,689 patients and 65% for anytime adherence among 5,085 patients. The authors noted that overall rates of adherence to Lung-RADS recommended screening intervals in clinical practices is low as compared with the over 90% adherence seen in the NLST, adversely affecting the mortality benefits of lung cancer screening.
Higher adherence rates were found in patients with Lung-RADS 3 (risk for lung cancer, 1%-2%) and 4 (risk, >5%) than Lung-RADS 1 and 2 (risk, <1%; P < .05), which the authors said suggests that tailored interventions based on Lung-RADS categories may be beneficial.
“It is likely that patients and referrers are more concerned about nodules at a higher risk for lung cancer, prompting greater adherence to recommended screening intervals in Lung-RADS 3-4,” the authors wrote. “It is crucial that patients and referrers alike understand that screening is most effective when performed regularly, including for those with negative baseline screens, as de novo nodules, those detected after a negative screen, are more aggressive than those detected at baseline screen.”
These low adherence rates seen in the clinical practices could be explained by patient characteristics, insurance coverage and interventions to ensure adherence, among other factors.
Further, inconsistent reporting of adherence rates was observed. Standardized reporting of adherence rates to lung cancer screening is needed to identify interventions to improve adherence, the authors wrote.
The authors of this study noted no conflicts of interest.
according to a review and meta-analysis published in the Journal of Thoracic Oncology.
“Lung cancer screening is effective in reducing mortality, particularly when patients adhere to follow-up recommendations standardized by the Lung CT Screening Reporting & Data System (Lung-RADS),” Yannan Lin, MD, MPH, of the University of California, Los Angeles, and colleagues wrote. ”Patient adherence to Lung-RADS–recommended screening intervals is suboptimal across clinical lung cancer screening programs in the U.S., especially among patients with Lung-RADS category 1-2 results.”
Lung cancer screening can identify tumors at earlier, more treatable stages, but patients with lung cancer diagnoses based on new nodules at incidence screening have shown shortened survivals. The National Lung Screening Trial (NLST) has shown a 20% relative reduction in lung cancer mortality with low-dose chest CT screening relative to chest radiography. The Lung-RADS guidelines to standardize the reporting of lung cancer screening were developed based on findings from the NLST and other screening studies, partly to reduce false-positive rates. Lung-RADS scores are based upon nodule size, characteristics and location, with management guidelines specific to Lung-RADS categories, ranging from low-dose chest CT in 12 months for Lung-RADS 1-2 to chest CT, PET/CT, or tissue sampling for Lung-RADS 4B/X.
The rate of adherence to lung cancer screening based on Lung-RADS guidelines is unclear. This systematic review and meta-analysis looked at patient adherence to Lung-RADS recommended screening intervals in clinical practice.
The meta-analysis included 21 studies. The pooled adherence rate was 57% for defined adherence, which included an annual incidence screen performed within 15 months, among 6,689 patients and 65% for anytime adherence among 5,085 patients. The authors noted that overall rates of adherence to Lung-RADS recommended screening intervals in clinical practices is low as compared with the over 90% adherence seen in the NLST, adversely affecting the mortality benefits of lung cancer screening.
Higher adherence rates were found in patients with Lung-RADS 3 (risk for lung cancer, 1%-2%) and 4 (risk, >5%) than Lung-RADS 1 and 2 (risk, <1%; P < .05), which the authors said suggests that tailored interventions based on Lung-RADS categories may be beneficial.
“It is likely that patients and referrers are more concerned about nodules at a higher risk for lung cancer, prompting greater adherence to recommended screening intervals in Lung-RADS 3-4,” the authors wrote. “It is crucial that patients and referrers alike understand that screening is most effective when performed regularly, including for those with negative baseline screens, as de novo nodules, those detected after a negative screen, are more aggressive than those detected at baseline screen.”
These low adherence rates seen in the clinical practices could be explained by patient characteristics, insurance coverage and interventions to ensure adherence, among other factors.
Further, inconsistent reporting of adherence rates was observed. Standardized reporting of adherence rates to lung cancer screening is needed to identify interventions to improve adherence, the authors wrote.
The authors of this study noted no conflicts of interest.
FROM THE JOURNAL OF THORACIC ONCOLOGY
Spiders, dogs, and PTSD: A virtual treatment for phobias and fear
At Wayne State University’s Stress, Trauma, and Anxiety Research Clinic (STARC) in Michigan, researchers are developing novel interventions for treating some very ancient phobias hardwired into the human brain. By using augmented reality as means of conducting exposure therapy, STARC researchers – including Shantanu Madaboosi, Rakesh Ramaswamy, and Lana Grasser – and STARC director Arash Javanbakht, MD, have produced compelling evidence that they can free patients of their often debilitating fears of spiders, dogs, and snakes. Yet their work doesn’t stop there, and research into treating anxiety and posttraumatic stress disorder among first responders and others with high-stress occupations is ongoing.
This news organization spoke with Dr. Javanbakht, a psychiatrist, about the technological advances that have made this work possible; the future of remote-based psychiatry; and his tarantula colleague, Tony.
Augmenting exposure therapy
How did you begin using artificial intelligence as a way of delivering exposure therapy?
Exposure therapy is a very effective treatment for phobias, obsessive-compulsive disorder, and PTSD. But the problem we had is that, if someone comes to me and says they’re afraid of dogs, snakes, or spiders, I don’t have those in my office. Or, if its social phobia, I can’t create those scenarios. So, despite being such an effective treatment, it’s not utilized as much as it should be.
Several years ago, I saw a TED talk by the CEO of an augmented reality company who happened to be a neuroscientist. I thought the concept was amazing, because it offered a way to overcome those limitations.
Mixed augmented reality allows us to bring all those feared objects to the clinic. I can bring my Labrador to the office for someone who’s afraid of dogs, and they can get the exposure to that one dog. But we know good exposure therapy needs to be generalizable, with as many different breeds of dogs as possible, and is context dependent. If the patient sees a dog in their neighborhood, their fear response may come back. Doing it in a real-life context, and offering as many contexts as possible, makes it more effective.
Augmented reality allows all of these options because you can have as many different types of virtual objects as you want, and the difference between augmented reality and virtual reality is that augmented reality happens in a real-life context. You wear the goggles and you can walk around the environment and track the object, so the context is more realistic.
When did you begin researching augmented reality as a clinical tool?
I became a faculty member here in 2015, right out of my residency training, and I think it was around 2016 or 2017 that we began this work.
I’m very much involved in exposure therapy, utilize it myself, train others, and research how it works and changes the brain. I knew the ins and outs and what would make a better exposure therapy, based on my knowledge of neuroscience.
We spend time thinking about how we can apply these neuroscientific principles in software that can also be easily used by a not very technologically savvy therapist. Because that has been a big barrier when it comes to technology and human use in medicine.
Initially, we had a company create the software for us, but we’ve since brought all the programming inside.
The cool thing about these augmented reality devices is that they have excellent surface mapping. As soon as the person wears the goggles, it automatically maps the surfaces and provides a 3D view of the patient’s environment on the therapist’s computer. Say you’re treating a patient with a fear of spiders. Through drop-down menus, the therapist can choose what type of spider, its color and size, where it should be placed, and the motion. I can choose to move the spider from 6 feet away on the floor to the walls to the ceiling.
Virtual phobias, real fear
A big question for a lot of people was if the spiders are virtual, will they be scary, because it has to be realistic enough to create a fear response for the therapy to work. We use a couple of wires that you can put on a person’s finger and hook them up to a tablet or a cell phone. This provides an online measure of a person’s autonomic sympathetic response.
Like a lie detector test?
Exactly. We put that on their fingers and exposed them to a real-life tarantula and to our virtual tarantulas, and the fear response was no different. That means these do create an objective fear reaction in the body.
We also had people who said, “I know this is not real. I won’t be scared.” And when we started the therapy, it was with a tiny spider 5 meters away from them, and they’d lift their legs off the floor.
With the treatment, we’d come to one room and start with a very little spider, far from them. Then gradually we move them up to bigger, more diverse types of spiders, which are moving around. The patient comes near and tries to touch them.
Then at some point, I’d put a spiderweb on the door, put a few spiders on that, open the door, and have the patient walk through it. They kept walking through this spiderweb.
When they were desensitized to these spiders in this context – and as I said, context is important – we’d go to another room. This was darker, more like a basement, and we’d continue the same thing. That would actually take much less time because they already had desensitized a lot.
In our field, sense of control is very important, especially for when a patient goes home. So at the end, I’d leave the room and talk to the patient via a baby monitor. The patient was surrounded by 20 tarantulas, without the prompt moving around the environment.
Now that they’re desensitized to my virtual spiders, the question is, how would that apply to a real spider? So, we had a real live tarantula, whose name was Tony Stark, because we’re the STARC lab. We’d put Tony at the end of a long hallway before the treatment and see how close the patients could get to him.
It was only one treatment session; nobody’s was longer than 1 hour, and the average treatment time was 38 minutes.
That’s pretty effective.
It’s pretty good, compared with other studies. And I believe this is because of all the components I mentioned: being able to use your real environment; combining it with the real tarantula; the variety of the types of the feared objects; and, of course, giving the patient a sense of autonomy at the end.
Then we had to see how prolonged the effects are. We had them come in 1 week and 1 month after the treatment. I’d remind them of the principles of good exposure therapy and ask them to keep practicing at home between the sessions, looking at pictures and videos. But we never tested who did or did not do it.
After 1 week and 1 month, the effects were either the same or better. A larger number of people at 1 month were able to touch the tarantula than right after treatment.
Treating PTSD in first responders
Did you start with spiders and dogs because those are common fears?
We started with spiders because that worked with the initial goal of creating a prototype. Spiders’ behavior is simple enough for the programming, which takes a lot of time. Another reason for choosing spiders was that we had a lot of other studies of real and virtual reality exposure therapy to compare against.
I think another reason for our success is that, when you do real exposure therapy, you have just one scared tarantula in the corner of their tank, and they don’t listen to you. But my spiders listen to me and do exactly what I tell them.
After our initial success, we obtained more funds to expand it to other phobias. The cool thing is that we don’t need separate software for different phobias. You can choose dogs or snakes, add it to the person’s environment, and decide their behaviors.
We just started a clinical trial using dogs, and another group in Turkey is running a clinical trial with dogs. Eastern Michigan University is working with spiders. And a clinic at the University of Nebraska Medical Center is going to start using them in real-world clinics, not for research.
We have another project whose goal is helping reduce the impact of trauma and also treating PTSD in first responders, who are exposed to a lot of horrible things. Rates of PTSD are around 20%-30% among cops, firefighters, and EMS personnel.
They commonly find it very painful being in crowds because the fight-or-flight instinct in the brain is constantly screening for any sign of threat in their environment. We’re working on them walking into an empty room wearing the goggles, and then their therapist can scale the stimulus up and down.
There’ll be two people in front of you talking to each other, and then another group comes in, and people get louder. People can look at you and talk to you. There’s kids running, Fourth of July fireworks, and other things that might bother someone who’s been involved in gun- or explosion-related traumas. You gradually scale up when the person is next to their therapist.
Another thing we’re doing is related to cardiopulmonary resuscitation. If a young person dies in a CPR situation, that is really painful and traumatic. So, for exposure therapy to that, we’re creating a difficult CPR scenario when that person may die. The responder wears the goggles and basically watches a group of people doing CPR while standing next to a therapist who can help them navigate it and then scale it off.
Another goal is combining this with telemedicine, where the person can do it in their real-life environment. Imagine a person with military trauma. You can put them back in the barracks, connected with their psychiatrists via telemedicine. Then we would put humans in military fatigues near them and have them interact with them to feel comfortable with that situation.
What else is next for you and your group?
The next biggest challenge that we’re tackling is PTSD, because of course creating human-encounter scenarios is much more complicated than spiders and dogs. We’re in the midst of developing this so we can basically bring it to people’s homes.
We’ve been working with some military personnel to see if we can basically give a device to a veteran with PTSD, so they can go home and practice on their own.
There’s another possibility for training. Let’s take the example of a police force, which can have a lot of difficulties and mistakes because of lack of exposure and training. They can wear these goggles, get fully geared up, and be placed in encounters with people of different backgrounds, of different severity, with people who could be severely mentally ill or present different challenges for the officers.
Those situations can teach them a lot. I’m the creator of this thing, but even I’m often surprised by how realistic this technology can be. I find myself interacting with avatars the same way I would if they were real humans. I actually had one of my colleagues, when we started launching the programming with the dogs, immediately jump back. It’s just like the animal brain reacts to them.
Last question: Do you actually interact with Tony, the tarantula?
Oh, Tony is my friend. Unfortunately, he’s not with our lab at this moment. He’s on a sabbatical at Eastern Michigan University for their clinical trials. But yes, I’ve held him. He’s very friendly.
A version of this article first appeared on Medscape.com.
At Wayne State University’s Stress, Trauma, and Anxiety Research Clinic (STARC) in Michigan, researchers are developing novel interventions for treating some very ancient phobias hardwired into the human brain. By using augmented reality as means of conducting exposure therapy, STARC researchers – including Shantanu Madaboosi, Rakesh Ramaswamy, and Lana Grasser – and STARC director Arash Javanbakht, MD, have produced compelling evidence that they can free patients of their often debilitating fears of spiders, dogs, and snakes. Yet their work doesn’t stop there, and research into treating anxiety and posttraumatic stress disorder among first responders and others with high-stress occupations is ongoing.
This news organization spoke with Dr. Javanbakht, a psychiatrist, about the technological advances that have made this work possible; the future of remote-based psychiatry; and his tarantula colleague, Tony.
Augmenting exposure therapy
How did you begin using artificial intelligence as a way of delivering exposure therapy?
Exposure therapy is a very effective treatment for phobias, obsessive-compulsive disorder, and PTSD. But the problem we had is that, if someone comes to me and says they’re afraid of dogs, snakes, or spiders, I don’t have those in my office. Or, if its social phobia, I can’t create those scenarios. So, despite being such an effective treatment, it’s not utilized as much as it should be.
Several years ago, I saw a TED talk by the CEO of an augmented reality company who happened to be a neuroscientist. I thought the concept was amazing, because it offered a way to overcome those limitations.
Mixed augmented reality allows us to bring all those feared objects to the clinic. I can bring my Labrador to the office for someone who’s afraid of dogs, and they can get the exposure to that one dog. But we know good exposure therapy needs to be generalizable, with as many different breeds of dogs as possible, and is context dependent. If the patient sees a dog in their neighborhood, their fear response may come back. Doing it in a real-life context, and offering as many contexts as possible, makes it more effective.
Augmented reality allows all of these options because you can have as many different types of virtual objects as you want, and the difference between augmented reality and virtual reality is that augmented reality happens in a real-life context. You wear the goggles and you can walk around the environment and track the object, so the context is more realistic.
When did you begin researching augmented reality as a clinical tool?
I became a faculty member here in 2015, right out of my residency training, and I think it was around 2016 or 2017 that we began this work.
I’m very much involved in exposure therapy, utilize it myself, train others, and research how it works and changes the brain. I knew the ins and outs and what would make a better exposure therapy, based on my knowledge of neuroscience.
We spend time thinking about how we can apply these neuroscientific principles in software that can also be easily used by a not very technologically savvy therapist. Because that has been a big barrier when it comes to technology and human use in medicine.
Initially, we had a company create the software for us, but we’ve since brought all the programming inside.
The cool thing about these augmented reality devices is that they have excellent surface mapping. As soon as the person wears the goggles, it automatically maps the surfaces and provides a 3D view of the patient’s environment on the therapist’s computer. Say you’re treating a patient with a fear of spiders. Through drop-down menus, the therapist can choose what type of spider, its color and size, where it should be placed, and the motion. I can choose to move the spider from 6 feet away on the floor to the walls to the ceiling.
