Seropositive rheumatoid arthritis (RA) patients had twice the risk for developing pneumonia, compared with seronegative patients, in a study of more than 4,000 RA patients from a single U.S. medical system.

“Patients with seropositive RA, particularly RF [rheumatoid factor]-positive RA, had increased risk for pneumonia throughout the RA disease course that was not explained by measured confounders, including smoking status, multimorbidity, medications, and [erythrocyte sedimentation rate] level,” Jeffrey A. Sparks, MD, said at the annual European Congress of Rheumatology, held online this year due to COVID-19.

“There has been much interest about the relationship between lung inflammation and the generation of RF and CCP [cyclic citrullinated protein] prior to the onset of RA. We hypothesized that patients with seropositive RA might have subclinical lung injury that could predispose them to pneumonia after clinical RA onset,” Dr. Sparks said in an interview. “Pneumonia is one of the most common serious infections in both patients with RA and the general population, and it causes serious morbidity and mortality.”

The doubled relative risk for pneumonia seen in the findings “translates into a clinically meaningful finding when considering the high rate and the many patients at risk since RA is relatively common,” said Dr. Sparks, a rheumatologist at Brigham and Women’s Hospital in Boston.

“Patients with RF-positive RA who present with symptoms concerning for pneumonia should be evaluated carefully for this and for other possible pulmonary manifestations of RA. Vaccination for pneumonia should be strongly considered for patients with RA who are on disease-modifying antirheumatic drugs, and we hope that our report encourages clinicians and patients” to undertake vaccination, he said.

His study used a database of more than 60,000 patients diagnosed with RA as of November 2013 in the records of a large Boston-area medical system that includes physicians affiliated with Brigham and Women’s Hospital and Massachusetts General Hospital. The researchers applied a validated algorithm for calculating a patient’s probability of having RA, and at the level of 97% probability they narrowed the cohort down to just under 10,000 patients. Additional winnowing because of missing data or a history of pneumonia yielded a study group of 4,110, which included 3,279 (80%) who were seropositive for either or both CCP and RF, and 831 (20%) who were seronegative. During a median follow-up of 7.8 years and total follow-up of more than 32,000 patient-years, the overall pneumonia incidence was 5.8%, with a 2.8% rate among the seronegatives and a 6.6% rate among seropositives. After adjustment for age, sex, glucocorticoid use, disease-modifying antirheumatic drug use, and several other possible confounders, the researchers calculated a 99% relative increased rate of pneumonia among all seropositive patients, compared with the seronegatives.

Further analysis looked at pneumonia incidence rates among patients positive only for CCP antibody, positive only for RF antibody, or both, compared with seronegative patients. This showed that CCP seropositivity had no statistically significant link with incident pneumonia, while RF seropositivity linked with a statistically significant, roughly twofold higher rate. Only 6% of all seropositive patients were positive only for CCP antibody, 59% were positive specifically for RF antibody, and 35% for both.

The data Dr. Sparks presented did not include information on pneumonia type, the timing of the pneumonia, compared with the onset of RA, disease activity, or smoking intensity.

“We anticipated that both RF positive and CCP positive would each be associated with pneumonia, so it was somewhat surprising that we only detected this for RF,” Dr. Sparks said. But he added that, because the number of patients with only CCP positivity was relatively so small, “it is still possible that CCP [antibody] could also increase pneumonia risk.”

The study had no commercial funding. Dr. Sparks had no disclosures.

mzoler@mdedge.com

SOURCE: Sparks JA et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:73, Abstract OP0111.

Seropositive rheumatoid arthritis (RA) patients had twice the risk for developing pneumonia, compared with seronegative patients, in a study of more than 4,000 RA patients from a single U.S. medical system.

“Patients with seropositive RA, particularly RF [rheumatoid factor]-positive RA, had increased risk for pneumonia throughout the RA disease course that was not explained by measured confounders, including smoking status, multimorbidity, medications, and [erythrocyte sedimentation rate] level,” Jeffrey A. Sparks, MD, said at the annual European Congress of Rheumatology, held online this year due to COVID-19.

“There has been much interest about the relationship between lung inflammation and the generation of RF and CCP [cyclic citrullinated protein] prior to the onset of RA. We hypothesized that patients with seropositive RA might have subclinical lung injury that could predispose them to pneumonia after clinical RA onset,” Dr. Sparks said in an interview. “Pneumonia is one of the most common serious infections in both patients with RA and the general population, and it causes serious morbidity and mortality.”

The doubled relative risk for pneumonia seen in the findings “translates into a clinically meaningful finding when considering the high rate and the many patients at risk since RA is relatively common,” said Dr. Sparks, a rheumatologist at Brigham and Women’s Hospital in Boston.

“Patients with RF-positive RA who present with symptoms concerning for pneumonia should be evaluated carefully for this and for other possible pulmonary manifestations of RA. Vaccination for pneumonia should be strongly considered for patients with RA who are on disease-modifying antirheumatic drugs, and we hope that our report encourages clinicians and patients” to undertake vaccination, he said.

His study used a database of more than 60,000 patients diagnosed with RA as of November 2013 in the records of a large Boston-area medical system that includes physicians affiliated with Brigham and Women’s Hospital and Massachusetts General Hospital. The researchers applied a validated algorithm for calculating a patient’s probability of having RA, and at the level of 97% probability they narrowed the cohort down to just under 10,000 patients. Additional winnowing because of missing data or a history of pneumonia yielded a study group of 4,110, which included 3,279 (80%) who were seropositive for either or both CCP and RF, and 831 (20%) who were seronegative. During a median follow-up of 7.8 years and total follow-up of more than 32,000 patient-years, the overall pneumonia incidence was 5.8%, with a 2.8% rate among the seronegatives and a 6.6% rate among seropositives. After adjustment for age, sex, glucocorticoid use, disease-modifying antirheumatic drug use, and several other possible confounders, the researchers calculated a 99% relative increased rate of pneumonia among all seropositive patients, compared with the seronegatives.

Further analysis looked at pneumonia incidence rates among patients positive only for CCP antibody, positive only for RF antibody, or both, compared with seronegative patients. This showed that CCP seropositivity had no statistically significant link with incident pneumonia, while RF seropositivity linked with a statistically significant, roughly twofold higher rate. Only 6% of all seropositive patients were positive only for CCP antibody, 59% were positive specifically for RF antibody, and 35% for both.

The data Dr. Sparks presented did not include information on pneumonia type, the timing of the pneumonia, compared with the onset of RA, disease activity, or smoking intensity.

“We anticipated that both RF positive and CCP positive would each be associated with pneumonia, so it was somewhat surprising that we only detected this for RF,” Dr. Sparks said. But he added that, because the number of patients with only CCP positivity was relatively so small, “it is still possible that CCP [antibody] could also increase pneumonia risk.”

The study had no commercial funding. Dr. Sparks had no disclosures.

mzoler@mdedge.com

SOURCE: Sparks JA et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:73, Abstract OP0111.

Seropositive rheumatoid arthritis (RA) patients had twice the risk for developing pneumonia, compared with seronegative patients, in a study of more than 4,000 RA patients from a single U.S. medical system.

“Patients with seropositive RA, particularly RF [rheumatoid factor]-positive RA, had increased risk for pneumonia throughout the RA disease course that was not explained by measured confounders, including smoking status, multimorbidity, medications, and [erythrocyte sedimentation rate] level,” Jeffrey A. Sparks, MD, said at the annual European Congress of Rheumatology, held online this year due to COVID-19.

“There has been much interest about the relationship between lung inflammation and the generation of RF and CCP [cyclic citrullinated protein] prior to the onset of RA. We hypothesized that patients with seropositive RA might have subclinical lung injury that could predispose them to pneumonia after clinical RA onset,” Dr. Sparks said in an interview. “Pneumonia is one of the most common serious infections in both patients with RA and the general population, and it causes serious morbidity and mortality.”

The doubled relative risk for pneumonia seen in the findings “translates into a clinically meaningful finding when considering the high rate and the many patients at risk since RA is relatively common,” said Dr. Sparks, a rheumatologist at Brigham and Women’s Hospital in Boston.

“Patients with RF-positive RA who present with symptoms concerning for pneumonia should be evaluated carefully for this and for other possible pulmonary manifestations of RA. Vaccination for pneumonia should be strongly considered for patients with RA who are on disease-modifying antirheumatic drugs, and we hope that our report encourages clinicians and patients” to undertake vaccination, he said.

His study used a database of more than 60,000 patients diagnosed with RA as of November 2013 in the records of a large Boston-area medical system that includes physicians affiliated with Brigham and Women’s Hospital and Massachusetts General Hospital. The researchers applied a validated algorithm for calculating a patient’s probability of having RA, and at the level of 97% probability they narrowed the cohort down to just under 10,000 patients. Additional winnowing because of missing data or a history of pneumonia yielded a study group of 4,110, which included 3,279 (80%) who were seropositive for either or both CCP and RF, and 831 (20%) who were seronegative. During a median follow-up of 7.8 years and total follow-up of more than 32,000 patient-years, the overall pneumonia incidence was 5.8%, with a 2.8% rate among the seronegatives and a 6.6% rate among seropositives. After adjustment for age, sex, glucocorticoid use, disease-modifying antirheumatic drug use, and several other possible confounders, the researchers calculated a 99% relative increased rate of pneumonia among all seropositive patients, compared with the seronegatives.

Further analysis looked at pneumonia incidence rates among patients positive only for CCP antibody, positive only for RF antibody, or both, compared with seronegative patients. This showed that CCP seropositivity had no statistically significant link with incident pneumonia, while RF seropositivity linked with a statistically significant, roughly twofold higher rate. Only 6% of all seropositive patients were positive only for CCP antibody, 59% were positive specifically for RF antibody, and 35% for both.

The data Dr. Sparks presented did not include information on pneumonia type, the timing of the pneumonia, compared with the onset of RA, disease activity, or smoking intensity.

“We anticipated that both RF positive and CCP positive would each be associated with pneumonia, so it was somewhat surprising that we only detected this for RF,” Dr. Sparks said. But he added that, because the number of patients with only CCP positivity was relatively so small, “it is still possible that CCP [antibody] could also increase pneumonia risk.”

The study had no commercial funding. Dr. Sparks had no disclosures.

mzoler@mdedge.com

SOURCE: Sparks JA et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:73, Abstract OP0111.

Psychosocial interventions, particularly cognitive-behavioral therapy (CBT), are associated with enhanced immune system function, new research suggests.

Results of a systematic review and meta-analysis that included 56 randomized controlled trials and more than 4,000 participants showed that over time, psychosocial interventions appeared to augment beneficial immune system function while concurrently decreasing harmful immune system function in comparison with control conditions.

“These associations were most reliable for cognitive-behavioral therapy and multiple or combined interventions and for studies that assessed proinflammatory cytokines or markers, which are key indicators of inflammation in the body,” study investigator George M. Slavich, PhD, said in an interview.

“The analysis helps address the question of which types of psychosocial interventions are most consistently associated with changes in immune system function, under what conditions, and for whom. This knowledge could, in turn, be used to inform research efforts and public policy aimed at using psychosocial interventions to improve immune-related health outcomes,” added Dr. Slavich, director of the Laboratory for Stress Assessment and Research, University of California, Los Angeles.

The study was published online June 3 in JAMA Psychiatry.

Link to serious physical, mental illnesses

There is substantial evidence that the immune system plays a role in a variety of mental and physical health problems. Such problems include anxiety disorders, depression, suicide, schizophrenia, cardiovascular disease, autoimmune disorders, and neurodegenerative diseases. It has been recently suggested that more than half of all deaths worldwide are attributable to inflammation-related conditions.

Although pharmacologic interventions can play a role in addressing inflammation, they are not without drawbacks, most notably, cost and adverse side effects.

The World Health Organization, the National Academy of Medicine, the National Institutes of Health, and other groups have emphasized the importance of addressing global disease burden through psychosocial interventions when possible.

Such recommendations are supported by scientific evidence. Previous research has shown that immune system processes are influenced by a variety of social, neurocognitive, and behavioral factors.

Given such findings, researchers have examined the effects of interventions that reduce stress or bolster psychological resources on immune system function.

However, such research has yielded conflicting findings. Some studies show that psychosocial interventions clearly enhance immunity, whereas others do not.

In addition, questions remain regarding which types of interventions reliably improve immune system function, under what conditions, and for whom.

“Research has shown that psychological factors – such as life stress, negative emotions, and social support – are associated with changes in immune system function,” Dr. Slavich noted.

“In addition, there is growing appreciation that immune system processes involved in inflammation may contribute to peoples’ risk for several major mental and physical health problems, including anxiety disorders, depression, heart disease, and autoimmune and neurodegenerative disorders.”
 

First study of its kind

To shed light on these potential links, the researchers conducted what they believe is the first systematic review and meta-analysis of randomized clinical trials of the effects of psychosocial interventions on immune system outcomes.

As part of the review, Dr. Slavich and colleagues estimated the associations between eight psychosocial interventions and seven markers of immune system function.

The eight psychosocial interventions were behavior therapy, cognitive therapy, CBT, CBT plus additive treatment or mode of delivery, bereavement or supportive therapy, multiple or combined interventions, other psychotherapy, and psychoeducation.

The seven immune outcomes that might be influenced by these interventions are proinflammatory cytokines and markers, anti-inflammatory cytokines, antibodies, immune cell counts, natural killer cell activity, viral load, and other immune outcomes.

The researchers also examined nine potential factors that might moderate the associations between psychosocial interventions and immune system function.

They searched a variety of databases for all relevant randomized controlled trials published through Dec. 31, 2018. Studies were eligible for inclusion if they included a psychosocial intervention and immune outcome, as well as preintervention and postintervention immunologic assessments.

The researchers identified 4,621 studies. Of these studies, 62 were eligible for inclusion; 56, which included 4,060 patients, were included in the final meta-analysis.

Results showed that psychosocial interventions were associated with enhanced immune system function (P < .001). There was relatively low heterogeneity between studies in these effect sizes, which, the investigators said, indicates that the association was relatively consistent across studies and conditions.

The meta-analysis showed that individuals who were assigned to a psychosocial intervention condition demonstrated a 14.7% improvement (95% confidence interval [CI], 5.7%–23.8%) in beneficial immune system function compared with their counterparts who were assigned to a control condition.

Similarly, participants who received psychosocial interventions demonstrated an 18.0% decrease (95% CI, 7.2%–28.8%) in harmful immune system function over time.

A standout

Regarding the effect of the type of intervention on the association, only CBT (31 studies; P < .001) and multiple or combined interventions (seven studies; P = .01) were significantly associated with changes in immune system outcomes.

The analysis also found that interventions that included a group component were more consistently associated with enhanced immune function than were those that did not include a group component. Nevertheless, this difference did not reach statistical significance (P = .06).

Contrary to the researchers’ expectations, the analysis also revealed that intervention length did not moderate the association between psychosocial interventions and immune system function (P = .93).

With respect to the type of immune marker studied, the meta-analysis found that psychosocial interventions had significantly different associations with the various immune markers studied. Of the seven immune outcomes investigated, only proinflammatory cytokine or marker levels (33 studies; P < .001) and immune cell counts (27 studies; P < .001) were significantly associated with the psychosocial interventions examined.

The associations between psychosocial intervention and immune system function persisted for at least 6 months following treatment and were robust across age, sex, and intervention duration.

These results suggest that psychosocial interventions – particularly CBT and multiple or combined psychotherapeutic modalities – may play an important role in improving immune-related health outcomes.

Such interventions may not only be effective, they may also prove to be affordable alternatives to current therapeutic options. The mean length of a CBT intervention in the meta-analysis was 10.4 weeks, which the investigators equated with a total cost of $1,560 per patient.

“By comparison, the cost of using infliximab to reduce inflammation in persons with an autoimmune disorder is approximately $25,000 per patient per year,” they wrote.

“The results suggest the possibility that psychotherapy may be helpful for reducing inflammation and improving immune-related health in certain circumstances,” Dr. Slavich concluded. “However, the studies that we examined differed in terms of their quality, and we did not examine health outcomes in the present investigation.