Virtual phobias, real fear
A big question for a lot of people was if the spiders are virtual, will they be scary, because it has to be realistic enough to create a fear response for the therapy to work. We use a couple of wires that you can put on a person’s finger and hook them up to a tablet or a cell phone. This provides an online measure of a person’s autonomic sympathetic response.
Like a lie detector test?
Exactly. We put that on their fingers and exposed them to a real-life tarantula and to our virtual tarantulas, and the fear response was no different. That means these do create an objective fear reaction in the body.
We also had people who said, “I know this is not real. I won’t be scared.” And when we started the therapy, it was with a tiny spider 5 meters away from them, and they’d lift their legs off the floor.
With the treatment, we’d come to one room and start with a very little spider, far from them. Then gradually we move them up to bigger, more diverse types of spiders, which are moving around. The patient comes near and tries to touch them.
Then at some point, I’d put a spiderweb on the door, put a few spiders on that, open the door, and have the patient walk through it. They kept walking through this spiderweb.
When they were desensitized to these spiders in this context – and as I said, context is important – we’d go to another room. This was darker, more like a basement, and we’d continue the same thing. That would actually take much less time because they already had desensitized a lot.
In our field, sense of control is very important, especially for when a patient goes home. So at the end, I’d leave the room and talk to the patient via a baby monitor. The patient was surrounded by 20 tarantulas, without the prompt moving around the environment.
Now that they’re desensitized to my virtual spiders, the question is, how would that apply to a real spider? So, we had a real live tarantula, whose name was Tony Stark, because we’re the STARC lab. We’d put Tony at the end of a long hallway before the treatment and see how close the patients could get to him.
It was only one treatment session; nobody’s was longer than 1 hour, and the average treatment time was 38 minutes.
That’s pretty effective.
It’s pretty good, compared with other studies. And I believe this is because of all the components I mentioned: being able to use your real environment; combining it with the real tarantula; the variety of the types of the feared objects; and, of course, giving the patient a sense of autonomy at the end.
Then we had to see how prolonged the effects are. We had them come in 1 week and 1 month after the treatment. I’d remind them of the principles of good exposure therapy and ask them to keep practicing at home between the sessions, looking at pictures and videos. But we never tested who did or did not do it.
After 1 week and 1 month, the effects were either the same or better. A larger number of people at 1 month were able to touch the tarantula than right after treatment.
Treating PTSD in first responders
Did you start with spiders and dogs because those are common fears?
We started with spiders because that worked with the initial goal of creating a prototype. Spiders’ behavior is simple enough for the programming, which takes a lot of time. Another reason for choosing spiders was that we had a lot of other studies of real and virtual reality exposure therapy to compare against.
I think another reason for our success is that, when you do real exposure therapy, you have just one scared tarantula in the corner of their tank, and they don’t listen to you. But my spiders listen to me and do exactly what I tell them.
After our initial success, we obtained more funds to expand it to other phobias. The cool thing is that we don’t need separate software for different phobias. You can choose dogs or snakes, add it to the person’s environment, and decide their behaviors.
We just started a clinical trial using dogs, and another group in Turkey is running a clinical trial with dogs. Eastern Michigan University is working with spiders. And a clinic at the University of Nebraska Medical Center is going to start using them in real-world clinics, not for research.
We have another project whose goal is helping reduce the impact of trauma and also treating PTSD in first responders, who are exposed to a lot of horrible things. Rates of PTSD are around 20%-30% among cops, firefighters, and EMS personnel.
They commonly find it very painful being in crowds because the fight-or-flight instinct in the brain is constantly screening for any sign of threat in their environment. We’re working on them walking into an empty room wearing the goggles, and then their therapist can scale the stimulus up and down.
There’ll be two people in front of you talking to each other, and then another group comes in, and people get louder. People can look at you and talk to you. There’s kids running, Fourth of July fireworks, and other things that might bother someone who’s been involved in gun- or explosion-related traumas. You gradually scale up when the person is next to their therapist.
Another thing we’re doing is related to cardiopulmonary resuscitation. If a young person dies in a CPR situation, that is really painful and traumatic. So, for exposure therapy to that, we’re creating a difficult CPR scenario when that person may die. The responder wears the goggles and basically watches a group of people doing CPR while standing next to a therapist who can help them navigate it and then scale it off.
Another goal is combining this with telemedicine, where the person can do it in their real-life environment. Imagine a person with military trauma. You can put them back in the barracks, connected with their psychiatrists via telemedicine. Then we would put humans in military fatigues near them and have them interact with them to feel comfortable with that situation.
What else is next for you and your group?
The next biggest challenge that we’re tackling is PTSD, because of course creating human-encounter scenarios is much more complicated than spiders and dogs. We’re in the midst of developing this so we can basically bring it to people’s homes.
We’ve been working with some military personnel to see if we can basically give a device to a veteran with PTSD, so they can go home and practice on their own.
There’s another possibility for training. Let’s take the example of a police force, which can have a lot of difficulties and mistakes because of lack of exposure and training. They can wear these goggles, get fully geared up, and be placed in encounters with people of different backgrounds, of different severity, with people who could be severely mentally ill or present different challenges for the officers.
Those situations can teach them a lot. I’m the creator of this thing, but even I’m often surprised by how realistic this technology can be. I find myself interacting with avatars the same way I would if they were real humans. I actually had one of my colleagues, when we started launching the programming with the dogs, immediately jump back. It’s just like the animal brain reacts to them.
Last question: Do you actually interact with Tony, the tarantula?
Oh, Tony is my friend. Unfortunately, he’s not with our lab at this moment. He’s on a sabbatical at Eastern Michigan University for their clinical trials. But yes, I’ve held him. He’s very friendly.
A version of this article first appeared on Medscape.com.
At Wayne State University’s Stress, Trauma, and Anxiety Research Clinic (STARC) in Michigan, researchers are developing novel interventions for treating some very ancient phobias hardwired into the human brain. By using augmented reality as means of conducting exposure therapy, STARC researchers – including Shantanu Madaboosi, Rakesh Ramaswamy, and Lana Grasser – and STARC director Arash Javanbakht, MD, have produced compelling evidence that they can free patients of their often debilitating fears of spiders, dogs, and snakes. Yet their work doesn’t stop there, and research into treating anxiety and posttraumatic stress disorder among first responders and others with high-stress occupations is ongoing.
This news organization spoke with Dr. Javanbakht, a psychiatrist, about the technological advances that have made this work possible; the future of remote-based psychiatry; and his tarantula colleague, Tony.
Augmenting exposure therapy
How did you begin using artificial intelligence as a way of delivering exposure therapy?
Exposure therapy is a very effective treatment for phobias, obsessive-compulsive disorder, and PTSD. But the problem we had is that, if someone comes to me and says they’re afraid of dogs, snakes, or spiders, I don’t have those in my office. Or, if its social phobia, I can’t create those scenarios. So, despite being such an effective treatment, it’s not utilized as much as it should be.
Several years ago, I saw a TED talk by the CEO of an augmented reality company who happened to be a neuroscientist. I thought the concept was amazing, because it offered a way to overcome those limitations.
Mixed augmented reality allows us to bring all those feared objects to the clinic. I can bring my Labrador to the office for someone who’s afraid of dogs, and they can get the exposure to that one dog. But we know good exposure therapy needs to be generalizable, with as many different breeds of dogs as possible, and is context dependent. If the patient sees a dog in their neighborhood, their fear response may come back. Doing it in a real-life context, and offering as many contexts as possible, makes it more effective.
Augmented reality allows all of these options because you can have as many different types of virtual objects as you want, and the difference between augmented reality and virtual reality is that augmented reality happens in a real-life context. You wear the goggles and you can walk around the environment and track the object, so the context is more realistic.
When did you begin researching augmented reality as a clinical tool?
I became a faculty member here in 2015, right out of my residency training, and I think it was around 2016 or 2017 that we began this work.
I’m very much involved in exposure therapy, utilize it myself, train others, and research how it works and changes the brain. I knew the ins and outs and what would make a better exposure therapy, based on my knowledge of neuroscience.
We spend time thinking about how we can apply these neuroscientific principles in software that can also be easily used by a not very technologically savvy therapist. Because that has been a big barrier when it comes to technology and human use in medicine.
Initially, we had a company create the software for us, but we’ve since brought all the programming inside.
The cool thing about these augmented reality devices is that they have excellent surface mapping. As soon as the person wears the goggles, it automatically maps the surfaces and provides a 3D view of the patient’s environment on the therapist’s computer. Say you’re treating a patient with a fear of spiders. Through drop-down menus, the therapist can choose what type of spider, its color and size, where it should be placed, and the motion. I can choose to move the spider from 6 feet away on the floor to the walls to the ceiling.
Virtual phobias, real fear
A big question for a lot of people was if the spiders are virtual, will they be scary, because it has to be realistic enough to create a fear response for the therapy to work. We use a couple of wires that you can put on a person’s finger and hook them up to a tablet or a cell phone. This provides an online measure of a person’s autonomic sympathetic response.
Like a lie detector test?
Exactly. We put that on their fingers and exposed them to a real-life tarantula and to our virtual tarantulas, and the fear response was no different. That means these do create an objective fear reaction in the body.
We also had people who said, “I know this is not real. I won’t be scared.” And when we started the therapy, it was with a tiny spider 5 meters away from them, and they’d lift their legs off the floor.
With the treatment, we’d come to one room and start with a very little spider, far from them. Then gradually we move them up to bigger, more diverse types of spiders, which are moving around. The patient comes near and tries to touch them.
Then at some point, I’d put a spiderweb on the door, put a few spiders on that, open the door, and have the patient walk through it. They kept walking through this spiderweb.
When they were desensitized to these spiders in this context – and as I said, context is important – we’d go to another room. This was darker, more like a basement, and we’d continue the same thing. That would actually take much less time because they already had desensitized a lot.
In our field, sense of control is very important, especially for when a patient goes home. So at the end, I’d leave the room and talk to the patient via a baby monitor. The patient was surrounded by 20 tarantulas, without the prompt moving around the environment.
Now that they’re desensitized to my virtual spiders, the question is, how would that apply to a real spider? So, we had a real live tarantula, whose name was Tony Stark, because we’re the STARC lab. We’d put Tony at the end of a long hallway before the treatment and see how close the patients could get to him.
It was only one treatment session; nobody’s was longer than 1 hour, and the average treatment time was 38 minutes.
That’s pretty effective.
It’s pretty good, compared with other studies. And I believe this is because of all the components I mentioned: being able to use your real environment; combining it with the real tarantula; the variety of the types of the feared objects; and, of course, giving the patient a sense of autonomy at the end.
Then we had to see how prolonged the effects are. We had them come in 1 week and 1 month after the treatment. I’d remind them of the principles of good exposure therapy and ask them to keep practicing at home between the sessions, looking at pictures and videos. But we never tested who did or did not do it.
After 1 week and 1 month, the effects were either the same or better. A larger number of people at 1 month were able to touch the tarantula than right after treatment.
Treating PTSD in first responders
Did you start with spiders and dogs because those are common fears?
We started with spiders because that worked with the initial goal of creating a prototype. Spiders’ behavior is simple enough for the programming, which takes a lot of time. Another reason for choosing spiders was that we had a lot of other studies of real and virtual reality exposure therapy to compare against.
I think another reason for our success is that, when you do real exposure therapy, you have just one scared tarantula in the corner of their tank, and they don’t listen to you. But my spiders listen to me and do exactly what I tell them.
After our initial success, we obtained more funds to expand it to other phobias. The cool thing is that we don’t need separate software for different phobias. You can choose dogs or snakes, add it to the person’s environment, and decide their behaviors.
We just started a clinical trial using dogs, and another group in Turkey is running a clinical trial with dogs. Eastern Michigan University is working with spiders. And a clinic at the University of Nebraska Medical Center is going to start using them in real-world clinics, not for research.
We have another project whose goal is helping reduce the impact of trauma and also treating PTSD in first responders, who are exposed to a lot of horrible things. Rates of PTSD are around 20%-30% among cops, firefighters, and EMS personnel.
They commonly find it very painful being in crowds because the fight-or-flight instinct in the brain is constantly screening for any sign of threat in their environment. We’re working on them walking into an empty room wearing the goggles, and then their therapist can scale the stimulus up and down.
There’ll be two people in front of you talking to each other, and then another group comes in, and people get louder. People can look at you and talk to you. There’s kids running, Fourth of July fireworks, and other things that might bother someone who’s been involved in gun- or explosion-related traumas. You gradually scale up when the person is next to their therapist.
Another thing we’re doing is related to cardiopulmonary resuscitation. If a young person dies in a CPR situation, that is really painful and traumatic. So, for exposure therapy to that, we’re creating a difficult CPR scenario when that person may die. The responder wears the goggles and basically watches a group of people doing CPR while standing next to a therapist who can help them navigate it and then scale it off.
Another goal is combining this with telemedicine, where the person can do it in their real-life environment. Imagine a person with military trauma. You can put them back in the barracks, connected with their psychiatrists via telemedicine. Then we would put humans in military fatigues near them and have them interact with them to feel comfortable with that situation.
What else is next for you and your group?
The next biggest challenge that we’re tackling is PTSD, because of course creating human-encounter scenarios is much more complicated than spiders and dogs. We’re in the midst of developing this so we can basically bring it to people’s homes.
We’ve been working with some military personnel to see if we can basically give a device to a veteran with PTSD, so they can go home and practice on their own.
There’s another possibility for training. Let’s take the example of a police force, which can have a lot of difficulties and mistakes because of lack of exposure and training. They can wear these goggles, get fully geared up, and be placed in encounters with people of different backgrounds, of different severity, with people who could be severely mentally ill or present different challenges for the officers.
Those situations can teach them a lot. I’m the creator of this thing, but even I’m often surprised by how realistic this technology can be. I find myself interacting with avatars the same way I would if they were real humans. I actually had one of my colleagues, when we started launching the programming with the dogs, immediately jump back. It’s just like the animal brain reacts to them.
Last question: Do you actually interact with Tony, the tarantula?
Oh, Tony is my friend. Unfortunately, he’s not with our lab at this moment. He’s on a sabbatical at Eastern Michigan University for their clinical trials. But yes, I’ve held him. He’s very friendly.
A version of this article first appeared on Medscape.com.
Cervical cancer mortality stagnates despite screening
Approximately 12,000 new cases of cervical cancer are diagnosed in women in the United States each year, based on data from the Centers for Disease Control and Prevention, said B.J. Rimel, MD, of Cedars-Sinai Medical Center, Los Angeles, in a presentation at the virtual Advancing NIH Research on the Health of Women conference sponsored by the National Institutes of Health.
Despite increased cervical cancer prevention and screening efforts, the incidence of, and mortality from, cervical cancer has remained stable for the past 2 decades, said Dr. Rimel.
Cervical cancer is the only cancer that can be prevented by vaccination, Dr. Rimel noted. It is essential to identify the women who are dying from cervical cancer, as well as who gets screened, who gets vaccinated, and who ends up in clinical trials, she said.
Novel agents for treating cervical cancer suggest that improvement in stagnant mortality rates is possible, said Dr. Rimel. She noted recent studies of cemiplimab, tisotumab vedotin, and a combination therapy involving pembrolizumab and platinum/paclitaxel, with and without bevacizumab.
Dr. Rimel suggested several opportunities to improve the identification and treatment of cervical cancer: Treat it like a rare disease; address structural racism through clinical trials; create opportunities for low–socioeconomic status patients to be involved in research; and develop solutions according to location (urban vs. rural), she said.
Compared with other cancers, cervical cancer is relatively rare in the United States, Dr. Rimel said. However, “It is important that those with cervical cancer can get treated and get healed from the disease,” she said. To better identify the women with cervical cancer who need treatment and to get them into clinical trials, she suggested using strategies employed by rare disease groups, such as seeking out patient support groups and registries.