“Therefore, more research needs to be done to determine how the present findings might be translated into treatment options or public policy.”
 

A path to better health

In an accompanying editorial, Veronika Engert, PhD, Joshua A. Grant, PhD, and Bernhard Strauss, PhD, noted that although infectious disease was once the primary cause of death in society, it has been supplanted by other complex and chronic illnesses, which often do not follow simple cause-and-effect associations.

“Rather,” they wrote, “these illnesses develop from a complex milieu of biological, psychological, and social factors that may also influence the disease progress and its prognosis. Against this backdrop, the meta-analysis by Shields and colleagues is an important confirmation of the biopsychosocial model.”

The editorialists explained that recent psychophysiological, neurobiological, and epigenetic research offers a glimpse into the relationship between psychological and social factors in pathogenesis. Nevertheless, the authors noted that a comprehensive examination of the potential effects of psychosocial interventions on immune parameters in various physical health conditions has been lacking.

“The evidence provided by Shields et al. is exactly what is needed to more fully shift treatment from an illness-centered to a patient-centered approach,” they wrote. “To that end, this meta-analysis may serve as a guide for policy makers aiming to improve immune-associated health.”

The research was supported by a Society in Science–Branco Weiss Fellowship, Brain and Behavior Research, and the National Institutes of Health. Dr. Slavich, Dr. Engert, Dr. Grant, and Dr. Strauss have disclosed no relevant financial relationships.
 

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

Psychosocial interventions, particularly cognitive-behavioral therapy (CBT), are associated with enhanced immune system function, new research suggests.

Results of a systematic review and meta-analysis that included 56 randomized controlled trials and more than 4,000 participants showed that over time, psychosocial interventions appeared to augment beneficial immune system function while concurrently decreasing harmful immune system function in comparison with control conditions.

“These associations were most reliable for cognitive-behavioral therapy and multiple or combined interventions and for studies that assessed proinflammatory cytokines or markers, which are key indicators of inflammation in the body,” study investigator George M. Slavich, PhD, said in an interview.

“The analysis helps address the question of which types of psychosocial interventions are most consistently associated with changes in immune system function, under what conditions, and for whom. This knowledge could, in turn, be used to inform research efforts and public policy aimed at using psychosocial interventions to improve immune-related health outcomes,” added Dr. Slavich, director of the Laboratory for Stress Assessment and Research, University of California, Los Angeles.

The study was published online June 3 in JAMA Psychiatry.

Link to serious physical, mental illnesses

There is substantial evidence that the immune system plays a role in a variety of mental and physical health problems. Such problems include anxiety disorders, depression, suicide, schizophrenia, cardiovascular disease, autoimmune disorders, and neurodegenerative diseases. It has been recently suggested that more than half of all deaths worldwide are attributable to inflammation-related conditions.

Although pharmacologic interventions can play a role in addressing inflammation, they are not without drawbacks, most notably, cost and adverse side effects.

The World Health Organization, the National Academy of Medicine, the National Institutes of Health, and other groups have emphasized the importance of addressing global disease burden through psychosocial interventions when possible.

Such recommendations are supported by scientific evidence. Previous research has shown that immune system processes are influenced by a variety of social, neurocognitive, and behavioral factors.

Given such findings, researchers have examined the effects of interventions that reduce stress or bolster psychological resources on immune system function.

However, such research has yielded conflicting findings. Some studies show that psychosocial interventions clearly enhance immunity, whereas others do not.

In addition, questions remain regarding which types of interventions reliably improve immune system function, under what conditions, and for whom.

“Research has shown that psychological factors – such as life stress, negative emotions, and social support – are associated with changes in immune system function,” Dr. Slavich noted.

“In addition, there is growing appreciation that immune system processes involved in inflammation may contribute to peoples’ risk for several major mental and physical health problems, including anxiety disorders, depression, heart disease, and autoimmune and neurodegenerative disorders.”
 

First study of its kind

To shed light on these potential links, the researchers conducted what they believe is the first systematic review and meta-analysis of randomized clinical trials of the effects of psychosocial interventions on immune system outcomes.

As part of the review, Dr. Slavich and colleagues estimated the associations between eight psychosocial interventions and seven markers of immune system function.

The eight psychosocial interventions were behavior therapy, cognitive therapy, CBT, CBT plus additive treatment or mode of delivery, bereavement or supportive therapy, multiple or combined interventions, other psychotherapy, and psychoeducation.

The seven immune outcomes that might be influenced by these interventions are proinflammatory cytokines and markers, anti-inflammatory cytokines, antibodies, immune cell counts, natural killer cell activity, viral load, and other immune outcomes.

The researchers also examined nine potential factors that might moderate the associations between psychosocial interventions and immune system function.

They searched a variety of databases for all relevant randomized controlled trials published through Dec. 31, 2018. Studies were eligible for inclusion if they included a psychosocial intervention and immune outcome, as well as preintervention and postintervention immunologic assessments.

The researchers identified 4,621 studies. Of these studies, 62 were eligible for inclusion; 56, which included 4,060 patients, were included in the final meta-analysis.

Results showed that psychosocial interventions were associated with enhanced immune system function (P < .001). There was relatively low heterogeneity between studies in these effect sizes, which, the investigators said, indicates that the association was relatively consistent across studies and conditions.

The meta-analysis showed that individuals who were assigned to a psychosocial intervention condition demonstrated a 14.7% improvement (95% confidence interval [CI], 5.7%–23.8%) in beneficial immune system function compared with their counterparts who were assigned to a control condition.

Similarly, participants who received psychosocial interventions demonstrated an 18.0% decrease (95% CI, 7.2%–28.8%) in harmful immune system function over time.

A standout

Regarding the effect of the type of intervention on the association, only CBT (31 studies; P < .001) and multiple or combined interventions (seven studies; P = .01) were significantly associated with changes in immune system outcomes.

The analysis also found that interventions that included a group component were more consistently associated with enhanced immune function than were those that did not include a group component. Nevertheless, this difference did not reach statistical significance (P = .06).

Contrary to the researchers’ expectations, the analysis also revealed that intervention length did not moderate the association between psychosocial interventions and immune system function (P = .93).

With respect to the type of immune marker studied, the meta-analysis found that psychosocial interventions had significantly different associations with the various immune markers studied. Of the seven immune outcomes investigated, only proinflammatory cytokine or marker levels (33 studies; P < .001) and immune cell counts (27 studies; P < .001) were significantly associated with the psychosocial interventions examined.

The associations between psychosocial intervention and immune system function persisted for at least 6 months following treatment and were robust across age, sex, and intervention duration.

These results suggest that psychosocial interventions – particularly CBT and multiple or combined psychotherapeutic modalities – may play an important role in improving immune-related health outcomes.

Such interventions may not only be effective, they may also prove to be affordable alternatives to current therapeutic options. The mean length of a CBT intervention in the meta-analysis was 10.4 weeks, which the investigators equated with a total cost of $1,560 per patient.

“By comparison, the cost of using infliximab to reduce inflammation in persons with an autoimmune disorder is approximately $25,000 per patient per year,” they wrote.

“The results suggest the possibility that psychotherapy may be helpful for reducing inflammation and improving immune-related health in certain circumstances,” Dr. Slavich concluded. “However, the studies that we examined differed in terms of their quality, and we did not examine health outcomes in the present investigation.

“Therefore, more research needs to be done to determine how the present findings might be translated into treatment options or public policy.”
 

A path to better health

In an accompanying editorial, Veronika Engert, PhD, Joshua A. Grant, PhD, and Bernhard Strauss, PhD, noted that although infectious disease was once the primary cause of death in society, it has been supplanted by other complex and chronic illnesses, which often do not follow simple cause-and-effect associations.

“Rather,” they wrote, “these illnesses develop from a complex milieu of biological, psychological, and social factors that may also influence the disease progress and its prognosis. Against this backdrop, the meta-analysis by Shields and colleagues is an important confirmation of the biopsychosocial model.”

The editorialists explained that recent psychophysiological, neurobiological, and epigenetic research offers a glimpse into the relationship between psychological and social factors in pathogenesis. Nevertheless, the authors noted that a comprehensive examination of the potential effects of psychosocial interventions on immune parameters in various physical health conditions has been lacking.

“The evidence provided by Shields et al. is exactly what is needed to more fully shift treatment from an illness-centered to a patient-centered approach,” they wrote. “To that end, this meta-analysis may serve as a guide for policy makers aiming to improve immune-associated health.”

The research was supported by a Society in Science–Branco Weiss Fellowship, Brain and Behavior Research, and the National Institutes of Health. Dr. Slavich, Dr. Engert, Dr. Grant, and Dr. Strauss have disclosed no relevant financial relationships.
 

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

Psychosocial interventions, particularly cognitive-behavioral therapy (CBT), are associated with enhanced immune system function, new research suggests.

Results of a systematic review and meta-analysis that included 56 randomized controlled trials and more than 4,000 participants showed that over time, psychosocial interventions appeared to augment beneficial immune system function while concurrently decreasing harmful immune system function in comparison with control conditions.

“These associations were most reliable for cognitive-behavioral therapy and multiple or combined interventions and for studies that assessed proinflammatory cytokines or markers, which are key indicators of inflammation in the body,” study investigator George M. Slavich, PhD, said in an interview.

“The analysis helps address the question of which types of psychosocial interventions are most consistently associated with changes in immune system function, under what conditions, and for whom. This knowledge could, in turn, be used to inform research efforts and public policy aimed at using psychosocial interventions to improve immune-related health outcomes,” added Dr. Slavich, director of the Laboratory for Stress Assessment and Research, University of California, Los Angeles.

The study was published online June 3 in JAMA Psychiatry.

Link to serious physical, mental illnesses

There is substantial evidence that the immune system plays a role in a variety of mental and physical health problems. Such problems include anxiety disorders, depression, suicide, schizophrenia, cardiovascular disease, autoimmune disorders, and neurodegenerative diseases. It has been recently suggested that more than half of all deaths worldwide are attributable to inflammation-related conditions.

Although pharmacologic interventions can play a role in addressing inflammation, they are not without drawbacks, most notably, cost and adverse side effects.

The World Health Organization, the National Academy of Medicine, the National Institutes of Health, and other groups have emphasized the importance of addressing global disease burden through psychosocial interventions when possible.

Such recommendations are supported by scientific evidence. Previous research has shown that immune system processes are influenced by a variety of social, neurocognitive, and behavioral factors.

Given such findings, researchers have examined the effects of interventions that reduce stress or bolster psychological resources on immune system function.

However, such research has yielded conflicting findings. Some studies show that psychosocial interventions clearly enhance immunity, whereas others do not.

In addition, questions remain regarding which types of interventions reliably improve immune system function, under what conditions, and for whom.

“Research has shown that psychological factors – such as life stress, negative emotions, and social support – are associated with changes in immune system function,” Dr. Slavich noted.

“In addition, there is growing appreciation that immune system processes involved in inflammation may contribute to peoples’ risk for several major mental and physical health problems, including anxiety disorders, depression, heart disease, and autoimmune and neurodegenerative disorders.”
 

First study of its kind

To shed light on these potential links, the researchers conducted what they believe is the first systematic review and meta-analysis of randomized clinical trials of the effects of psychosocial interventions on immune system outcomes.

As part of the review, Dr. Slavich and colleagues estimated the associations between eight psychosocial interventions and seven markers of immune system function.

The eight psychosocial interventions were behavior therapy, cognitive therapy, CBT, CBT plus additive treatment or mode of delivery, bereavement or supportive therapy, multiple or combined interventions, other psychotherapy, and psychoeducation.

The seven immune outcomes that might be influenced by these interventions are proinflammatory cytokines and markers, anti-inflammatory cytokines, antibodies, immune cell counts, natural killer cell activity, viral load, and other immune outcomes.

The researchers also examined nine potential factors that might moderate the associations between psychosocial interventions and immune system function.

They searched a variety of databases for all relevant randomized controlled trials published through Dec. 31, 2018. Studies were eligible for inclusion if they included a psychosocial intervention and immune outcome, as well as preintervention and postintervention immunologic assessments.

The researchers identified 4,621 studies. Of these studies, 62 were eligible for inclusion; 56, which included 4,060 patients, were included in the final meta-analysis.

Results showed that psychosocial interventions were associated with enhanced immune system function (P < .001). There was relatively low heterogeneity between studies in these effect sizes, which, the investigators said, indicates that the association was relatively consistent across studies and conditions.

The meta-analysis showed that individuals who were assigned to a psychosocial intervention condition demonstrated a 14.7% improvement (95% confidence interval [CI], 5.7%–23.8%) in beneficial immune system function compared with their counterparts who were assigned to a control condition.

Similarly, participants who received psychosocial interventions demonstrated an 18.0% decrease (95% CI, 7.2%–28.8%) in harmful immune system function over time.

A standout

Regarding the effect of the type of intervention on the association, only CBT (31 studies; P < .001) and multiple or combined interventions (seven studies; P = .01) were significantly associated with changes in immune system outcomes.

The analysis also found that interventions that included a group component were more consistently associated with enhanced immune function than were those that did not include a group component. Nevertheless, this difference did not reach statistical significance (P = .06).

Contrary to the researchers’ expectations, the analysis also revealed that intervention length did not moderate the association between psychosocial interventions and immune system function (P = .93).

With respect to the type of immune marker studied, the meta-analysis found that psychosocial interventions had significantly different associations with the various immune markers studied. Of the seven immune outcomes investigated, only proinflammatory cytokine or marker levels (33 studies; P < .001) and immune cell counts (27 studies; P < .001) were significantly associated with the psychosocial interventions examined.

The associations between psychosocial intervention and immune system function persisted for at least 6 months following treatment and were robust across age, sex, and intervention duration.

These results suggest that psychosocial interventions – particularly CBT and multiple or combined psychotherapeutic modalities – may play an important role in improving immune-related health outcomes.

Such interventions may not only be effective, they may also prove to be affordable alternatives to current therapeutic options. The mean length of a CBT intervention in the meta-analysis was 10.4 weeks, which the investigators equated with a total cost of $1,560 per patient.

“By comparison, the cost of using infliximab to reduce inflammation in persons with an autoimmune disorder is approximately $25,000 per patient per year,” they wrote.

“The results suggest the possibility that psychotherapy may be helpful for reducing inflammation and improving immune-related health in certain circumstances,” Dr. Slavich concluded. “However, the studies that we examined differed in terms of their quality, and we did not examine health outcomes in the present investigation.

“Therefore, more research needs to be done to determine how the present findings might be translated into treatment options or public policy.”
 

A path to better health

In an accompanying editorial, Veronika Engert, PhD, Joshua A. Grant, PhD, and Bernhard Strauss, PhD, noted that although infectious disease was once the primary cause of death in society, it has been supplanted by other complex and chronic illnesses, which often do not follow simple cause-and-effect associations.

“Rather,” they wrote, “these illnesses develop from a complex milieu of biological, psychological, and social factors that may also influence the disease progress and its prognosis. Against this backdrop, the meta-analysis by Shields and colleagues is an important confirmation of the biopsychosocial model.”

The editorialists explained that recent psychophysiological, neurobiological, and epigenetic research offers a glimpse into the relationship between psychological and social factors in pathogenesis. Nevertheless, the authors noted that a comprehensive examination of the potential effects of psychosocial interventions on immune parameters in various physical health conditions has been lacking.

“The evidence provided by Shields et al. is exactly what is needed to more fully shift treatment from an illness-centered to a patient-centered approach,” they wrote. “To that end, this meta-analysis may serve as a guide for policy makers aiming to improve immune-associated health.”

The research was supported by a Society in Science–Branco Weiss Fellowship, Brain and Behavior Research, and the National Institutes of Health. Dr. Slavich, Dr. Engert, Dr. Grant, and Dr. Strauss have disclosed no relevant financial relationships.
 