Significant racial and ethnic disparities persist in cervical cancer, Dr. Rimel emphasized. Data from the CDC show that Black and Hispanic women in the United States are diagnosed with cervical cancer more frequently than women of other races and ethnicities and are less likely to survive.
“Reimagine cervical cancer as a disease of patients who are historically underrepresented due to race, language, poverty, and location,” she said.
Improving equity in cervical cancer care involves structural and trial-specific issues, said Dr. Rimel. Structural issues start with addressing how women enter into the health care system, she said. Consider where women receive care, and whether women have the opportunity to be vaccinated, and later screened, she said. Consider barriers to cervical cancer trials in centers with larger underserved populations, not only cost or insurance, but also issues of language and trust between patients and health care providers, she noted.
To improve the equity of cervical cancer clinical trials, consider potential barriers to enrollment, she added.
“Low English fluency is a barrier to trial enrollment,” said Dr. Rimel. In-person translation is essential for consent to participate in a trial, and “clinical trial budgets must reflect this requirement,” she added. Patient-reported outcomes need to be in the patient’s preferred language, “this includes online content,” Dr. Rimel said.
Dr. Rimel presented other strategies for clinical trial designs to improve equity.
“Compensate patients for their travel, or provide them with tech to allow for off-site monitoring,” she proposed. Patients of lower socioeconomic status in rural and urban areas have different barriers to enrollment, but virtual visits might be an option for those able to access the Internet when given a device. For others, smaller trial sites closer to home, combined with compensation for travel or missed work, might create more opportunities to participate, Dr. Rimel said. Finally, researchers should consider potential roles for smaller or broader studies that involve less travel and testing that would be feasible for more patients who might not otherwise participate in a clinical trial, she concluded.
Dr. Rimel had no financial conflicts to disclose.
Approximately 12,000 new cases of cervical cancer are diagnosed in women in the United States each year, based on data from the Centers for Disease Control and Prevention, said B.J. Rimel, MD, of Cedars-Sinai Medical Center, Los Angeles, in a presentation at the virtual Advancing NIH Research on the Health of Women conference sponsored by the National Institutes of Health.
Despite increased cervical cancer prevention and screening efforts, the incidence of, and mortality from, cervical cancer has remained stable for the past 2 decades, said Dr. Rimel.
Cervical cancer is the only cancer that can be prevented by vaccination, Dr. Rimel noted. It is essential to identify the women who are dying from cervical cancer, as well as who gets screened, who gets vaccinated, and who ends up in clinical trials, she said.
Novel agents for treating cervical cancer suggest that improvement in stagnant mortality rates is possible, said Dr. Rimel. She noted recent studies of cemiplimab, tisotumab vedotin, and a combination therapy involving pembrolizumab and platinum/paclitaxel, with and without bevacizumab.
Dr. Rimel suggested several opportunities to improve the identification and treatment of cervical cancer: Treat it like a rare disease; address structural racism through clinical trials; create opportunities for low–socioeconomic status patients to be involved in research; and develop solutions according to location (urban vs. rural), she said.
Compared with other cancers, cervical cancer is relatively rare in the United States, Dr. Rimel said. However, “It is important that those with cervical cancer can get treated and get healed from the disease,” she said. To better identify the women with cervical cancer who need treatment and to get them into clinical trials, she suggested using strategies employed by rare disease groups, such as seeking out patient support groups and registries.
Significant racial and ethnic disparities persist in cervical cancer, Dr. Rimel emphasized. Data from the CDC show that Black and Hispanic women in the United States are diagnosed with cervical cancer more frequently than women of other races and ethnicities and are less likely to survive.
“Reimagine cervical cancer as a disease of patients who are historically underrepresented due to race, language, poverty, and location,” she said.
Improving equity in cervical cancer care involves structural and trial-specific issues, said Dr. Rimel. Structural issues start with addressing how women enter into the health care system, she said. Consider where women receive care, and whether women have the opportunity to be vaccinated, and later screened, she said. Consider barriers to cervical cancer trials in centers with larger underserved populations, not only cost or insurance, but also issues of language and trust between patients and health care providers, she noted.
To improve the equity of cervical cancer clinical trials, consider potential barriers to enrollment, she added.
“Low English fluency is a barrier to trial enrollment,” said Dr. Rimel. In-person translation is essential for consent to participate in a trial, and “clinical trial budgets must reflect this requirement,” she added. Patient-reported outcomes need to be in the patient’s preferred language, “this includes online content,” Dr. Rimel said.
Dr. Rimel presented other strategies for clinical trial designs to improve equity.
“Compensate patients for their travel, or provide them with tech to allow for off-site monitoring,” she proposed. Patients of lower socioeconomic status in rural and urban areas have different barriers to enrollment, but virtual visits might be an option for those able to access the Internet when given a device. For others, smaller trial sites closer to home, combined with compensation for travel or missed work, might create more opportunities to participate, Dr. Rimel said. Finally, researchers should consider potential roles for smaller or broader studies that involve less travel and testing that would be feasible for more patients who might not otherwise participate in a clinical trial, she concluded.
Dr. Rimel had no financial conflicts to disclose.
Approximately 12,000 new cases of cervical cancer are diagnosed in women in the United States each year, based on data from the Centers for Disease Control and Prevention, said B.J. Rimel, MD, of Cedars-Sinai Medical Center, Los Angeles, in a presentation at the virtual Advancing NIH Research on the Health of Women conference sponsored by the National Institutes of Health.
Despite increased cervical cancer prevention and screening efforts, the incidence of, and mortality from, cervical cancer has remained stable for the past 2 decades, said Dr. Rimel.
Cervical cancer is the only cancer that can be prevented by vaccination, Dr. Rimel noted. It is essential to identify the women who are dying from cervical cancer, as well as who gets screened, who gets vaccinated, and who ends up in clinical trials, she said.
Novel agents for treating cervical cancer suggest that improvement in stagnant mortality rates is possible, said Dr. Rimel. She noted recent studies of cemiplimab, tisotumab vedotin, and a combination therapy involving pembrolizumab and platinum/paclitaxel, with and without bevacizumab.
Dr. Rimel suggested several opportunities to improve the identification and treatment of cervical cancer: Treat it like a rare disease; address structural racism through clinical trials; create opportunities for low–socioeconomic status patients to be involved in research; and develop solutions according to location (urban vs. rural), she said.
Compared with other cancers, cervical cancer is relatively rare in the United States, Dr. Rimel said. However, “It is important that those with cervical cancer can get treated and get healed from the disease,” she said. To better identify the women with cervical cancer who need treatment and to get them into clinical trials, she suggested using strategies employed by rare disease groups, such as seeking out patient support groups and registries.
Significant racial and ethnic disparities persist in cervical cancer, Dr. Rimel emphasized. Data from the CDC show that Black and Hispanic women in the United States are diagnosed with cervical cancer more frequently than women of other races and ethnicities and are less likely to survive.
“Reimagine cervical cancer as a disease of patients who are historically underrepresented due to race, language, poverty, and location,” she said.
Improving equity in cervical cancer care involves structural and trial-specific issues, said Dr. Rimel. Structural issues start with addressing how women enter into the health care system, she said. Consider where women receive care, and whether women have the opportunity to be vaccinated, and later screened, she said. Consider barriers to cervical cancer trials in centers with larger underserved populations, not only cost or insurance, but also issues of language and trust between patients and health care providers, she noted.
To improve the equity of cervical cancer clinical trials, consider potential barriers to enrollment, she added.
“Low English fluency is a barrier to trial enrollment,” said Dr. Rimel. In-person translation is essential for consent to participate in a trial, and “clinical trial budgets must reflect this requirement,” she added. Patient-reported outcomes need to be in the patient’s preferred language, “this includes online content,” Dr. Rimel said.
Dr. Rimel presented other strategies for clinical trial designs to improve equity.
“Compensate patients for their travel, or provide them with tech to allow for off-site monitoring,” she proposed. Patients of lower socioeconomic status in rural and urban areas have different barriers to enrollment, but virtual visits might be an option for those able to access the Internet when given a device. For others, smaller trial sites closer to home, combined with compensation for travel or missed work, might create more opportunities to participate, Dr. Rimel said. Finally, researchers should consider potential roles for smaller or broader studies that involve less travel and testing that would be feasible for more patients who might not otherwise participate in a clinical trial, she concluded.
Dr. Rimel had no financial conflicts to disclose.
FROM ADVANCING NIH RESEARCH ON THE HEALTH OF WOMEN
Clinical Edge Journal Scan Commentary: HCC November 2021
Tyrosine kinase inhibitors are the mainstay of systemic HCC therapy, however treatment at FDA-approved doses frequently leads to unacceptable toxicities, leading to reductions in the prescribed dose. Tokunaga et al. investigated whether lenvatinib dose intensity affects outcomes of patients with unresectable HCC. This was a retrospective analysis of 100 patients who received lenvatinib in the first- or later-line settings. Fifty-one patients started lenvatinib at the standard dose and 49 patients at a reduced dose. Dose reduction was carried out in 29 patients during cycle 1, and 62 patients during all cycles, with the cumulative dose reduction rate in all cycles of 79.9%. Upon analysis, the authors confirmed that tumor responses and stable disease on lenvatinib correlated favorably with overall survival (OS) and time to progression (TTP). In addition, they found that higher dose intensity correlated with a higher response rate, though most (56%) patients were unable to maintain the recommended dose intensity due to unacceptable adverse events. In the final analysis, dose modification was not negatively associated with OS, TTP, or disease control with lenvatinib. Therefore, it remains reasonable to adjust the dose of lenvatinib to minimize toxicity that would affect adversely patient quality of life. Disease control remains the best predictor of longer survival, though it does not seem that highest doses of lenvatinib are needed to achieve that benefit.
Cabozantinib is approved for previously treated patients with unresectable HCC based on the phase III CELESTIAL trial that enrolled patients with Child Pugh A liver disease who had received up to two previous systemic treatments, one of which was sorafenib. This study demonstrated a statistically significant improvement in overall- and disease-free survival. Kelley et al analyzed the outcomes based on the albumin-bilirubin (ALBI) grade, an objective measure of liver function, of patients in the CELESTIAL trial. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin. The median OS was 17.5 months in the cabozantinib arm versus 11.4 months in the placebo arm for the ALBI grade 1 subgroup, and 8.0 months in the cabozantinib arm versus 6.4 months in the placebo arm for the ALBI grade 2 subgroup. The authors concluded that cabozantinib benefits patients with unresectable HCC irrespective of their ALBI grade, though liver dysfunction remains a poor prognostic indicator in patients with HCC.
Finally, Liu et al analyzed 27 patients with HCC (8 with extrahepatic spread) who received a combination of chemotherapy via hepatic artery infusion, anti-PD-1 immunotherapy, and tyrosine kinase inhibitor. Combination chemotherapy and immunotherapy resulted in a median progression-free survival of 10.6 months with a median 12.9 months’ follow up; the objective response rate was 63.0% and the disease control rate was 92.6%. The authors concluded that this combination of therapies was effective and well-tolerated, with a confirmatory phase 3 study planned.
Tyrosine kinase inhibitors are the mainstay of systemic HCC therapy, however treatment at FDA-approved doses frequently leads to unacceptable toxicities, leading to reductions in the prescribed dose. Tokunaga et al. investigated whether lenvatinib dose intensity affects outcomes of patients with unresectable HCC. This was a retrospective analysis of 100 patients who received lenvatinib in the first- or later-line settings. Fifty-one patients started lenvatinib at the standard dose and 49 patients at a reduced dose. Dose reduction was carried out in 29 patients during cycle 1, and 62 patients during all cycles, with the cumulative dose reduction rate in all cycles of 79.9%. Upon analysis, the authors confirmed that tumor responses and stable disease on lenvatinib correlated favorably with overall survival (OS) and time to progression (TTP). In addition, they found that higher dose intensity correlated with a higher response rate, though most (56%) patients were unable to maintain the recommended dose intensity due to unacceptable adverse events. In the final analysis, dose modification was not negatively associated with OS, TTP, or disease control with lenvatinib. Therefore, it remains reasonable to adjust the dose of lenvatinib to minimize toxicity that would affect adversely patient quality of life. Disease control remains the best predictor of longer survival, though it does not seem that highest doses of lenvatinib are needed to achieve that benefit.
Cabozantinib is approved for previously treated patients with unresectable HCC based on the phase III CELESTIAL trial that enrolled patients with Child Pugh A liver disease who had received up to two previous systemic treatments, one of which was sorafenib. This study demonstrated a statistically significant improvement in overall- and disease-free survival. Kelley et al analyzed the outcomes based on the albumin-bilirubin (ALBI) grade, an objective measure of liver function, of patients in the CELESTIAL trial. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin. The median OS was 17.5 months in the cabozantinib arm versus 11.4 months in the placebo arm for the ALBI grade 1 subgroup, and 8.0 months in the cabozantinib arm versus 6.4 months in the placebo arm for the ALBI grade 2 subgroup. The authors concluded that cabozantinib benefits patients with unresectable HCC irrespective of their ALBI grade, though liver dysfunction remains a poor prognostic indicator in patients with HCC.
Finally, Liu et al analyzed 27 patients with HCC (8 with extrahepatic spread) who received a combination of chemotherapy via hepatic artery infusion, anti-PD-1 immunotherapy, and tyrosine kinase inhibitor. Combination chemotherapy and immunotherapy resulted in a median progression-free survival of 10.6 months with a median 12.9 months’ follow up; the objective response rate was 63.0% and the disease control rate was 92.6%. The authors concluded that this combination of therapies was effective and well-tolerated, with a confirmatory phase 3 study planned.
Tyrosine kinase inhibitors are the mainstay of systemic HCC therapy, however treatment at FDA-approved doses frequently leads to unacceptable toxicities, leading to reductions in the prescribed dose. Tokunaga et al. investigated whether lenvatinib dose intensity affects outcomes of patients with unresectable HCC. This was a retrospective analysis of 100 patients who received lenvatinib in the first- or later-line settings. Fifty-one patients started lenvatinib at the standard dose and 49 patients at a reduced dose. Dose reduction was carried out in 29 patients during cycle 1, and 62 patients during all cycles, with the cumulative dose reduction rate in all cycles of 79.9%. Upon analysis, the authors confirmed that tumor responses and stable disease on lenvatinib correlated favorably with overall survival (OS) and time to progression (TTP). In addition, they found that higher dose intensity correlated with a higher response rate, though most (56%) patients were unable to maintain the recommended dose intensity due to unacceptable adverse events. In the final analysis, dose modification was not negatively associated with OS, TTP, or disease control with lenvatinib. Therefore, it remains reasonable to adjust the dose of lenvatinib to minimize toxicity that would affect adversely patient quality of life. Disease control remains the best predictor of longer survival, though it does not seem that highest doses of lenvatinib are needed to achieve that benefit.
Cabozantinib is approved for previously treated patients with unresectable HCC based on the phase III CELESTIAL trial that enrolled patients with Child Pugh A liver disease who had received up to two previous systemic treatments, one of which was sorafenib. This study demonstrated a statistically significant improvement in overall- and disease-free survival. Kelley et al analyzed the outcomes based on the albumin-bilirubin (ALBI) grade, an objective measure of liver function, of patients in the CELESTIAL trial. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin. The median OS was 17.5 months in the cabozantinib arm versus 11.4 months in the placebo arm for the ALBI grade 1 subgroup, and 8.0 months in the cabozantinib arm versus 6.4 months in the placebo arm for the ALBI grade 2 subgroup. The authors concluded that cabozantinib benefits patients with unresectable HCC irrespective of their ALBI grade, though liver dysfunction remains a poor prognostic indicator in patients with HCC.