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

Six of eight relapsed/refractory acute myeloid leukemia patients, and one patient with accelerated phase chronic myelogenous leukemia, had no sign of residual disease 4 weeks after receiving compound CAR T therapy targeting both CD33 and CLL1.

Six patients moved on to subsequent hematopoietic stem cell transplantation (HSCT); the seventh responder withdrew from the study for personal reasons, according to a report at the virtual annual congress of the European Hematology Association.

Much work remains, but the initial results suggest that “CLL1-CD33 compound CAR T cell therapy could be developed as a bridge to transplant, a supplement to chemotherapy, or a standalone therapy for patients with acute myeloid leukemia” and other myeloid malignancies. The approach might also allow for reduced intensity conditioning or nonmyeloablative conditioning for HSCT, said lead investigator Fang Liu, MD, PhD, of the department of hematology at the Chengdu Military General Hospital, in Sichuan province, China.

It’s “a topic that will interest a lot of us.” For the first time, “a compound CAR with two independent CAR units induced remissions in AML,” said Pieter Sonneveld, MD, PhD, of the Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands, who introduced Dr. Liu’s presentation.

Chimeric antigen receptor (CAR) T cell therapy works well for B-cell malignancies, but translation to AML is “yet to be accomplished.” Meanwhile, despite progress against AML, about one-third of patients still relapse, “and prognosis for relapsed or refractory AML is dismal,” Dr. Liu and her team said.

CAR T is generally aimed against a single target, but AML bears heterogeneous cells that offset killing by single target therapies, resulting in disease relapse.

That problem suggested targeting multiple antigens simultaneously. CLL1 is an “ideal target,” Dr. Liu said, because the myeloid lineage antigen is highly expressed in AML, but absent in normal hematopoietic stem cells. CD33, meanwhile, is expressed on bulk AML cells in the majority of patients.

The CAR T cells were manufactured from autologous cells in eight of the subjects, and from a human leukocyte antigen-matched sibling donor cells for the ninth. The patients were lymphodepleted with fludarabine and cyclophosphamide, then infused with the therapeutic cells by a dose escalation at approximately 1-3 x 10⁶/kg in a single or split dose.

On disease reevaluation within 4 weeks, seven of nine patients – all with relapsed or refractory disease after multiple conventional treatments – were minimal residual disease negative by flow cytometry. The other two had no response, one of whom was CD33 positive but CLL1 negative, “indicating the importance of [the] CLL1 target in CAR T treatment,” the investigators said.

All nine patients developed grade 4 pancytopenia; eight had cytokine release syndrome (CRS), which was grade 3 in two; and four subjects developed neurotoxicity, which was grade 3 in three.

Five subjects had mild liver enzyme elevations; four had a coagulation disorder; four developed diarrhea; three developed sepsis; two fungal infections; and three pneumonia. One subject had a skin rash and one developed renal insufficiency.

The adverse events resolved after treatment. “Early intervention with steroids had a positive effect on the reduction of CRS and neurotoxicity,” the team noted.

Of the six patients who went on to HCST, one had standard myeloablative conditioning, but the rest had reduced intensity conditioning. Five subjects successfully engrafted with persistent full chimerism, but one died of sepsis before engraftment.

The median age was 32 years. The median bone marrow blast count before treatment was 47%. Seven subjects had de novo AML; one – a 6-year-old girl – had juvenile myelomonocytic leukemia that transformed into AML; and one had accelerated phase chronic myelogenous leukemia.

A phase 1 trial is underway (NCT03795779).

The work was funded by iCell Gene Therapeutics. Several investigators were employees. Dr. Liu didn’t report any disclosures.

aotto@mdedge.com

SOURCE: Liu F et al. EHA Congress. Abstract S149.

Six of eight relapsed/refractory acute myeloid leukemia patients, and one patient with accelerated phase chronic myelogenous leukemia, had no sign of residual disease 4 weeks after receiving compound CAR T therapy targeting both CD33 and CLL1.

Six patients moved on to subsequent hematopoietic stem cell transplantation (HSCT); the seventh responder withdrew from the study for personal reasons, according to a report at the virtual annual congress of the European Hematology Association.

Much work remains, but the initial results suggest that “CLL1-CD33 compound CAR T cell therapy could be developed as a bridge to transplant, a supplement to chemotherapy, or a standalone therapy for patients with acute myeloid leukemia” and other myeloid malignancies. The approach might also allow for reduced intensity conditioning or nonmyeloablative conditioning for HSCT, said lead investigator Fang Liu, MD, PhD, of the department of hematology at the Chengdu Military General Hospital, in Sichuan province, China.

It’s “a topic that will interest a lot of us.” For the first time, “a compound CAR with two independent CAR units induced remissions in AML,” said Pieter Sonneveld, MD, PhD, of the Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands, who introduced Dr. Liu’s presentation.

Chimeric antigen receptor (CAR) T cell therapy works well for B-cell malignancies, but translation to AML is “yet to be accomplished.” Meanwhile, despite progress against AML, about one-third of patients still relapse, “and prognosis for relapsed or refractory AML is dismal,” Dr. Liu and her team said.

CAR T is generally aimed against a single target, but AML bears heterogeneous cells that offset killing by single target therapies, resulting in disease relapse.

That problem suggested targeting multiple antigens simultaneously. CLL1 is an “ideal target,” Dr. Liu said, because the myeloid lineage antigen is highly expressed in AML, but absent in normal hematopoietic stem cells. CD33, meanwhile, is expressed on bulk AML cells in the majority of patients.

The CAR T cells were manufactured from autologous cells in eight of the subjects, and from a human leukocyte antigen-matched sibling donor cells for the ninth. The patients were lymphodepleted with fludarabine and cyclophosphamide, then infused with the therapeutic cells by a dose escalation at approximately 1-3 x 10⁶/kg in a single or split dose.

On disease reevaluation within 4 weeks, seven of nine patients – all with relapsed or refractory disease after multiple conventional treatments – were minimal residual disease negative by flow cytometry. The other two had no response, one of whom was CD33 positive but CLL1 negative, “indicating the importance of [the] CLL1 target in CAR T treatment,” the investigators said.

All nine patients developed grade 4 pancytopenia; eight had cytokine release syndrome (CRS), which was grade 3 in two; and four subjects developed neurotoxicity, which was grade 3 in three.

Five subjects had mild liver enzyme elevations; four had a coagulation disorder; four developed diarrhea; three developed sepsis; two fungal infections; and three pneumonia. One subject had a skin rash and one developed renal insufficiency.

The adverse events resolved after treatment. “Early intervention with steroids had a positive effect on the reduction of CRS and neurotoxicity,” the team noted.

Of the six patients who went on to HCST, one had standard myeloablative conditioning, but the rest had reduced intensity conditioning. Five subjects successfully engrafted with persistent full chimerism, but one died of sepsis before engraftment.

The median age was 32 years. The median bone marrow blast count before treatment was 47%. Seven subjects had de novo AML; one – a 6-year-old girl – had juvenile myelomonocytic leukemia that transformed into AML; and one had accelerated phase chronic myelogenous leukemia.

A phase 1 trial is underway (NCT03795779).

The work was funded by iCell Gene Therapeutics. Several investigators were employees. Dr. Liu didn’t report any disclosures.

aotto@mdedge.com

SOURCE: Liu F et al. EHA Congress. Abstract S149.

Six of eight relapsed/refractory acute myeloid leukemia patients, and one patient with accelerated phase chronic myelogenous leukemia, had no sign of residual disease 4 weeks after receiving compound CAR T therapy targeting both CD33 and CLL1.

Six patients moved on to subsequent hematopoietic stem cell transplantation (HSCT); the seventh responder withdrew from the study for personal reasons, according to a report at the virtual annual congress of the European Hematology Association.

Much work remains, but the initial results suggest that “CLL1-CD33 compound CAR T cell therapy could be developed as a bridge to transplant, a supplement to chemotherapy, or a standalone therapy for patients with acute myeloid leukemia” and other myeloid malignancies. The approach might also allow for reduced intensity conditioning or nonmyeloablative conditioning for HSCT, said lead investigator Fang Liu, MD, PhD, of the department of hematology at the Chengdu Military General Hospital, in Sichuan province, China.