Finally, Liu et al analyzed 27 patients with HCC (8 with extrahepatic spread) who received a combination of chemotherapy via hepatic artery infusion, anti-PD-1 immunotherapy, and tyrosine kinase inhibitor. Combination chemotherapy and immunotherapy resulted in a median progression-free survival of 10.6 months with a median 12.9 months’ follow up; the objective response rate was 63.0% and the disease control rate was 92.6%. The authors concluded that this combination of therapies was effective and well-tolerated, with a confirmatory phase 3 study planned.
Ohio records more deaths than births for first time
In 2020, around 143,661 Ohioans died and 129,313 Ohioans were born, according to The Columbus Dispatch. The trend appears to have continued so far this year, with 107,462 deaths and 100,781 births reported to date.
Deaths haven’t surpassed births in the 112 years since the state began compiling data in 1909, the newspaper reported. The state’s birth rate has been declining for years while the number of deaths has risen, though data shows that the COVID-19 pandemic accelerated the shift.
“It doesn’t surprise me at all,” Joseph Gastaldo, MD, the medical director of infectious diseases for OhioHealth, told the newspaper.
Ohio’s birth rate fell by 4% in 2020, which defied public expectations about a pandemic birth boom. In addition, the state reported 13,927 COVID-19 deaths throughout the year.
“It’s COVID, clearly,” he noted.
Alabama also recorded more deaths than births for the first time last year, according to The New York Times. The state reported 64,714 deaths and 57,641 births in 2020.
“Our state literally shrunk in 2020,” Scott Harris, MD, the state health officer for Alabama, said at a news conference in September.
The state had never recorded a gap that large, even during World War I, World War II, and the 1918 flu pandemic, he said. Alabama has kept records on the numbers since 1900.
“We’ve never had a time when deaths exceeded births,” Dr. Harris said.
In fact, about half of U.S. states reported death rates higher than birth rates in 2020, according to a recent study from researchers at the University of New Hampshire. In 2019, only five states --Maine, New Hampshire, Rhode Island, Vermont, and West Virginia -- reported more deaths than births.
In 2020, the United States reported a record of nearly 3.4 million deaths, which was 18% more than in 2019, the researchers found. COVID-19 was the primary reason for the increase in deaths, accounting for about 11% of total deaths. Meanwhile, births dropped by 4% to about 3.6 million.
The surplus of births over deaths added 229,000 people to the U.S. population in 2020, as compared to 892,000 in 2019, which means the country’s population growth slowed last year. The decline, paired with lower immigration rates during the pandemic, led to the smallest annual percentage population gain in at least 100 years.
“Deaths will likely exceed births again in many states in 2021,” Kenneth Johnson, PhD, a senior demographer and study author, wrote in a statement.
“How large or protracted these fertility declines and mortality increases will be remains to be seen, but they have already dramatically reduced population growth in the United States,” he said.
A version of this article first appeared on WebMD.com.
In 2020, around 143,661 Ohioans died and 129,313 Ohioans were born, according to The Columbus Dispatch. The trend appears to have continued so far this year, with 107,462 deaths and 100,781 births reported to date.
Deaths haven’t surpassed births in the 112 years since the state began compiling data in 1909, the newspaper reported. The state’s birth rate has been declining for years while the number of deaths has risen, though data shows that the COVID-19 pandemic accelerated the shift.
“It doesn’t surprise me at all,” Joseph Gastaldo, MD, the medical director of infectious diseases for OhioHealth, told the newspaper.
Ohio’s birth rate fell by 4% in 2020, which defied public expectations about a pandemic birth boom. In addition, the state reported 13,927 COVID-19 deaths throughout the year.
“It’s COVID, clearly,” he noted.
Alabama also recorded more deaths than births for the first time last year, according to The New York Times. The state reported 64,714 deaths and 57,641 births in 2020.
“Our state literally shrunk in 2020,” Scott Harris, MD, the state health officer for Alabama, said at a news conference in September.
The state had never recorded a gap that large, even during World War I, World War II, and the 1918 flu pandemic, he said. Alabama has kept records on the numbers since 1900.
“We’ve never had a time when deaths exceeded births,” Dr. Harris said.
In fact, about half of U.S. states reported death rates higher than birth rates in 2020, according to a recent study from researchers at the University of New Hampshire. In 2019, only five states --Maine, New Hampshire, Rhode Island, Vermont, and West Virginia -- reported more deaths than births.
In 2020, the United States reported a record of nearly 3.4 million deaths, which was 18% more than in 2019, the researchers found. COVID-19 was the primary reason for the increase in deaths, accounting for about 11% of total deaths. Meanwhile, births dropped by 4% to about 3.6 million.
The surplus of births over deaths added 229,000 people to the U.S. population in 2020, as compared to 892,000 in 2019, which means the country’s population growth slowed last year. The decline, paired with lower immigration rates during the pandemic, led to the smallest annual percentage population gain in at least 100 years.
“Deaths will likely exceed births again in many states in 2021,” Kenneth Johnson, PhD, a senior demographer and study author, wrote in a statement.
“How large or protracted these fertility declines and mortality increases will be remains to be seen, but they have already dramatically reduced population growth in the United States,” he said.
A version of this article first appeared on WebMD.com.
In 2020, around 143,661 Ohioans died and 129,313 Ohioans were born, according to The Columbus Dispatch. The trend appears to have continued so far this year, with 107,462 deaths and 100,781 births reported to date.
Deaths haven’t surpassed births in the 112 years since the state began compiling data in 1909, the newspaper reported. The state’s birth rate has been declining for years while the number of deaths has risen, though data shows that the COVID-19 pandemic accelerated the shift.
“It doesn’t surprise me at all,” Joseph Gastaldo, MD, the medical director of infectious diseases for OhioHealth, told the newspaper.
Ohio’s birth rate fell by 4% in 2020, which defied public expectations about a pandemic birth boom. In addition, the state reported 13,927 COVID-19 deaths throughout the year.
“It’s COVID, clearly,” he noted.
Alabama also recorded more deaths than births for the first time last year, according to The New York Times. The state reported 64,714 deaths and 57,641 births in 2020.
“Our state literally shrunk in 2020,” Scott Harris, MD, the state health officer for Alabama, said at a news conference in September.
The state had never recorded a gap that large, even during World War I, World War II, and the 1918 flu pandemic, he said. Alabama has kept records on the numbers since 1900.
“We’ve never had a time when deaths exceeded births,” Dr. Harris said.
In fact, about half of U.S. states reported death rates higher than birth rates in 2020, according to a recent study from researchers at the University of New Hampshire. In 2019, only five states --Maine, New Hampshire, Rhode Island, Vermont, and West Virginia -- reported more deaths than births.
In 2020, the United States reported a record of nearly 3.4 million deaths, which was 18% more than in 2019, the researchers found. COVID-19 was the primary reason for the increase in deaths, accounting for about 11% of total deaths. Meanwhile, births dropped by 4% to about 3.6 million.
The surplus of births over deaths added 229,000 people to the U.S. population in 2020, as compared to 892,000 in 2019, which means the country’s population growth slowed last year. The decline, paired with lower immigration rates during the pandemic, led to the smallest annual percentage population gain in at least 100 years.
“Deaths will likely exceed births again in many states in 2021,” Kenneth Johnson, PhD, a senior demographer and study author, wrote in a statement.
“How large or protracted these fertility declines and mortality increases will be remains to be seen, but they have already dramatically reduced population growth in the United States,” he said.
A version of this article first appeared on WebMD.com.
Risk-based antenatal type-and-screen blood testing safe and economical
Implementing a selective type-and-screen blood testing policy in the labor and delivery unit was associated with projected annual savings of close to $200,000, a large single-center study found. Furthermore, there was no evidence of increased maternal morbidity in the university-based facility performing more than 4,400 deliveries per year, according to Ashley E. Benson, MD, MA, of the department of obstetrics and gynecology at the University of Utah, Salt Lake City, and colleagues.
The study, published in Obstetrics & Gynecology, evaluated patient safety, resource utilization, and transfusion-related costs after a policy change from universal type and screen to selective, risk-based type and screen on admission to labor and delivery.
“There had been some national interest in moving toward decreased resource utilization, and findings that universal screening was not cost effective,” Dr. Benson, who has since relocated to Oregon Health & Science University, Portland, said in an interview. An earlier cost-effective modeling study at her center had suggested that universal test and screen was not cost effective and likely not safer either. “So based on that data we felt an implementation study was warranted.”
The switch to a selective policy was made in 2018, after which her group compared outcomes from October 2017 to September 2019, looking those both 1 year preimplementation and 1 year post implementation.
One year post implementation, the following outcomes emerged, compared with preimplementation:
- Overall projected saving of $181,000 a year in the maternity unit
- Lower mean monthly type- and screen-related costs, such as those for ABO typing, antibody screen, and antibody workup. cross-matches, hold clots, and transfused products: $9,753 vs. $20,676 in the preimplementation year (P < .001)
- A lower mean monthly cost of total transfusion preparedness: $25,090 vs. $39,211 (P < .001)
- No differences in emergency-release transfusion events (four vs. three, P = .99),the study’s primary safety outcome
- Fewer emergency-release red blood cell units transfused (9 vs. 24, P = .002) and O-negative RBC units transfused (8 vs. 18, P = .016)
- No differences in hysterectomies (0.05% vs. 0.1%, P = .44) and ICU admissions (0.45% vs. 0.51%, P = .43)
“In a year of selective type and screen, we saw a 51% reduction in costs related to type and screen, and a 38% reduction in overall transfusion-related costs,” the authors wrote. “This study supports other literature suggesting that more judicious use of type and screen may be safe and cost effective.”
Dr. Benson said the results were positively received when presented a meeting 2 years ago but the published version has yet to prompt feedback.
The study
Antepartum patients underwent transfusion preparedness tests according to the center’s standard antenatal admission order sets and were risk stratified in alignment with California Maternal Quality Care Collaborative recommendations. The mean maternal age of patients in both time periods was similar at just over 29 years and the mean gestational age at delivery was just under 38 weeks.
Under the new policy, a “hold clot” is obtained for women stratified as low or medium risk on admission. In this instance, a tube of patient blood is held in the blood bank but processed only if needed, as in the event of active hemorrhage or an order for transfusion. A blood cross-match is obtained on all women stratified as high risk or having a prior positive antibody screen.
Relevant costs were the direct costs of transfusion-related testing in the labor and delivery unit from a health system perspective.
Obstetric hemorrhage is the leading cause of maternal death worldwide, the authors pointed out. While transfusion in obstetric patients occurs in only 1% or 2% of all deliveries it is nevertheless difficult to predict which patients will need transfusion, with only 2%-8% of those stratified as high risk ultimately requiring transfusion. Although obstetric hemorrhage safety bundles recommend risk stratification on admission to labor and delivery with selective type and screen for higher-risk individuals, for safety and simplicity’s sake, many labor and delivery units perform universal type and screen.
The authors cautioned that these results occurred in an academic tertiary care center with systems fine-tuned to deal with active hemorrhage and deliver timely transfusable blood. “At the moment we don’t have enough data to say whether the selective approach would be safe in hospitals with more limited blood bank capacity and access and fewer transfusion specialists in a setting optimized to respond to emergent needs, Dr. Benson said.
Katayoun F. M. Fomani, MD, a transfusion medicine specialist and medical director of blood bank and transfusion services at Long Island Jewish Medical Center, New York, agreed. “This approach only works in a controlled environment such as in this study where eligible women were assessed antenatally at the same center, but it would not work at every institution,” she said in an interview. “In addition, all patients were assessed according to the California Collaborative guideline, which itself increases the safety level but is not followed everywhere.”
The obstetric division at her hospital in New York adheres to the universal type and screen. “We have patients coming in from outside whose antenatal testing was not done at our hospital,” she said. “For this selective approach to work you need a controlled population and the electronic resources and personnel to follow each patient carefully.”
The authors indicated no specific funding for this study and disclosed no potential conflicts of interest. Dr. Fomani had no potential competing interests to declare.
Implementing a selective type-and-screen blood testing policy in the labor and delivery unit was associated with projected annual savings of close to $200,000, a large single-center study found. Furthermore, there was no evidence of increased maternal morbidity in the university-based facility performing more than 4,400 deliveries per year, according to Ashley E. Benson, MD, MA, of the department of obstetrics and gynecology at the University of Utah, Salt Lake City, and colleagues.
The study, published in Obstetrics & Gynecology, evaluated patient safety, resource utilization, and transfusion-related costs after a policy change from universal type and screen to selective, risk-based type and screen on admission to labor and delivery.
“There had been some national interest in moving toward decreased resource utilization, and findings that universal screening was not cost effective,” Dr. Benson, who has since relocated to Oregon Health & Science University, Portland, said in an interview. An earlier cost-effective modeling study at her center had suggested that universal test and screen was not cost effective and likely not safer either. “So based on that data we felt an implementation study was warranted.”
The switch to a selective policy was made in 2018, after which her group compared outcomes from October 2017 to September 2019, looking those both 1 year preimplementation and 1 year post implementation.
One year post implementation, the following outcomes emerged, compared with preimplementation:
- Overall projected saving of $181,000 a year in the maternity unit
- Lower mean monthly type- and screen-related costs, such as those for ABO typing, antibody screen, and antibody workup. cross-matches, hold clots, and transfused products: $9,753 vs. $20,676 in the preimplementation year (P < .001)
- A lower mean monthly cost of total transfusion preparedness: $25,090 vs. $39,211 (P < .001)
- No differences in emergency-release transfusion events (four vs. three, P = .99),the study’s primary safety outcome
- Fewer emergency-release red blood cell units transfused (9 vs. 24, P = .002) and O-negative RBC units transfused (8 vs. 18, P = .016)
- No differences in hysterectomies (0.05% vs. 0.1%, P = .44) and ICU admissions (0.45% vs. 0.51%, P = .43)
“In a year of selective type and screen, we saw a 51% reduction in costs related to type and screen, and a 38% reduction in overall transfusion-related costs,” the authors wrote. “This study supports other literature suggesting that more judicious use of type and screen may be safe and cost effective.”
Dr. Benson said the results were positively received when presented a meeting 2 years ago but the published version has yet to prompt feedback.
The study
Antepartum patients underwent transfusion preparedness tests according to the center’s standard antenatal admission order sets and were risk stratified in alignment with California Maternal Quality Care Collaborative recommendations. The mean maternal age of patients in both time periods was similar at just over 29 years and the mean gestational age at delivery was just under 38 weeks.
Under the new policy, a “hold clot” is obtained for women stratified as low or medium risk on admission. In this instance, a tube of patient blood is held in the blood bank but processed only if needed, as in the event of active hemorrhage or an order for transfusion. A blood cross-match is obtained on all women stratified as high risk or having a prior positive antibody screen.
Relevant costs were the direct costs of transfusion-related testing in the labor and delivery unit from a health system perspective.
Obstetric hemorrhage is the leading cause of maternal death worldwide, the authors pointed out. While transfusion in obstetric patients occurs in only 1% or 2% of all deliveries it is nevertheless difficult to predict which patients will need transfusion, with only 2%-8% of those stratified as high risk ultimately requiring transfusion. Although obstetric hemorrhage safety bundles recommend risk stratification on admission to labor and delivery with selective type and screen for higher-risk individuals, for safety and simplicity’s sake, many labor and delivery units perform universal type and screen.
The authors cautioned that these results occurred in an academic tertiary care center with systems fine-tuned to deal with active hemorrhage and deliver timely transfusable blood. “At the moment we don’t have enough data to say whether the selective approach would be safe in hospitals with more limited blood bank capacity and access and fewer transfusion specialists in a setting optimized to respond to emergent needs, Dr. Benson said.