It’s “a topic that will interest a lot of us.” For the first time, “a compound CAR with two independent CAR units induced remissions in AML,” said Pieter Sonneveld, MD, PhD, of the Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands, who introduced Dr. Liu’s presentation.

Chimeric antigen receptor (CAR) T cell therapy works well for B-cell malignancies, but translation to AML is “yet to be accomplished.” Meanwhile, despite progress against AML, about one-third of patients still relapse, “and prognosis for relapsed or refractory AML is dismal,” Dr. Liu and her team said.

CAR T is generally aimed against a single target, but AML bears heterogeneous cells that offset killing by single target therapies, resulting in disease relapse.

That problem suggested targeting multiple antigens simultaneously. CLL1 is an “ideal target,” Dr. Liu said, because the myeloid lineage antigen is highly expressed in AML, but absent in normal hematopoietic stem cells. CD33, meanwhile, is expressed on bulk AML cells in the majority of patients.

The CAR T cells were manufactured from autologous cells in eight of the subjects, and from a human leukocyte antigen-matched sibling donor cells for the ninth. The patients were lymphodepleted with fludarabine and cyclophosphamide, then infused with the therapeutic cells by a dose escalation at approximately 1-3 x 10⁶/kg in a single or split dose.

On disease reevaluation within 4 weeks, seven of nine patients – all with relapsed or refractory disease after multiple conventional treatments – were minimal residual disease negative by flow cytometry. The other two had no response, one of whom was CD33 positive but CLL1 negative, “indicating the importance of [the] CLL1 target in CAR T treatment,” the investigators said.

All nine patients developed grade 4 pancytopenia; eight had cytokine release syndrome (CRS), which was grade 3 in two; and four subjects developed neurotoxicity, which was grade 3 in three.

Five subjects had mild liver enzyme elevations; four had a coagulation disorder; four developed diarrhea; three developed sepsis; two fungal infections; and three pneumonia. One subject had a skin rash and one developed renal insufficiency.

The adverse events resolved after treatment. “Early intervention with steroids had a positive effect on the reduction of CRS and neurotoxicity,” the team noted.

Of the six patients who went on to HCST, one had standard myeloablative conditioning, but the rest had reduced intensity conditioning. Five subjects successfully engrafted with persistent full chimerism, but one died of sepsis before engraftment.

The median age was 32 years. The median bone marrow blast count before treatment was 47%. Seven subjects had de novo AML; one – a 6-year-old girl – had juvenile myelomonocytic leukemia that transformed into AML; and one had accelerated phase chronic myelogenous leukemia.

A phase 1 trial is underway (NCT03795779).

The work was funded by iCell Gene Therapeutics. Several investigators were employees. Dr. Liu didn’t report any disclosures.

aotto@mdedge.com

SOURCE: Liu F et al. EHA Congress. Abstract S149.

Optimizing glycemic control “is the key to overall treatment in people with diabetes and COVID-19,” said Antonio Ceriello, MD, during a June 5 webinar sponsored by Harvard Medical School, Boston.

©Tashatuvango/Thinkstockphotos.com

Dr. Ceriello, a research consultant with the Italian Ministry of Health, IRCCS Multi-Medica, Milan, highlighted a recent study that examined the association of blood glucose control and outcomes in COVID-19 patients with preexisting type 2 diabetes.

Among 7,000 cases of COVID-19, type 2 diabetes correlated with a higher death rate. However, those with well-controlled blood glucose (upper limit ≤10 mmol/L) had a survival rate of 98.9%, compared with just 11% among those with poorly controlled blood glucose (upper limit >10 mmol/L), a reduction in risk of 86% (adjusted hazard ratio, 0.14; Cell Metab. 2020 May 1. doi: 10.1016/j.cmet.2020.04.021).

Clinicians should also consider the possible side effects of hypoglycemic agents in the evolution of this disease. This is true of all patients, not just diabetes patients, Dr. Ceriello said. “We have data showing that ... hyperglycemia contributes directly to worsening the prognosis of COVID-19 independent of the presence of diabetes.”

One study found that the glycosylation of ACE-2 played an important role in allowing cellular entry of the virus (Am J Physiol Endocrinol Metab. 2020 Mar 31;318:E736-41). “This is something that could be related to hyperglycemia,” he added.

Another risk factor is thrombosis, a clear contributor to death rates in COVID-19. Research on thrombosis incidence in COVID-19 patients with diabetes reported higher levels of D-dimer levels in people with diabetes, especially among those who couldn’t manage their disease.

Tying all of these factors together, Dr. Ceriello discussed how ACE-2 glycosylation, in combination with other factors in SARS-CoV-2 infection, could lead to hyperglycemia, thrombosis, and subsequently multiorgan damage in diabetes patients.

Other research has associated higher HbA1c levels (mean HbA1c, 7.5%) with higher mortality risk in COVID-19 patients, said another speaker, Linong Ji, MD, director for endocrinology and metabolism at Peking University People’s Hospital, Beijing, and director of Peking University’s Diabetes Center. Proper guidance is key to ensuring early detection of hyperglycemic crisis in people with diabetes, advised Dr. Ji.

Global management of diabetes in SARS-CoV-2 patients is “quite challenging,” given that most patients don’t have their diabetes under control, said host and moderator A. Enrique Caballero, MD, an endocrinologist/investigator in the division of endocrinology, diabetes, and hypertension and division of global health equity at Brigham and Women’s Hospital, Boston. “They are not meeting treatment targets for cholesterol or glucose control. So we’re not managing optimal care. And now on top of this, we have COVID-19.”

Optimizing glycemic control “is the key to overall treatment in people with diabetes and COVID-19,” said Antonio Ceriello, MD, during a June 5 webinar sponsored by Harvard Medical School, Boston.

©Tashatuvango/Thinkstockphotos.com

Dr. Ceriello, a research consultant with the Italian Ministry of Health, IRCCS Multi-Medica, Milan, highlighted a recent study that examined the association of blood glucose control and outcomes in COVID-19 patients with preexisting type 2 diabetes.

Among 7,000 cases of COVID-19, type 2 diabetes correlated with a higher death rate. However, those with well-controlled blood glucose (upper limit ≤10 mmol/L) had a survival rate of 98.9%, compared with just 11% among those with poorly controlled blood glucose (upper limit >10 mmol/L), a reduction in risk of 86% (adjusted hazard ratio, 0.14; Cell Metab. 2020 May 1. doi: 10.1016/j.cmet.2020.04.021).

Clinicians should also consider the possible side effects of hypoglycemic agents in the evolution of this disease. This is true of all patients, not just diabetes patients, Dr. Ceriello said. “We have data showing that ... hyperglycemia contributes directly to worsening the prognosis of COVID-19 independent of the presence of diabetes.”

One study found that the glycosylation of ACE-2 played an important role in allowing cellular entry of the virus (Am J Physiol Endocrinol Metab. 2020 Mar 31;318:E736-41). “This is something that could be related to hyperglycemia,” he added.

Another risk factor is thrombosis, a clear contributor to death rates in COVID-19. Research on thrombosis incidence in COVID-19 patients with diabetes reported higher levels of D-dimer levels in people with diabetes, especially among those who couldn’t manage their disease.

Tying all of these factors together, Dr. Ceriello discussed how ACE-2 glycosylation, in combination with other factors in SARS-CoV-2 infection, could lead to hyperglycemia, thrombosis, and subsequently multiorgan damage in diabetes patients.

Other research has associated higher HbA1c levels (mean HbA1c, 7.5%) with higher mortality risk in COVID-19 patients, said another speaker, Linong Ji, MD, director for endocrinology and metabolism at Peking University People’s Hospital, Beijing, and director of Peking University’s Diabetes Center. Proper guidance is key to ensuring early detection of hyperglycemic crisis in people with diabetes, advised Dr. Ji.

Global management of diabetes in SARS-CoV-2 patients is “quite challenging,” given that most patients don’t have their diabetes under control, said host and moderator A. Enrique Caballero, MD, an endocrinologist/investigator in the division of endocrinology, diabetes, and hypertension and division of global health equity at Brigham and Women’s Hospital, Boston. “They are not meeting treatment targets for cholesterol or glucose control. So we’re not managing optimal care. And now on top of this, we have COVID-19.”