Katayoun F. M. Fomani, MD, a transfusion medicine specialist and medical director of blood bank and transfusion services at Long Island Jewish Medical Center, New York, agreed. “This approach only works in a controlled environment such as in this study where eligible women were assessed antenatally at the same center, but it would not work at every institution,” she said in an interview. “In addition, all patients were assessed according to the California Collaborative guideline, which itself increases the safety level but is not followed everywhere.”
The obstetric division at her hospital in New York adheres to the universal type and screen. “We have patients coming in from outside whose antenatal testing was not done at our hospital,” she said. “For this selective approach to work you need a controlled population and the electronic resources and personnel to follow each patient carefully.”
The authors indicated no specific funding for this study and disclosed no potential conflicts of interest. Dr. Fomani had no potential competing interests to declare.
Implementing a selective type-and-screen blood testing policy in the labor and delivery unit was associated with projected annual savings of close to $200,000, a large single-center study found. Furthermore, there was no evidence of increased maternal morbidity in the university-based facility performing more than 4,400 deliveries per year, according to Ashley E. Benson, MD, MA, of the department of obstetrics and gynecology at the University of Utah, Salt Lake City, and colleagues.
The study, published in Obstetrics & Gynecology, evaluated patient safety, resource utilization, and transfusion-related costs after a policy change from universal type and screen to selective, risk-based type and screen on admission to labor and delivery.
“There had been some national interest in moving toward decreased resource utilization, and findings that universal screening was not cost effective,” Dr. Benson, who has since relocated to Oregon Health & Science University, Portland, said in an interview. An earlier cost-effective modeling study at her center had suggested that universal test and screen was not cost effective and likely not safer either. “So based on that data we felt an implementation study was warranted.”
The switch to a selective policy was made in 2018, after which her group compared outcomes from October 2017 to September 2019, looking those both 1 year preimplementation and 1 year post implementation.
One year post implementation, the following outcomes emerged, compared with preimplementation:
- Overall projected saving of $181,000 a year in the maternity unit
- Lower mean monthly type- and screen-related costs, such as those for ABO typing, antibody screen, and antibody workup. cross-matches, hold clots, and transfused products: $9,753 vs. $20,676 in the preimplementation year (P < .001)
- A lower mean monthly cost of total transfusion preparedness: $25,090 vs. $39,211 (P < .001)
- No differences in emergency-release transfusion events (four vs. three, P = .99),the study’s primary safety outcome
- Fewer emergency-release red blood cell units transfused (9 vs. 24, P = .002) and O-negative RBC units transfused (8 vs. 18, P = .016)
- No differences in hysterectomies (0.05% vs. 0.1%, P = .44) and ICU admissions (0.45% vs. 0.51%, P = .43)
“In a year of selective type and screen, we saw a 51% reduction in costs related to type and screen, and a 38% reduction in overall transfusion-related costs,” the authors wrote. “This study supports other literature suggesting that more judicious use of type and screen may be safe and cost effective.”
Dr. Benson said the results were positively received when presented a meeting 2 years ago but the published version has yet to prompt feedback.
The study
Antepartum patients underwent transfusion preparedness tests according to the center’s standard antenatal admission order sets and were risk stratified in alignment with California Maternal Quality Care Collaborative recommendations. The mean maternal age of patients in both time periods was similar at just over 29 years and the mean gestational age at delivery was just under 38 weeks.
Under the new policy, a “hold clot” is obtained for women stratified as low or medium risk on admission. In this instance, a tube of patient blood is held in the blood bank but processed only if needed, as in the event of active hemorrhage or an order for transfusion. A blood cross-match is obtained on all women stratified as high risk or having a prior positive antibody screen.
Relevant costs were the direct costs of transfusion-related testing in the labor and delivery unit from a health system perspective.
Obstetric hemorrhage is the leading cause of maternal death worldwide, the authors pointed out. While transfusion in obstetric patients occurs in only 1% or 2% of all deliveries it is nevertheless difficult to predict which patients will need transfusion, with only 2%-8% of those stratified as high risk ultimately requiring transfusion. Although obstetric hemorrhage safety bundles recommend risk stratification on admission to labor and delivery with selective type and screen for higher-risk individuals, for safety and simplicity’s sake, many labor and delivery units perform universal type and screen.
The authors cautioned that these results occurred in an academic tertiary care center with systems fine-tuned to deal with active hemorrhage and deliver timely transfusable blood. “At the moment we don’t have enough data to say whether the selective approach would be safe in hospitals with more limited blood bank capacity and access and fewer transfusion specialists in a setting optimized to respond to emergent needs, Dr. Benson said.
Katayoun F. M. Fomani, MD, a transfusion medicine specialist and medical director of blood bank and transfusion services at Long Island Jewish Medical Center, New York, agreed. “This approach only works in a controlled environment such as in this study where eligible women were assessed antenatally at the same center, but it would not work at every institution,” she said in an interview. “In addition, all patients were assessed according to the California Collaborative guideline, which itself increases the safety level but is not followed everywhere.”
The obstetric division at her hospital in New York adheres to the universal type and screen. “We have patients coming in from outside whose antenatal testing was not done at our hospital,” she said. “For this selective approach to work you need a controlled population and the electronic resources and personnel to follow each patient carefully.”
The authors indicated no specific funding for this study and disclosed no potential conflicts of interest. Dr. Fomani had no potential competing interests to declare.
FROM OBSTETRICS & GYNECOLOGY
Vitamin D status may play a pivotal role in colon cancer prevention
This is according to an observational study published in the journal Gastroenterology. The study included 94,205 women (aged 25-42 years) who were followed between 1991 and 2015 during which 111 incident cases of early-onset colorectal cancer were diagnosed. Among 29,186 women who had at least one lower endoscopy from 1991 to 2011, 1,439 newly diagnosed conventional adenomas and 1,878 serrated polyps were found.
Women who consumed the highest average levels of total vitamin D of 450 IU per day, compared with those consuming less than 300 IU per day, showed a significantly reduced risk of early-onset colorectal cancer. Consuming 400 IU each day was associated with a 54% reduced risk of early-onset colorectal cancer.
“If confirmed, our findings could potentially lead to recommendations for higher vitamin D intake as an inexpensive low-risk complement to colorectal cancer screening as a prevention strategy for adults younger than age 50,” wrote the study authors, led by Edward L. Giovannucci, MD, ScD, of the Harvard School of Public Health, Boston.
Associations between vitamin D levels and colorectal cancer have been documented in review articles over the years. The link is the subject of 10 recently completed or ongoing clinical trials. Few studies have focused on early colorectal cancer and vitamin D intake. Unlike advanced colorectal cancer, the early-onset form of the disease is not as strongly associated with the traditional risk factors of a family history of colorectal cancer and it is therefore believed to be more strongly linked to other factors, such as lifestyle and diet – including vitamin D supplementation.
The evidence is in, but it’s incomplete
In addition to the new study in Gastroenterology, other observational studies, as well as laboratory and animal studies, suggest that vitamin D plays a role in inhibiting carcinogenesis. Vitamin D, researchers theorize, contains anti-inflammatory, immunomodulatory, and tumor angiogenesis properties that can slow the growth of tumors, but the evidence is mixed.
A meta-analysis of 137,567 patients published in 2013 in Preventive Medicine found an inverse association between 25-hydroxyvitamin D (25[OH]D) and total cancer mortality in women, but not among men. Three meta-analyses published in 2014 and 2019 found that vitamin D supplementation does not affect cancer incidence but does significantly reduce total cancer mortality rates by 12%-13%.
In 2019, researchers led by Marjorie McCullough, ScD, RD, senior scientific director of epidemiology research for the American Cancer Society, described a causal relationship between circulating vitamin D and colorectal cancer risk among 17 cohorts from a pooled analysis. “Our study suggests that optimal circulating 25(OH)D concentrations for colorectal cancer risk reduction are 75-100 nmol/L, [which is] higher than current Institute of Medicine recommendations for bone health,” she and colleagues wrote. Their findings were published in the Journal of the National Cancer Institute.
The Vitamin D and Omega-3 Trial (VITAL) published in 2019 in the New England Journal of Medicine, showed no significant effect of vitamin D3 supplementation of 2,000 IU/day in lowering the risk of invasive cancer or cardiovascular events.
Despite the mixed results, studies offer valuable insights into cancer risks, said Scott Kopetz, MD, PhD, codirector of the colorectal cancer moon shot research program at the University of Texas MD Anderson Cancer Center, Houston.
The Gastroenterology study is noteworthy because it focuses on early-onset colorectal cancer, he said.
“[The authors] demonstrate for the first time that there is an association of vitamin D intake with early-onset colorectal incidence, especially in the left side of the colon and rectum where the increase in early onset colorectal cancer manifests,” Dr. Kopetz said. “The analysis suggests that it may require long-term vitamin D intake to derive the benefit, which may explain why some shorter-term randomized studies failed to demonstrate.”
In animal models, vitamin D3 is “estimated to lower the incidence of colorectal cancer by 50%,” according to Lidija Klampfer, PhD, formerly a molecular biologist and senior research scientist with the Southern Research Institute, Birmingham, Ala.
Dr. Klampfer, a founding partner of ProteXase Therapeutics, is the author of an article on vitamin D and colon cancer published in 2014 in the World Journal of Gastrointestinal Oncology.
“The levels of vitamin D3 appear to be an essential determinant for the development and progression of colon cancer and supplementation with vitamin D3 is effective in suppressing intestinal tumorigenesis in animal models,” she wrote. “Studies have shown that 1,25 dihydroxyvitamin D3 can inhibit tumor-promoting inflammation leading to the development and progression of colon cancer.”
The hazards of a vitamin D deficiency
A severe vitamin D deficiency is associated with compromised bone and muscle health, calcium absorption, immunity, heart function and it can affect mood. Other studies have linked vitamin D deficiency to colorectal cancer, blood cancers, and bowel cancer.
Serum 25(OH)D is the primary circulating form of vitamin D and is considered the best marker for assessing vitamin D status, says Karin Amrein, MD, MSc, an endocrinologist with the Medical University of Graz (Austria). She was the lead author of a review on vitamin D deficiency published in January 2020 in the European Journal of Clinical Nutrition.
The Global Consensus Recommendations define vitamin D insufficiency as 12-20 ng/mL (30-50 nmol/L) and a deficiency as a serum 25OHD concentration less than 12 ng/mL (30 nmol/L). A deficiency in adults is usually treated with 50,000 IU of vitamin D2 or D3 once weekly for 8 weeks followed by maintenance dosages of cholecalciferol (vitamin D3) at 800-1,000 IU daily from dietary and supplemental sources.
Screening is recommended for individuals who exhibit symptoms and conditions associated with a vitamin D deficiency, but there is little agreement on recommended serum levels because every individual is different, according to the U.S. Preventive Services Task Force which updated its vitamin D recommendations in April for the first time in 7 years.
This is according to an observational study published in the journal Gastroenterology. The study included 94,205 women (aged 25-42 years) who were followed between 1991 and 2015 during which 111 incident cases of early-onset colorectal cancer were diagnosed. Among 29,186 women who had at least one lower endoscopy from 1991 to 2011, 1,439 newly diagnosed conventional adenomas and 1,878 serrated polyps were found.
Women who consumed the highest average levels of total vitamin D of 450 IU per day, compared with those consuming less than 300 IU per day, showed a significantly reduced risk of early-onset colorectal cancer. Consuming 400 IU each day was associated with a 54% reduced risk of early-onset colorectal cancer.
“If confirmed, our findings could potentially lead to recommendations for higher vitamin D intake as an inexpensive low-risk complement to colorectal cancer screening as a prevention strategy for adults younger than age 50,” wrote the study authors, led by Edward L. Giovannucci, MD, ScD, of the Harvard School of Public Health, Boston.
Associations between vitamin D levels and colorectal cancer have been documented in review articles over the years. The link is the subject of 10 recently completed or ongoing clinical trials. Few studies have focused on early colorectal cancer and vitamin D intake. Unlike advanced colorectal cancer, the early-onset form of the disease is not as strongly associated with the traditional risk factors of a family history of colorectal cancer and it is therefore believed to be more strongly linked to other factors, such as lifestyle and diet – including vitamin D supplementation.
The evidence is in, but it’s incomplete
In addition to the new study in Gastroenterology, other observational studies, as well as laboratory and animal studies, suggest that vitamin D plays a role in inhibiting carcinogenesis. Vitamin D, researchers theorize, contains anti-inflammatory, immunomodulatory, and tumor angiogenesis properties that can slow the growth of tumors, but the evidence is mixed.
A meta-analysis of 137,567 patients published in 2013 in Preventive Medicine found an inverse association between 25-hydroxyvitamin D (25[OH]D) and total cancer mortality in women, but not among men. Three meta-analyses published in 2014 and 2019 found that vitamin D supplementation does not affect cancer incidence but does significantly reduce total cancer mortality rates by 12%-13%.
In 2019, researchers led by Marjorie McCullough, ScD, RD, senior scientific director of epidemiology research for the American Cancer Society, described a causal relationship between circulating vitamin D and colorectal cancer risk among 17 cohorts from a pooled analysis. “Our study suggests that optimal circulating 25(OH)D concentrations for colorectal cancer risk reduction are 75-100 nmol/L, [which is] higher than current Institute of Medicine recommendations for bone health,” she and colleagues wrote. Their findings were published in the Journal of the National Cancer Institute.
The Vitamin D and Omega-3 Trial (VITAL) published in 2019 in the New England Journal of Medicine, showed no significant effect of vitamin D3 supplementation of 2,000 IU/day in lowering the risk of invasive cancer or cardiovascular events.
Despite the mixed results, studies offer valuable insights into cancer risks, said Scott Kopetz, MD, PhD, codirector of the colorectal cancer moon shot research program at the University of Texas MD Anderson Cancer Center, Houston.
The Gastroenterology study is noteworthy because it focuses on early-onset colorectal cancer, he said.
“[The authors] demonstrate for the first time that there is an association of vitamin D intake with early-onset colorectal incidence, especially in the left side of the colon and rectum where the increase in early onset colorectal cancer manifests,” Dr. Kopetz said. “The analysis suggests that it may require long-term vitamin D intake to derive the benefit, which may explain why some shorter-term randomized studies failed to demonstrate.”
In animal models, vitamin D3 is “estimated to lower the incidence of colorectal cancer by 50%,” according to Lidija Klampfer, PhD, formerly a molecular biologist and senior research scientist with the Southern Research Institute, Birmingham, Ala.
Dr. Klampfer, a founding partner of ProteXase Therapeutics, is the author of an article on vitamin D and colon cancer published in 2014 in the World Journal of Gastrointestinal Oncology.
“The levels of vitamin D3 appear to be an essential determinant for the development and progression of colon cancer and supplementation with vitamin D3 is effective in suppressing intestinal tumorigenesis in animal models,” she wrote. “Studies have shown that 1,25 dihydroxyvitamin D3 can inhibit tumor-promoting inflammation leading to the development and progression of colon cancer.”
The hazards of a vitamin D deficiency
A severe vitamin D deficiency is associated with compromised bone and muscle health, calcium absorption, immunity, heart function and it can affect mood. Other studies have linked vitamin D deficiency to colorectal cancer, blood cancers, and bowel cancer.
Serum 25(OH)D is the primary circulating form of vitamin D and is considered the best marker for assessing vitamin D status, says Karin Amrein, MD, MSc, an endocrinologist with the Medical University of Graz (Austria). She was the lead author of a review on vitamin D deficiency published in January 2020 in the European Journal of Clinical Nutrition.
The Global Consensus Recommendations define vitamin D insufficiency as 12-20 ng/mL (30-50 nmol/L) and a deficiency as a serum 25OHD concentration less than 12 ng/mL (30 nmol/L). A deficiency in adults is usually treated with 50,000 IU of vitamin D2 or D3 once weekly for 8 weeks followed by maintenance dosages of cholecalciferol (vitamin D3) at 800-1,000 IU daily from dietary and supplemental sources.