Optimizing glycemic control “is the key to overall treatment in people with diabetes and COVID-19,” said Antonio Ceriello, MD, during a June 5 webinar sponsored by Harvard Medical School, Boston.

©Tashatuvango/Thinkstockphotos.com

Dr. Ceriello, a research consultant with the Italian Ministry of Health, IRCCS Multi-Medica, Milan, highlighted a recent study that examined the association of blood glucose control and outcomes in COVID-19 patients with preexisting type 2 diabetes.

Among 7,000 cases of COVID-19, type 2 diabetes correlated with a higher death rate. However, those with well-controlled blood glucose (upper limit ≤10 mmol/L) had a survival rate of 98.9%, compared with just 11% among those with poorly controlled blood glucose (upper limit >10 mmol/L), a reduction in risk of 86% (adjusted hazard ratio, 0.14; Cell Metab. 2020 May 1. doi: 10.1016/j.cmet.2020.04.021).

Clinicians should also consider the possible side effects of hypoglycemic agents in the evolution of this disease. This is true of all patients, not just diabetes patients, Dr. Ceriello said. “We have data showing that ... hyperglycemia contributes directly to worsening the prognosis of COVID-19 independent of the presence of diabetes.”

One study found that the glycosylation of ACE-2 played an important role in allowing cellular entry of the virus (Am J Physiol Endocrinol Metab. 2020 Mar 31;318:E736-41). “This is something that could be related to hyperglycemia,” he added.

Another risk factor is thrombosis, a clear contributor to death rates in COVID-19. Research on thrombosis incidence in COVID-19 patients with diabetes reported higher levels of D-dimer levels in people with diabetes, especially among those who couldn’t manage their disease.

Tying all of these factors together, Dr. Ceriello discussed how ACE-2 glycosylation, in combination with other factors in SARS-CoV-2 infection, could lead to hyperglycemia, thrombosis, and subsequently multiorgan damage in diabetes patients.

Other research has associated higher HbA1c levels (mean HbA1c, 7.5%) with higher mortality risk in COVID-19 patients, said another speaker, Linong Ji, MD, director for endocrinology and metabolism at Peking University People’s Hospital, Beijing, and director of Peking University’s Diabetes Center. Proper guidance is key to ensuring early detection of hyperglycemic crisis in people with diabetes, advised Dr. Ji.

Global management of diabetes in SARS-CoV-2 patients is “quite challenging,” given that most patients don’t have their diabetes under control, said host and moderator A. Enrique Caballero, MD, an endocrinologist/investigator in the division of endocrinology, diabetes, and hypertension and division of global health equity at Brigham and Women’s Hospital, Boston. “They are not meeting treatment targets for cholesterol or glucose control. So we’re not managing optimal care. And now on top of this, we have COVID-19.”

For patients with high-risk chronic lymphocytic leukemia (CLL), first-line therapy with a triple combination of targeted agents showed encouraging response rates in the phase 2 CLL2-GIVe trial.

Among 41 patients with untreated CLL bearing deleterious TP53 mutations and/or the 17p chromosomal deletion who received the GIVe regimen consisting of obinutuzumab (Gazyva), ibrutinib (Imbruvica), and venetoclax (Venclexta), the complete response rate at final restaging was 58.5%, and 33 patients with a confirmed response were negative for minimal residual disease after a median follow-up of 18.6 months, reported Henriette Huber, MD, of University Hospital Ulm, Germany.

“The GIVe regimen is promising first-line therapy for patients with high-risk CLL,” she said in a presentation during the virtual annual congress of the European Hematology Association.

The overall safety profile of the combination was acceptable, she said, but added that “some higher-grade infections are of concern.” The rate of grade 3 or greater infections/infestations in the study was 19.5%.

Sound rationale (with caveat)

Another adverse event of concern is the rate of atrial fibrillation in the comparatively young patient population (median age 62), noted Alexey Danilov, MD, PhD, of City of Hope in Duarte Calif., who commented on the study for MDedge.

He pointed out that second-generation Bruton’s tyrosine kinase (BTK) inhibitors such as acalabrutinib (Calquence) may pose a lower risk of atrial fibrillation than the BTK inhibitor ibrutinib used in the CLL2-GIVe study.

In general, however, the rationale for the combination is sound, Dr. Danilov said.

“Of all the patient populations that we deal with within CLL, this probably would be most appropriate for this type of therapy. Patients with deletion 17p or TP53 mutations still represent an unmet medical need compared to other patients who don’t have those mutations,” he said.

Patients with CLL bearing the mutations have lower clinical response rates to novel therapies and generally do not respond well to chemoimmunotherapy, he said.

“The question becomes whether using these all at the same time, versus sequential strategies – using one drug and then after that, at relapse, another – is better, and obviously this trial doesn’t address that,” he said.
 

Three targets

The investigators enrolled 24 men and 17 women with untreated CLL with del(17p) and/or TP53 mutations and adequate organ function (creatinine clearance rate of more than 50 mL/min). The median age was 62 (range 35-85 years); 78% of patients had Binet stage B or C disease. The median Cumulative Illness Rating Scale (CIRS) score was 3 (range 0 to 8).

All patients received treatment with the combination for 6 months. The CD20 inhibitor obinutuzumab was given in a dose of 1,000 mg on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6. The BTK inhibitor ibrutinib was given continuously at a dose of 420 mg per day beginning on the first day of the first cycle. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, was started on day 22 of cycle 1, and was increased to 400 mg per day over 5 weeks until the end of cycle 12.

If patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) according to International Workshop on CLL criteria at final restaging (performed with imaging at the end of cycle 12 followed by bone marrow biopsy 2 months later), ibrutinib would be stopped beginning at cycle 15. Patients who did not have a CR or CRi would continue on ibrutinib until cycle 36.

Encouraging results

All but 3 of the 41 patients reached final restaging. Analyses of efficacy and safety included all 41 patients.

The CR/CRi rate at final restaging, the primary endpoint, was accomplished in 24 patients (58.8%), and 14 patients (34.1%) had a partial response.

Of the three patients for whom responses could not be assessed, two died (one from ovarian cancer which was retrospectively determined to have been present at enrollment, and one at cycle 9 from cardiac failure), and the third patient withdrew consent at cycle 10.

In all, 33 patients (80.5%) were MRD-negative in peripheral blood, 4 remained MRD positive, and 4 were not assessed. Per protocol, 22 patients with undetectable MRD and a CR or CRi discontinued therapy at week 15. An additional 13 patients also discontinued therapy because of adverse events or other reasons, and 6 remained on therapy beyond cycle 15.

The most frequent adverse events of any grade through the end of cycle 14 were gastrointestinal disorders in 83%, none higher than grade 2; infections and infestations in 70.7%, of which 19.5% were grade 3 or greater in severity; and blood and lymphatic system disorders in 58.5%, most of which (53.7%) were grade 3 or greater.

Cardiac disorders were reported in 19.5% of all patients, including 12.2% with atrial fibrillation; grade 3 or greater atrial fibrillation occurred in 2.4% of patients.

There was one case each of cerebral aspergillosis, progressive multifocal leukoencephalopathy (without PCR testing), urosepsis, staphylococcal sepsis and febrile infection.

Laboratory confirmed tumor lysis syndrome, all grade 3 or greater, was reported in 9.8% of patients. Infusion-related reactions were reported in 29.3% of patients, with a total of 7.3% being grade 3 or greater.

The trial was supported by Janssen-Cilag and Roche. Dr. Huber disclosed travel reimbursement from Novartis. Dr. Danilov disclosed consulting for AbbVie, Janssen, and Genentech.

SOURCE: Huber H et al. EHA Congress. Abstract S157.

For patients with high-risk chronic lymphocytic leukemia (CLL), first-line therapy with a triple combination of targeted agents showed encouraging response rates in the phase 2 CLL2-GIVe trial.