Screening is recommended for individuals who exhibit symptoms and conditions associated with a vitamin D deficiency, but there is little agreement on recommended serum levels because every individual is different, according to the U.S. Preventive Services Task Force which updated its vitamin D recommendations in April for the first time in 7 years.
This is according to an observational study published in the journal Gastroenterology. The study included 94,205 women (aged 25-42 years) who were followed between 1991 and 2015 during which 111 incident cases of early-onset colorectal cancer were diagnosed. Among 29,186 women who had at least one lower endoscopy from 1991 to 2011, 1,439 newly diagnosed conventional adenomas and 1,878 serrated polyps were found.
Women who consumed the highest average levels of total vitamin D of 450 IU per day, compared with those consuming less than 300 IU per day, showed a significantly reduced risk of early-onset colorectal cancer. Consuming 400 IU each day was associated with a 54% reduced risk of early-onset colorectal cancer.
“If confirmed, our findings could potentially lead to recommendations for higher vitamin D intake as an inexpensive low-risk complement to colorectal cancer screening as a prevention strategy for adults younger than age 50,” wrote the study authors, led by Edward L. Giovannucci, MD, ScD, of the Harvard School of Public Health, Boston.
Associations between vitamin D levels and colorectal cancer have been documented in review articles over the years. The link is the subject of 10 recently completed or ongoing clinical trials. Few studies have focused on early colorectal cancer and vitamin D intake. Unlike advanced colorectal cancer, the early-onset form of the disease is not as strongly associated with the traditional risk factors of a family history of colorectal cancer and it is therefore believed to be more strongly linked to other factors, such as lifestyle and diet – including vitamin D supplementation.
The evidence is in, but it’s incomplete
In addition to the new study in Gastroenterology, other observational studies, as well as laboratory and animal studies, suggest that vitamin D plays a role in inhibiting carcinogenesis. Vitamin D, researchers theorize, contains anti-inflammatory, immunomodulatory, and tumor angiogenesis properties that can slow the growth of tumors, but the evidence is mixed.
A meta-analysis of 137,567 patients published in 2013 in Preventive Medicine found an inverse association between 25-hydroxyvitamin D (25[OH]D) and total cancer mortality in women, but not among men. Three meta-analyses published in 2014 and 2019 found that vitamin D supplementation does not affect cancer incidence but does significantly reduce total cancer mortality rates by 12%-13%.
In 2019, researchers led by Marjorie McCullough, ScD, RD, senior scientific director of epidemiology research for the American Cancer Society, described a causal relationship between circulating vitamin D and colorectal cancer risk among 17 cohorts from a pooled analysis. “Our study suggests that optimal circulating 25(OH)D concentrations for colorectal cancer risk reduction are 75-100 nmol/L, [which is] higher than current Institute of Medicine recommendations for bone health,” she and colleagues wrote. Their findings were published in the Journal of the National Cancer Institute.
The Vitamin D and Omega-3 Trial (VITAL) published in 2019 in the New England Journal of Medicine, showed no significant effect of vitamin D3 supplementation of 2,000 IU/day in lowering the risk of invasive cancer or cardiovascular events.
Despite the mixed results, studies offer valuable insights into cancer risks, said Scott Kopetz, MD, PhD, codirector of the colorectal cancer moon shot research program at the University of Texas MD Anderson Cancer Center, Houston.
The Gastroenterology study is noteworthy because it focuses on early-onset colorectal cancer, he said.
“[The authors] demonstrate for the first time that there is an association of vitamin D intake with early-onset colorectal incidence, especially in the left side of the colon and rectum where the increase in early onset colorectal cancer manifests,” Dr. Kopetz said. “The analysis suggests that it may require long-term vitamin D intake to derive the benefit, which may explain why some shorter-term randomized studies failed to demonstrate.”
In animal models, vitamin D3 is “estimated to lower the incidence of colorectal cancer by 50%,” according to Lidija Klampfer, PhD, formerly a molecular biologist and senior research scientist with the Southern Research Institute, Birmingham, Ala.
Dr. Klampfer, a founding partner of ProteXase Therapeutics, is the author of an article on vitamin D and colon cancer published in 2014 in the World Journal of Gastrointestinal Oncology.
“The levels of vitamin D3 appear to be an essential determinant for the development and progression of colon cancer and supplementation with vitamin D3 is effective in suppressing intestinal tumorigenesis in animal models,” she wrote. “Studies have shown that 1,25 dihydroxyvitamin D3 can inhibit tumor-promoting inflammation leading to the development and progression of colon cancer.”
The hazards of a vitamin D deficiency
A severe vitamin D deficiency is associated with compromised bone and muscle health, calcium absorption, immunity, heart function and it can affect mood. Other studies have linked vitamin D deficiency to colorectal cancer, blood cancers, and bowel cancer.
Serum 25(OH)D is the primary circulating form of vitamin D and is considered the best marker for assessing vitamin D status, says Karin Amrein, MD, MSc, an endocrinologist with the Medical University of Graz (Austria). She was the lead author of a review on vitamin D deficiency published in January 2020 in the European Journal of Clinical Nutrition.
The Global Consensus Recommendations define vitamin D insufficiency as 12-20 ng/mL (30-50 nmol/L) and a deficiency as a serum 25OHD concentration less than 12 ng/mL (30 nmol/L). A deficiency in adults is usually treated with 50,000 IU of vitamin D2 or D3 once weekly for 8 weeks followed by maintenance dosages of cholecalciferol (vitamin D3) at 800-1,000 IU daily from dietary and supplemental sources.
Screening is recommended for individuals who exhibit symptoms and conditions associated with a vitamin D deficiency, but there is little agreement on recommended serum levels because every individual is different, according to the U.S. Preventive Services Task Force which updated its vitamin D recommendations in April for the first time in 7 years.
FROM GASTROENTEROLOGY
Sleep time ‘sweet spot’ to slow cognitive decline identified?
In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.
“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” said lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis.
The study, published online Oct. 20 in Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
A complex relationship
Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, Alzheimer’s disease, and cognitive function.
An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of Alzheimer’s disease, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid beta, a hallmark sign of Alzheimer’s disease.
For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University. Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta42 and wore a small EEG device on their forehead while they slept.
The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR >0, with most reporting mild cognitive impairment.
As expected, CSF analysis showed greater evidence of Alzheimer’s disease pathology in those with a baseline CDR greater than 0.
Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale-Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale-Revised, and the Mini-Mental State Examination.
Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both). The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).
The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta-42 ratio, APOE ε4 allele carrier status, years of education, and sex.
Understanding how sleep changes at different stages of Alzheimer’s disease could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.
“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
A component of cognitive health
Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.
“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.
“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”
The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships. Full disclosures are included in the original article.
A version of this article first appeared on Medscape.com.
In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.
“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” said lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis.
The study, published online Oct. 20 in Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
A complex relationship
Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, Alzheimer’s disease, and cognitive function.
An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of Alzheimer’s disease, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid beta, a hallmark sign of Alzheimer’s disease.
For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University. Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta42 and wore a small EEG device on their forehead while they slept.
The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR >0, with most reporting mild cognitive impairment.
As expected, CSF analysis showed greater evidence of Alzheimer’s disease pathology in those with a baseline CDR greater than 0.
Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale-Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale-Revised, and the Mini-Mental State Examination.
Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both). The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).
The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta-42 ratio, APOE ε4 allele carrier status, years of education, and sex.
Understanding how sleep changes at different stages of Alzheimer’s disease could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.
“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
A component of cognitive health
Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.
“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.
“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”
The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships. Full disclosures are included in the original article.
A version of this article first appeared on Medscape.com.
In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.
“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” said lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis.
The study, published online Oct. 20 in Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
A complex relationship
Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, Alzheimer’s disease, and cognitive function.
An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of Alzheimer’s disease, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid beta, a hallmark sign of Alzheimer’s disease.
For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University. Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta42 and wore a small EEG device on their forehead while they slept.
The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR >0, with most reporting mild cognitive impairment.
As expected, CSF analysis showed greater evidence of Alzheimer’s disease pathology in those with a baseline CDR greater than 0.
Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale-Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale-Revised, and the Mini-Mental State Examination.
Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both). The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).
The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta-42 ratio, APOE ε4 allele carrier status, years of education, and sex.
Understanding how sleep changes at different stages of Alzheimer’s disease could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.
“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
A component of cognitive health
Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.
“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.
“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”
The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships. Full disclosures are included in the original article.
A version of this article first appeared on Medscape.com.
From Brain
Researchers parse which patients with T2D need SGLT2 inhibition
Agents that form the sodium-glucose cotransporter 2 inhibitor class – including canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) – have show remarkably consistent cardiovascular efficacy and safety for treating patients with heart failure, chronic kidney disease, and higher-risk patients with type 2 diabetes.
But despite an essential role now established for drugs in the SGLT2 inhibitor class for patients with heart failure with reduced ejection fraction, progressive renal dysfunction, or – most recently – patients with heart failure with preserved ejection fraction, the scope may be less clear when using these agents in patients with type 2 diabetes because they fall across a broad spectrum of risk for cardiorenal disease.
“What makes patients with type 2 diabetes distinct from other patients in whom SGLT2 inhibitors have been studied, such as patients with heart failure, is that they have a much wider spectrum of risk. Low-risk patients with type 2 diabetes were not included in the SGLT2 inhibitor trials. Defining risk in patients with type 2 diabetes has the potential to inform prioritization” for treatment with an SGLT2 inhibitor, explained David D. Berg, MD, who has led one effort to develop risk scores that can risk-stratify patients with type 2 diabetes based on their vulnerability to incident heart failure and hospitalization for these episodes,
The hefty cost for these drugs, with retail prices that run over $6,000 annually for the most widely used and most potent agents in the class, has spurred researchers to try to find cost-effective ways to identify patients with type 2 diabetes who stand to benefit most from taking an SGLT2 inhibitor.
‘Cost must be considered’
“Cost must be considered, and at this point it’s probably more responsible on a societal level to advise using SGLT2 inhibitors mainly in patients [with type 2 diabetes] with compelling indications,” said Silvio Inzucchi, MD, professor and director of the Yale Medicine Diabetes Center in New Haven, Conn. Dr. Inzucchi added, however, that “I can easily foresee a day when these agents are considered foundational therapy for all patients with type 2 diabetes, after they go generic and cost is not a major issue. I’m starting to lean toward this very simplified approach, but the costs are prohibitive at this time.”
“If the SGLT2 inhibitors were available at a low cost, I’d argue that they should be used in all patients with type 2 diabetes who have no contraindications or tolerability issues; but we live in a world where they are not yet low cost,” agreed Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute in Kansas City, Mo.
“We can’t give SGLT2 inhibitors to everyone with type 2 diabetes right now because that would be too costly; these agents are so expensive. You start by targeting the patients with the highest risk” for incident heart failure, said Ambarish Pandey, MD, a cardiologist at the University of Texas Southwestern Medical Center, Dallas.
The spotlight the SGLT2 inhibitor class has received, based on its unexpectedly potent efficacy in cutting rates of acute heart failure episodes in patients with type 2 diabetes, has also sharply raised the profile of this complication of type 2 diabetes, an outcome that until recently many clinicians had largely ignored, overshadowed by a focus on adverse outcomes from atherosclerotic cardiovascular disease such as MIs and strokes.
“Results from the SGLT2 inhibitor trials have reignited interest in the relationship between type 2 diabetes and heart failure and have started to shift the mindset of clinicians toward thinking about reducing both atherothrombotic risk and heart failure risk in patients with type 2 diabetes,” said Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston.
“Prior to the SGLT2 inhibitor trials, heart failure was on the radar of diabetes clinicians only as something to watch for as a potential side effect of certain glucose-lowering therapies. Now that there are therapies that can lower heart failure hospitalization, it’s made us think more about heart failure, how common it is in patients with type 2 diabetes, and what can we do to lower this risk,” commented Alice Y.Y. Cheng, MD, a diabetes specialist at the University of Toronto.
Banking on biomarkers
Risk scores for assessing the likelihood of people developing incident heart failure date back more than a decade. More recent efforts have focused on patients with type 2 diabetes, starting with scores that relied entirely on clinical markers of risk such as prior heart failure, established coronary artery disease, and chronic kidney disease. Reports of two of these validated scores appeared in 2019, one from a team led by Dr. Berg and associates in 2019, and a second score developed by Dr. Pandey and associates.
More recently, both research teams behind these two scores validated newer versions that further refined assessment of patients with diabetes by including biomarkers of incipient heart failure, such as N-terminal of the prohormone brain natriuretic peptide (NT-proBNP). The UT Southwestern group’s biomarker-based score relies on levels of NT-proBNP as well as on levels of high sensitivity troponin T (hsTnT) and C-reactive protein, plus ECG-based assessment of left ventricular hypertrophy to assess risk for incident heart failure. Developers reported in 2021 that this biomarker score could account for 74% (C-statistic) of the 5-year risk for heart failure among patients with diabetes.
The biomarker-based score devised by Dr. Berg and associates, relies on NT-proBNP, hsTnT, and a history of heart failure to predict the risk for a future hospitalization for heart failure. They reported in Diabetes Care that in validation testing this score accounted for 84% of the risk.
“I’m hopeful that both our original clinically-based risk score and our new biomarker-based score will be endorsed by professional society guidelines. The intent of the biomarker-based score is not to replace the clinical one,” Dr. Berg stressed in an interview. But he acknowledged that it uses biomarker values that currently are not routinely collected in U.S. practice. Biomarkers like NT-proBNP “are highly associated with future heart failure risk, but are not yet routinely assessed,” he said. Because of this, “widespread adoption of the [biomarker] risk tool will require some education.”
It may also require some sort of preliminary screening to determine the appropriateness of using it in a specific patient because of the relative expense of a test for NT-proBNP.
A Texas two-step process
“We can’t perform a [NT-proBNP] test on every patient with type 2 diabetes because cost is a huge barrier,” with a U.K. price of roughly £28 (about $40) per test, commented Naveed Sattar, MD, PhD, professor of metabolic medicine at the University of Glasgow. “NT-proBNP is the best biomarker by far to predict risk” for heart failure,” but “it’s too expensive. It’s not going to happen in everyone,” he said in an interview. He suggested taking a two-step approach to identify patients to test for NT-proBNP based on clinical measures like blood pressure, weight and height, lipid levels and renal function and the presence of suggestive symptoms like dyspnea, fatigue, and peripheral edema, an argument he recently spelled out in detail in an editorial he coauthored.
“More work is needed to define which patients would usefully have cardiac biomarkers measured,” Dr. Sattar wrote with his associate.
Two-step is the approach used in routine practice by clinicians at UT Southwestern Medical Center. “We screen all patients with type 2 diabetes and no diagnosed heart failure who are not already on an SGLT2 inhibitor” using their 2019 screening tool, called the WATCH-DM Risk score, said Dr. Pandey. Patients flagged at high risk by their clinical score receive an SGLT2 inhibitor (presuming no contraindications). The remaining patients with low or intermediate risk may then undergo biomarker-based assessment to find additional patients who warrant SGLT2 inhibitor treatment, he said in an interview.
Often, a record of the most important biomarker, NT-proBNP, is already in the patient’s record and less than a year old, in which case clinicians use that value. An NT-proBNP level of at least 125 pg/mL indicates increased risk in people with a body mass index of less than 30 kg/m2, while for those with higher body mass indexes clinicians at Southwestern apply a threshold for higher risk of at least 100 pg/mL.
In addition to starting those patients on an SGLT2 inhibitor, the Southwestern protocol calls for intensified efforts at weight loss and improved fitness to further lower incident heart failure risk, and they are also considering targeting treatment with a glucagonlike peptide–1 receptor agonist to these patients as well. They have a research protocol in place, called WATCH-DM, that will prospectively assess the efficacy of this strategy.
Despite the cost, others also believe that the time is right for biomarker-based tests to boost access to the benefits that treatment with SGLT2 inhibitors can give patients with type 2 diabetes.
“In theory it’s reasonable” to use a risk score like the recent one reported by Dr. Berg and coauthors, said Vanita R. Aroda, MD, an endocrinologist and director of diabetes clinical research at Brigham and Women’s Hospital in Boston. “We need to pay attention to heart failure as an outcome and use risk stratification” to decide which patients with type 2 diabetes but without established cardiovascular disease warrant treatment with an SGLT2 inhibitor, she said in an interview. “Given the data, we need more concrete recommendations” from medical societies on how to reasonably use biomarkers and imaging to identify patients with type 2 diabetes who are at increased risk for heart failure and hence would benefit from treatment. “This should be of high interest to guidelines committees,” she added.
The earlier version of Dr. Berg’s score, based exclusively on clinical observations and conventional measures like estimated glomerular filtration rate and urinary creatinine to albumin ratio, had overlap with established criteria for starting treatment with an SGLT2 inhibitor, such as the presence of chronic kidney disease, she noted. “A biomarker-based score may provide the additional level of discrimination needed to characterize risk and potential benefit.”
Asymptomatic diabetic cardiomyopathy
Dr. Aroda and several coauthors recently published a review that describes a subset of patients with type 2 diabetes who might get picked up by intensified screening for heart failure risk: those with asymptomatic diabetic cardiomyopathy, a clinical state that they said represents patients with stage B heart failure based on the new Universal Definition and Classification of Heart Failure. Until recently, these patients with type 2 diabetes and asymptomatic cardiomyopathy have mostly gone unrecognized.
A recent report from Dr. Pandey and associates reviewed records from 2,900 U.S. patients with diabetes and no symptoms who had been included in any of three cohort studies and found echocardiographic evidence of early-stage cardiomyopathy in as many as two-thirds. In an editorial about this report, Dr. Aroda and coauthors called these patients a potential “window of opportunity for prevention and treatment of heart failure.”
“There is evidence of structural cardiac changes that progress through the stages of heart failure,” and starting treatment with an SGLT2 inhibitor during an earlier stage can potentially slow or prevent this progression and thereby limit future functional decline, Dr. Aroda said.
Dr. Sattar agreed. Type 2 diabetes appears to help cause “fluid derangements” and abnormal hemodynamics that produces cardiac stress, changes in heart structure, and adverse remodeling of the heart, a process that “some call cardiomyopathy,” which is exacerbated by other pathologic forces that are also often present in these patients such as obesity and hypertension. SGLT2 inhibitors can help these patients by producing “reverse remodeling of the heart.”
“This process was neglected because for many years our focus was on ischemic heart disease in patients with type 2 diabetes. It was there in plain sight, but we were missing it,” explained Dr. Sattar. Having agents from the SGLT2 inhibitor class “has allowed us to better understand this mechanism.”
The SGLT2 inhibitors are “absolutely the driving reason” why the diabetes–heart failure link has become so important, said Dr. Inzucchi. Having drugs that reduce heart failure risk provided clinicians with a tool that has “changed our mindset.”
“Heart failure prevention has been largely neglected in patients with type 2 diabetes. Reprioritizing heart failure prevention to first and foremost among patients with type 2 diabetes is long overdue,” commented Gregg C. Fonarow, MD, professor and chief of cardiology at the University of California, Los Angeles.
Clinicians don’t like risk scores
Will systematic screening for heart failure risk in selected patients with type 2 diabetes take hold, and with it expanded and better-targeted use of SGLT2 inhibitors?
“I hope so,” said Dr. Kosiborod, but one challenge is that “for the most part clinicians don’t like using risk scores.” Only a few have ever been widely incorporated into practice; mostly they become tools for research. Plus, SGLT2 inhibitor uptake has in general been slow to catch on, which Dr. Kosiborod blames primarily on clinical inertia, a pervasive issue that has also hampered optimal use of drugs as commonplace as statins, ACE inhibitors, and angiotensin-receptor blockers.
“Given the avalanche of positive data, uptake of SGLT2 inhibitors will continue to improve and accelerate; but unfortunately, unless something dramatic happens we’ll likely see their continued underuse for several more years,” he predicted. “Designing better systems of care that prioritize prevention are absolutely needed to improve implementation of effective therapies, including SGLT2 inhibitors.”
Despite their underuse the SGLT2 inhibitor class has, in just 6 years since results from the EMPA-REG OUTCOME trial came out and launched the current treatment era, transformed thinking about the risk that heart failure poses to patients with type 2 diabetes and the need to manage this risk.
“I thank the SGLT2 inhibitors for raising awareness of heart failure risk in patients with diabetes,” and for giving clinicians a new way to mitigate this risk, said Dr. Cheng.
Dr. Berg has been a consultant to AstraZeneca, and received research grant support to his institution from AstraZeneca and Pfizer. Dr. Cheng has received personal fees from multiple pharmaceutical companies. Dr. Kosiborod has been an adviser and consultant to multiple pharmaceutical companies; has received research grants from AstraZeneca and Boehringer Ingelheim; and has received other research support from AstraZeneca. Dr. Pandey has been an adviser to Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; and has received research support from Gilead Sciences, Myovista, and Applied Therapeutics. Dr. Sattar has received consulting honoraria from multiple pharmaceutical companies, and has received grant support from Boehringer Ingelheim, Roche Diagnostics, and Novartis. Dr. Aroda has been a consultant for several pharmaceutical companies; has a spouse employed with Janssen; and has received research support (institutional contracts) from multiple pharmaceutical companies. Dr. Fonarow has been a consultant to several pharmaceutical companies.
Agents that form the sodium-glucose cotransporter 2 inhibitor class – including canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) – have show remarkably consistent cardiovascular efficacy and safety for treating patients with heart failure, chronic kidney disease, and higher-risk patients with type 2 diabetes.
But despite an essential role now established for drugs in the SGLT2 inhibitor class for patients with heart failure with reduced ejection fraction, progressive renal dysfunction, or – most recently – patients with heart failure with preserved ejection fraction, the scope may be less clear when using these agents in patients with type 2 diabetes because they fall across a broad spectrum of risk for cardiorenal disease.
“What makes patients with type 2 diabetes distinct from other patients in whom SGLT2 inhibitors have been studied, such as patients with heart failure, is that they have a much wider spectrum of risk. Low-risk patients with type 2 diabetes were not included in the SGLT2 inhibitor trials. Defining risk in patients with type 2 diabetes has the potential to inform prioritization” for treatment with an SGLT2 inhibitor, explained David D. Berg, MD, who has led one effort to develop risk scores that can risk-stratify patients with type 2 diabetes based on their vulnerability to incident heart failure and hospitalization for these episodes,
The hefty cost for these drugs, with retail prices that run over $6,000 annually for the most widely used and most potent agents in the class, has spurred researchers to try to find cost-effective ways to identify patients with type 2 diabetes who stand to benefit most from taking an SGLT2 inhibitor.
‘Cost must be considered’
“Cost must be considered, and at this point it’s probably more responsible on a societal level to advise using SGLT2 inhibitors mainly in patients [with type 2 diabetes] with compelling indications,” said Silvio Inzucchi, MD, professor and director of the Yale Medicine Diabetes Center in New Haven, Conn. Dr. Inzucchi added, however, that “I can easily foresee a day when these agents are considered foundational therapy for all patients with type 2 diabetes, after they go generic and cost is not a major issue. I’m starting to lean toward this very simplified approach, but the costs are prohibitive at this time.”
“If the SGLT2 inhibitors were available at a low cost, I’d argue that they should be used in all patients with type 2 diabetes who have no contraindications or tolerability issues; but we live in a world where they are not yet low cost,” agreed Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute in Kansas City, Mo.
“We can’t give SGLT2 inhibitors to everyone with type 2 diabetes right now because that would be too costly; these agents are so expensive. You start by targeting the patients with the highest risk” for incident heart failure, said Ambarish Pandey, MD, a cardiologist at the University of Texas Southwestern Medical Center, Dallas.
The spotlight the SGLT2 inhibitor class has received, based on its unexpectedly potent efficacy in cutting rates of acute heart failure episodes in patients with type 2 diabetes, has also sharply raised the profile of this complication of type 2 diabetes, an outcome that until recently many clinicians had largely ignored, overshadowed by a focus on adverse outcomes from atherosclerotic cardiovascular disease such as MIs and strokes.
“Results from the SGLT2 inhibitor trials have reignited interest in the relationship between type 2 diabetes and heart failure and have started to shift the mindset of clinicians toward thinking about reducing both atherothrombotic risk and heart failure risk in patients with type 2 diabetes,” said Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston.
“Prior to the SGLT2 inhibitor trials, heart failure was on the radar of diabetes clinicians only as something to watch for as a potential side effect of certain glucose-lowering therapies. Now that there are therapies that can lower heart failure hospitalization, it’s made us think more about heart failure, how common it is in patients with type 2 diabetes, and what can we do to lower this risk,” commented Alice Y.Y. Cheng, MD, a diabetes specialist at the University of Toronto.
Banking on biomarkers
Risk scores for assessing the likelihood of people developing incident heart failure date back more than a decade. More recent efforts have focused on patients with type 2 diabetes, starting with scores that relied entirely on clinical markers of risk such as prior heart failure, established coronary artery disease, and chronic kidney disease. Reports of two of these validated scores appeared in 2019, one from a team led by Dr. Berg and associates in 2019, and a second score developed by Dr. Pandey and associates.
More recently, both research teams behind these two scores validated newer versions that further refined assessment of patients with diabetes by including biomarkers of incipient heart failure, such as N-terminal of the prohormone brain natriuretic peptide (NT-proBNP). The UT Southwestern group’s biomarker-based score relies on levels of NT-proBNP as well as on levels of high sensitivity troponin T (hsTnT) and C-reactive protein, plus ECG-based assessment of left ventricular hypertrophy to assess risk for incident heart failure. Developers reported in 2021 that this biomarker score could account for 74% (C-statistic) of the 5-year risk for heart failure among patients with diabetes.
The biomarker-based score devised by Dr. Berg and associates, relies on NT-proBNP, hsTnT, and a history of heart failure to predict the risk for a future hospitalization for heart failure. They reported in Diabetes Care that in validation testing this score accounted for 84% of the risk.
“I’m hopeful that both our original clinically-based risk score and our new biomarker-based score will be endorsed by professional society guidelines. The intent of the biomarker-based score is not to replace the clinical one,” Dr. Berg stressed in an interview. But he acknowledged that it uses biomarker values that currently are not routinely collected in U.S. practice. Biomarkers like NT-proBNP “are highly associated with future heart failure risk, but are not yet routinely assessed,” he said. Because of this, “widespread adoption of the [biomarker] risk tool will require some education.”
It may also require some sort of preliminary screening to determine the appropriateness of using it in a specific patient because of the relative expense of a test for NT-proBNP.
A Texas two-step process
“We can’t perform a [NT-proBNP] test on every patient with type 2 diabetes because cost is a huge barrier,” with a U.K. price of roughly £28 (about $40) per test, commented Naveed Sattar, MD, PhD, professor of metabolic medicine at the University of Glasgow. “NT-proBNP is the best biomarker by far to predict risk” for heart failure,” but “it’s too expensive. It’s not going to happen in everyone,” he said in an interview. He suggested taking a two-step approach to identify patients to test for NT-proBNP based on clinical measures like blood pressure, weight and height, lipid levels and renal function and the presence of suggestive symptoms like dyspnea, fatigue, and peripheral edema, an argument he recently spelled out in detail in an editorial he coauthored.
“More work is needed to define which patients would usefully have cardiac biomarkers measured,” Dr. Sattar wrote with his associate.
Two-step is the approach used in routine practice by clinicians at UT Southwestern Medical Center. “We screen all patients with type 2 diabetes and no diagnosed heart failure who are not already on an SGLT2 inhibitor” using their 2019 screening tool, called the WATCH-DM Risk score, said Dr. Pandey. Patients flagged at high risk by their clinical score receive an SGLT2 inhibitor (presuming no contraindications). The remaining patients with low or intermediate risk may then undergo biomarker-based assessment to find additional patients who warrant SGLT2 inhibitor treatment, he said in an interview.
Often, a record of the most important biomarker, NT-proBNP, is already in the patient’s record and less than a year old, in which case clinicians use that value. An NT-proBNP level of at least 125 pg/mL indicates increased risk in people with a body mass index of less than 30 kg/m2, while for those with higher body mass indexes clinicians at Southwestern apply a threshold for higher risk of at least 100 pg/mL.
In addition to starting those patients on an SGLT2 inhibitor, the Southwestern protocol calls for intensified efforts at weight loss and improved fitness to further lower incident heart failure risk, and they are also considering targeting treatment with a glucagonlike peptide–1 receptor agonist to these patients as well. They have a research protocol in place, called WATCH-DM, that will prospectively assess the efficacy of this strategy.
Despite the cost, others also believe that the time is right for biomarker-based tests to boost access to the benefits that treatment with SGLT2 inhibitors can give patients with type 2 diabetes.
“In theory it’s reasonable” to use a risk score like the recent one reported by Dr. Berg and coauthors, said Vanita R. Aroda, MD, an endocrinologist and director of diabetes clinical research at Brigham and Women’s Hospital in Boston. “We need to pay attention to heart failure as an outcome and use risk stratification” to decide which patients with type 2 diabetes but without established cardiovascular disease warrant treatment with an SGLT2 inhibitor, she said in an interview. “Given the data, we need more concrete recommendations” from medical societies on how to reasonably use biomarkers and imaging to identify patients with type 2 diabetes who are at increased risk for heart failure and hence would benefit from treatment. “This should be of high interest to guidelines committees,” she added.
The earlier version of Dr. Berg’s score, based exclusively on clinical observations and conventional measures like estimated glomerular filtration rate and urinary creatinine to albumin ratio, had overlap with established criteria for starting treatment with an SGLT2 inhibitor, such as the presence of chronic kidney disease, she noted. “A biomarker-based score may provide the additional level of discrimination needed to characterize risk and potential benefit.”
Asymptomatic diabetic cardiomyopathy
Dr. Aroda and several coauthors recently published a review that describes a subset of patients with type 2 diabetes who might get picked up by intensified screening for heart failure risk: those with asymptomatic diabetic cardiomyopathy, a clinical state that they said represents patients with stage B heart failure based on the new Universal Definition and Classification of Heart Failure. Until recently, these patients with type 2 diabetes and asymptomatic cardiomyopathy have mostly gone unrecognized.
A recent report from Dr. Pandey and associates reviewed records from 2,900 U.S. patients with diabetes and no symptoms who had been included in any of three cohort studies and found echocardiographic evidence of early-stage cardiomyopathy in as many as two-thirds. In an editorial about this report, Dr. Aroda and coauthors called these patients a potential “window of opportunity for prevention and treatment of heart failure.”
“There is evidence of structural cardiac changes that progress through the stages of heart failure,” and starting treatment with an SGLT2 inhibitor during an earlier stage can potentially slow or prevent this progression and thereby limit future functional decline, Dr. Aroda said.
Dr. Sattar agreed. Type 2 diabetes appears to help cause “fluid derangements” and abnormal hemodynamics that produces cardiac stress, changes in heart structure, and adverse remodeling of the heart, a process that “some call cardiomyopathy,” which is exacerbated by other pathologic forces that are also often present in these patients such as obesity and hypertension. SGLT2 inhibitors can help these patients by producing “reverse remodeling of the heart.”
“This process was neglected because for many years our focus was on ischemic heart disease in patients with type 2 diabetes. It was there in plain sight, but we were missing it,” explained Dr. Sattar. Having agents from the SGLT2 inhibitor class “has allowed us to better understand this mechanism.”
The SGLT2 inhibitors are “absolutely the driving reason” why the diabetes–heart failure link has become so important, said Dr. Inzucchi. Having drugs that reduce heart failure risk provided clinicians with a tool that has “changed our mindset.”
“Heart failure prevention has been largely neglected in patients with type 2 diabetes. Reprioritizing heart failure prevention to first and foremost among patients with type 2 diabetes is long overdue,” commented Gregg C. Fonarow, MD, professor and chief of cardiology at the University of California, Los Angeles.
Clinicians don’t like risk scores
Will systematic screening for heart failure risk in selected patients with type 2 diabetes take hold, and with it expanded and better-targeted use of SGLT2 inhibitors?
“I hope so,” said Dr. Kosiborod, but one challenge is that “for the most part clinicians don’t like using risk scores.” Only a few have ever been widely incorporated into practice; mostly they become tools for research. Plus, SGLT2 inhibitor uptake has in general been slow to catch on, which Dr. Kosiborod blames primarily on clinical inertia, a pervasive issue that has also hampered optimal use of drugs as commonplace as statins, ACE inhibitors, and angiotensin-receptor blockers.
“Given the avalanche of positive data, uptake of SGLT2 inhibitors will continue to improve and accelerate; but unfortunately, unless something dramatic happens we’ll likely see their continued underuse for several more years,” he predicted. “Designing better systems of care that prioritize prevention are absolutely needed to improve implementation of effective therapies, including SGLT2 inhibitors.”
Despite their underuse the SGLT2 inhibitor class has, in just 6 years since results from the EMPA-REG OUTCOME trial came out and launched the current treatment era, transformed thinking about the risk that heart failure poses to patients with type 2 diabetes and the need to manage this risk.
“I thank the SGLT2 inhibitors for raising awareness of heart failure risk in patients with diabetes,” and for giving clinicians a new way to mitigate this risk, said Dr. Cheng.
Dr. Berg has been a consultant to AstraZeneca, and received research grant support to his institution from AstraZeneca and Pfizer. Dr. Cheng has received personal fees from multiple pharmaceutical companies. Dr. Kosiborod has been an adviser and consultant to multiple pharmaceutical companies; has received research grants from AstraZeneca and Boehringer Ingelheim; and has received other research support from AstraZeneca. Dr. Pandey has been an adviser to Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; and has received research support from Gilead Sciences, Myovista, and Applied Therapeutics. Dr. Sattar has received consulting honoraria from multiple pharmaceutical companies, and has received grant support from Boehringer Ingelheim, Roche Diagnostics, and Novartis. Dr. Aroda has been a consultant for several pharmaceutical companies; has a spouse employed with Janssen; and has received research support (institutional contracts) from multiple pharmaceutical companies. Dr. Fonarow has been a consultant to several pharmaceutical companies.
Agents that form the sodium-glucose cotransporter 2 inhibitor class – including canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) – have show remarkably consistent cardiovascular efficacy and safety for treating patients with heart failure, chronic kidney disease, and higher-risk patients with type 2 diabetes.
But despite an essential role now established for drugs in the SGLT2 inhibitor class for patients with heart failure with reduced ejection fraction, progressive renal dysfunction, or – most recently – patients with heart failure with preserved ejection fraction, the scope may be less clear when using these agents in patients with type 2 diabetes because they fall across a broad spectrum of risk for cardiorenal disease.
“What makes patients with type 2 diabetes distinct from other patients in whom SGLT2 inhibitors have been studied, such as patients with heart failure, is that they have a much wider spectrum of risk. Low-risk patients with type 2 diabetes were not included in the SGLT2 inhibitor trials. Defining risk in patients with type 2 diabetes has the potential to inform prioritization” for treatment with an SGLT2 inhibitor, explained David D. Berg, MD, who has led one effort to develop risk scores that can risk-stratify patients with type 2 diabetes based on their vulnerability to incident heart failure and hospitalization for these episodes,
The hefty cost for these drugs, with retail prices that run over $6,000 annually for the most widely used and most potent agents in the class, has spurred researchers to try to find cost-effective ways to identify patients with type 2 diabetes who stand to benefit most from taking an SGLT2 inhibitor.
‘Cost must be considered’
“Cost must be considered, and at this point it’s probably more responsible on a societal level to advise using SGLT2 inhibitors mainly in patients [with type 2 diabetes] with compelling indications,” said Silvio Inzucchi, MD, professor and director of the Yale Medicine Diabetes Center in New Haven, Conn. Dr. Inzucchi added, however, that “I can easily foresee a day when these agents are considered foundational therapy for all patients with type 2 diabetes, after they go generic and cost is not a major issue. I’m starting to lean toward this very simplified approach, but the costs are prohibitive at this time.”
“If the SGLT2 inhibitors were available at a low cost, I’d argue that they should be used in all patients with type 2 diabetes who have no contraindications or tolerability issues; but we live in a world where they are not yet low cost,” agreed Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute in Kansas City, Mo.
“We can’t give SGLT2 inhibitors to everyone with type 2 diabetes right now because that would be too costly; these agents are so expensive. You start by targeting the patients with the highest risk” for incident heart failure, said Ambarish Pandey, MD, a cardiologist at the University of Texas Southwestern Medical Center, Dallas.
The spotlight the SGLT2 inhibitor class has received, based on its unexpectedly potent efficacy in cutting rates of acute heart failure episodes in patients with type 2 diabetes, has also sharply raised the profile of this complication of type 2 diabetes, an outcome that until recently many clinicians had largely ignored, overshadowed by a focus on adverse outcomes from atherosclerotic cardiovascular disease such as MIs and strokes.
“Results from the SGLT2 inhibitor trials have reignited interest in the relationship between type 2 diabetes and heart failure and have started to shift the mindset of clinicians toward thinking about reducing both atherothrombotic risk and heart failure risk in patients with type 2 diabetes,” said Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston.
“Prior to the SGLT2 inhibitor trials, heart failure was on the radar of diabetes clinicians only as something to watch for as a potential side effect of certain glucose-lowering therapies. Now that there are therapies that can lower heart failure hospitalization, it’s made us think more about heart failure, how common it is in patients with type 2 diabetes, and what can we do to lower this risk,” commented Alice Y.Y. Cheng, MD, a diabetes specialist at the University of Toronto.
Banking on biomarkers
Risk scores for assessing the likelihood of people developing incident heart failure date back more than a decade. More recent efforts have focused on patients with type 2 diabetes, starting with scores that relied entirely on clinical markers of risk such as prior heart failure, established coronary artery disease, and chronic kidney disease. Reports of two of these validated scores appeared in 2019, one from a team led by Dr. Berg and associates in 2019, and a second score developed by Dr. Pandey and associates.
More recently, both research teams behind these two scores validated newer versions that further refined assessment of patients with diabetes by including biomarkers of incipient heart failure, such as N-terminal of the prohormone brain natriuretic peptide (NT-proBNP). The UT Southwestern group’s biomarker-based score relies on levels of NT-proBNP as well as on levels of high sensitivity troponin T (hsTnT) and C-reactive protein, plus ECG-based assessment of left ventricular hypertrophy to assess risk for incident heart failure. Developers reported in 2021 that this biomarker score could account for 74% (C-statistic) of the 5-year risk for heart failure among patients with diabetes.
The biomarker-based score devised by Dr. Berg and associates, relies on NT-proBNP, hsTnT, and a history of heart failure to predict the risk for a future hospitalization for heart failure. They reported in Diabetes Care that in validation testing this score accounted for 84% of the risk.
“I’m hopeful that both our original clinically-based risk score and our new biomarker-based score will be endorsed by professional society guidelines. The intent of the biomarker-based score is not to replace the clinical one,” Dr. Berg stressed in an interview. But he acknowledged that it uses biomarker values that currently are not routinely collected in U.S. practice. Biomarkers like NT-proBNP “are highly associated with future heart failure risk, but are not yet routinely assessed,” he said. Because of this, “widespread adoption of the [biomarker] risk tool will require some education.”
It may also require some sort of preliminary screening to determine the appropriateness of using it in a specific patient because of the relative expense of a test for NT-proBNP.
A Texas two-step process
“We can’t perform a [NT-proBNP] test on every patient with type 2 diabetes because cost is a huge barrier,” with a U.K. price of roughly £28 (about $40) per test, commented Naveed Sattar, MD, PhD, professor of metabolic medicine at the University of Glasgow. “NT-proBNP is the best biomarker by far to predict risk” for heart failure,” but “it’s too expensive. It’s not going to happen in everyone,” he said in an interview. He suggested taking a two-step approach to identify patients to test for NT-proBNP based on clinical measures like blood pressure, weight and height, lipid levels and renal function and the presence of suggestive symptoms like dyspnea, fatigue, and peripheral edema, an argument he recently spelled out in detail in an editorial he coauthored.
“More work is needed to define which patients would usefully have cardiac biomarkers measured,” Dr. Sattar wrote with his associate.
Two-step is the approach used in routine practice by clinicians at UT Southwestern Medical Center. “We screen all patients with type 2 diabetes and no diagnosed heart failure who are not already on an SGLT2 inhibitor” using their 2019 screening tool, called the WATCH-DM Risk score, said Dr. Pandey. Patients flagged at high risk by their clinical score receive an SGLT2 inhibitor (presuming no contraindications). The remaining patients with low or intermediate risk may then undergo biomarker-based assessment to find additional patients who warrant SGLT2 inhibitor treatment, he said in an interview.
Often, a record of the most important biomarker, NT-proBNP, is already in the patient’s record and less than a year old, in which case clinicians use that value. An NT-proBNP level of at least 125 pg/mL indicates increased risk in people with a body mass index of less than 30 kg/m2, while for those with higher body mass indexes clinicians at Southwestern apply a threshold for higher risk of at least 100 pg/mL.
In addition to starting those patients on an SGLT2 inhibitor, the Southwestern protocol calls for intensified efforts at weight loss and improved fitness to further lower incident heart failure risk, and they are also considering targeting treatment with a glucagonlike peptide–1 receptor agonist to these patients as well. They have a research protocol in place, called WATCH-DM, that will prospectively assess the efficacy of this strategy.
Despite the cost, others also believe that the time is right for biomarker-based tests to boost access to the benefits that treatment with SGLT2 inhibitors can give patients with type 2 diabetes.
“In theory it’s reasonable” to use a risk score like the recent one reported by Dr. Berg and coauthors, said Vanita R. Aroda, MD, an endocrinologist and director of diabetes clinical research at Brigham and Women’s Hospital in Boston. “We need to pay attention to heart failure as an outcome and use risk stratification” to decide which patients with type 2 diabetes but without established cardiovascular disease warrant treatment with an SGLT2 inhibitor, she said in an interview. “Given the data, we need more concrete recommendations” from medical societies on how to reasonably use biomarkers and imaging to identify patients with type 2 diabetes who are at increased risk for heart failure and hence would benefit from treatment. “This should be of high interest to guidelines committees,” she added.
The earlier version of Dr. Berg’s score, based exclusively on clinical observations and conventional measures like estimated glomerular filtration rate and urinary creatinine to albumin ratio, had overlap with established criteria for starting treatment with an SGLT2 inhibitor, such as the presence of chronic kidney disease, she noted. “A biomarker-based score may provide the additional level of discrimination needed to characterize risk and potential benefit.”
Asymptomatic diabetic cardiomyopathy
Dr. Aroda and several coauthors recently published a review that describes a subset of patients with type 2 diabetes who might get picked up by intensified screening for heart failure risk: those with asymptomatic diabetic cardiomyopathy, a clinical state that they said represents patients with stage B heart failure based on the new Universal Definition and Classification of Heart Failure. Until recently, these patients with type 2 diabetes and asymptomatic cardiomyopathy have mostly gone unrecognized.
A recent report from Dr. Pandey and associates reviewed records from 2,900 U.S. patients with diabetes and no symptoms who had been included in any of three cohort studies and found echocardiographic evidence of early-stage cardiomyopathy in as many as two-thirds. In an editorial about this report, Dr. Aroda and coauthors called these patients a potential “window of opportunity for prevention and treatment of heart failure.”
“There is evidence of structural cardiac changes that progress through the stages of heart failure,” and starting treatment with an SGLT2 inhibitor during an earlier stage can potentially slow or prevent this progression and thereby limit future functional decline, Dr. Aroda said.
Dr. Sattar agreed. Type 2 diabetes appears to help cause “fluid derangements” and abnormal hemodynamics that produces cardiac stress, changes in heart structure, and adverse remodeling of the heart, a process that “some call cardiomyopathy,” which is exacerbated by other pathologic forces that are also often present in these patients such as obesity and hypertension. SGLT2 inhibitors can help these patients by producing “reverse remodeling of the heart.”
“This process was neglected because for many years our focus was on ischemic heart disease in patients with type 2 diabetes. It was there in plain sight, but we were missing it,” explained Dr. Sattar. Having agents from the SGLT2 inhibitor class “has allowed us to better understand this mechanism.”
The SGLT2 inhibitors are “absolutely the driving reason” why the diabetes–heart failure link has become so important, said Dr. Inzucchi. Having drugs that reduce heart failure risk provided clinicians with a tool that has “changed our mindset.”
“Heart failure prevention has been largely neglected in patients with type 2 diabetes. Reprioritizing heart failure prevention to first and foremost among patients with type 2 diabetes is long overdue,” commented Gregg C. Fonarow, MD, professor and chief of cardiology at the University of California, Los Angeles.
Clinicians don’t like risk scores
Will systematic screening for heart failure risk in selected patients with type 2 diabetes take hold, and with it expanded and better-targeted use of SGLT2 inhibitors?
“I hope so,” said Dr. Kosiborod, but one challenge is that “for the most part clinicians don’t like using risk scores.” Only a few have ever been widely incorporated into practice; mostly they become tools for research. Plus, SGLT2 inhibitor uptake has in general been slow to catch on, which Dr. Kosiborod blames primarily on clinical inertia, a pervasive issue that has also hampered optimal use of drugs as commonplace as statins, ACE inhibitors, and angiotensin-receptor blockers.
“Given the avalanche of positive data, uptake of SGLT2 inhibitors will continue to improve and accelerate; but unfortunately, unless something dramatic happens we’ll likely see their continued underuse for several more years,” he predicted. “Designing better systems of care that prioritize prevention are absolutely needed to improve implementation of effective therapies, including SGLT2 inhibitors.”
Despite their underuse the SGLT2 inhibitor class has, in just 6 years since results from the EMPA-REG OUTCOME trial came out and launched the current treatment era, transformed thinking about the risk that heart failure poses to patients with type 2 diabetes and the need to manage this risk.
“I thank the SGLT2 inhibitors for raising awareness of heart failure risk in patients with diabetes,” and for giving clinicians a new way to mitigate this risk, said Dr. Cheng.
Dr. Berg has been a consultant to AstraZeneca, and received research grant support to his institution from AstraZeneca and Pfizer. Dr. Cheng has received personal fees from multiple pharmaceutical companies. Dr. Kosiborod has been an adviser and consultant to multiple pharmaceutical companies; has received research grants from AstraZeneca and Boehringer Ingelheim; and has received other research support from AstraZeneca. Dr. Pandey has been an adviser to Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; and has received research support from Gilead Sciences, Myovista, and Applied Therapeutics. Dr. Sattar has received consulting honoraria from multiple pharmaceutical companies, and has received grant support from Boehringer Ingelheim, Roche Diagnostics, and Novartis. Dr. Aroda has been a consultant for several pharmaceutical companies; has a spouse employed with Janssen; and has received research support (institutional contracts) from multiple pharmaceutical companies. Dr. Fonarow has been a consultant to several pharmaceutical companies.
FROM DIABETES CARE