Among 41 patients with untreated CLL bearing deleterious TP53 mutations and/or the 17p chromosomal deletion who received the GIVe regimen consisting of obinutuzumab (Gazyva), ibrutinib (Imbruvica), and venetoclax (Venclexta), the complete response rate at final restaging was 58.5%, and 33 patients with a confirmed response were negative for minimal residual disease after a median follow-up of 18.6 months, reported Henriette Huber, MD, of University Hospital Ulm, Germany.

“The GIVe regimen is promising first-line therapy for patients with high-risk CLL,” she said in a presentation during the virtual annual congress of the European Hematology Association.

The overall safety profile of the combination was acceptable, she said, but added that “some higher-grade infections are of concern.” The rate of grade 3 or greater infections/infestations in the study was 19.5%.

Sound rationale (with caveat)

Another adverse event of concern is the rate of atrial fibrillation in the comparatively young patient population (median age 62), noted Alexey Danilov, MD, PhD, of City of Hope in Duarte Calif., who commented on the study for MDedge.

He pointed out that second-generation Bruton’s tyrosine kinase (BTK) inhibitors such as acalabrutinib (Calquence) may pose a lower risk of atrial fibrillation than the BTK inhibitor ibrutinib used in the CLL2-GIVe study.

In general, however, the rationale for the combination is sound, Dr. Danilov said.

“Of all the patient populations that we deal with within CLL, this probably would be most appropriate for this type of therapy. Patients with deletion 17p or TP53 mutations still represent an unmet medical need compared to other patients who don’t have those mutations,” he said.

Patients with CLL bearing the mutations have lower clinical response rates to novel therapies and generally do not respond well to chemoimmunotherapy, he said.

“The question becomes whether using these all at the same time, versus sequential strategies – using one drug and then after that, at relapse, another – is better, and obviously this trial doesn’t address that,” he said.
 

Three targets

The investigators enrolled 24 men and 17 women with untreated CLL with del(17p) and/or TP53 mutations and adequate organ function (creatinine clearance rate of more than 50 mL/min). The median age was 62 (range 35-85 years); 78% of patients had Binet stage B or C disease. The median Cumulative Illness Rating Scale (CIRS) score was 3 (range 0 to 8).

All patients received treatment with the combination for 6 months. The CD20 inhibitor obinutuzumab was given in a dose of 1,000 mg on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6. The BTK inhibitor ibrutinib was given continuously at a dose of 420 mg per day beginning on the first day of the first cycle. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, was started on day 22 of cycle 1, and was increased to 400 mg per day over 5 weeks until the end of cycle 12.

If patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) according to International Workshop on CLL criteria at final restaging (performed with imaging at the end of cycle 12 followed by bone marrow biopsy 2 months later), ibrutinib would be stopped beginning at cycle 15. Patients who did not have a CR or CRi would continue on ibrutinib until cycle 36.

Encouraging results

All but 3 of the 41 patients reached final restaging. Analyses of efficacy and safety included all 41 patients.

The CR/CRi rate at final restaging, the primary endpoint, was accomplished in 24 patients (58.8%), and 14 patients (34.1%) had a partial response.

Of the three patients for whom responses could not be assessed, two died (one from ovarian cancer which was retrospectively determined to have been present at enrollment, and one at cycle 9 from cardiac failure), and the third patient withdrew consent at cycle 10.

In all, 33 patients (80.5%) were MRD-negative in peripheral blood, 4 remained MRD positive, and 4 were not assessed. Per protocol, 22 patients with undetectable MRD and a CR or CRi discontinued therapy at week 15. An additional 13 patients also discontinued therapy because of adverse events or other reasons, and 6 remained on therapy beyond cycle 15.

The most frequent adverse events of any grade through the end of cycle 14 were gastrointestinal disorders in 83%, none higher than grade 2; infections and infestations in 70.7%, of which 19.5% were grade 3 or greater in severity; and blood and lymphatic system disorders in 58.5%, most of which (53.7%) were grade 3 or greater.

Cardiac disorders were reported in 19.5% of all patients, including 12.2% with atrial fibrillation; grade 3 or greater atrial fibrillation occurred in 2.4% of patients.

There was one case each of cerebral aspergillosis, progressive multifocal leukoencephalopathy (without PCR testing), urosepsis, staphylococcal sepsis and febrile infection.

Laboratory confirmed tumor lysis syndrome, all grade 3 or greater, was reported in 9.8% of patients. Infusion-related reactions were reported in 29.3% of patients, with a total of 7.3% being grade 3 or greater.

The trial was supported by Janssen-Cilag and Roche. Dr. Huber disclosed travel reimbursement from Novartis. Dr. Danilov disclosed consulting for AbbVie, Janssen, and Genentech.

SOURCE: Huber H et al. EHA Congress. Abstract S157.

For patients with high-risk chronic lymphocytic leukemia (CLL), first-line therapy with a triple combination of targeted agents showed encouraging response rates in the phase 2 CLL2-GIVe trial.

Among 41 patients with untreated CLL bearing deleterious TP53 mutations and/or the 17p chromosomal deletion who received the GIVe regimen consisting of obinutuzumab (Gazyva), ibrutinib (Imbruvica), and venetoclax (Venclexta), the complete response rate at final restaging was 58.5%, and 33 patients with a confirmed response were negative for minimal residual disease after a median follow-up of 18.6 months, reported Henriette Huber, MD, of University Hospital Ulm, Germany.

“The GIVe regimen is promising first-line therapy for patients with high-risk CLL,” she said in a presentation during the virtual annual congress of the European Hematology Association.

The overall safety profile of the combination was acceptable, she said, but added that “some higher-grade infections are of concern.” The rate of grade 3 or greater infections/infestations in the study was 19.5%.

Sound rationale (with caveat)

Another adverse event of concern is the rate of atrial fibrillation in the comparatively young patient population (median age 62), noted Alexey Danilov, MD, PhD, of City of Hope in Duarte Calif., who commented on the study for MDedge.

He pointed out that second-generation Bruton’s tyrosine kinase (BTK) inhibitors such as acalabrutinib (Calquence) may pose a lower risk of atrial fibrillation than the BTK inhibitor ibrutinib used in the CLL2-GIVe study.

In general, however, the rationale for the combination is sound, Dr. Danilov said.

“Of all the patient populations that we deal with within CLL, this probably would be most appropriate for this type of therapy. Patients with deletion 17p or TP53 mutations still represent an unmet medical need compared to other patients who don’t have those mutations,” he said.

Patients with CLL bearing the mutations have lower clinical response rates to novel therapies and generally do not respond well to chemoimmunotherapy, he said.

“The question becomes whether using these all at the same time, versus sequential strategies – using one drug and then after that, at relapse, another – is better, and obviously this trial doesn’t address that,” he said.
 

Three targets

The investigators enrolled 24 men and 17 women with untreated CLL with del(17p) and/or TP53 mutations and adequate organ function (creatinine clearance rate of more than 50 mL/min). The median age was 62 (range 35-85 years); 78% of patients had Binet stage B or C disease. The median Cumulative Illness Rating Scale (CIRS) score was 3 (range 0 to 8).

All patients received treatment with the combination for 6 months. The CD20 inhibitor obinutuzumab was given in a dose of 1,000 mg on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6. The BTK inhibitor ibrutinib was given continuously at a dose of 420 mg per day beginning on the first day of the first cycle. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, was started on day 22 of cycle 1, and was increased to 400 mg per day over 5 weeks until the end of cycle 12.

If patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) according to International Workshop on CLL criteria at final restaging (performed with imaging at the end of cycle 12 followed by bone marrow biopsy 2 months later), ibrutinib would be stopped beginning at cycle 15. Patients who did not have a CR or CRi would continue on ibrutinib until cycle 36.

Encouraging results

All but 3 of the 41 patients reached final restaging. Analyses of efficacy and safety included all 41 patients.

The CR/CRi rate at final restaging, the primary endpoint, was accomplished in 24 patients (58.8%), and 14 patients (34.1%) had a partial response.

Of the three patients for whom responses could not be assessed, two died (one from ovarian cancer which was retrospectively determined to have been present at enrollment, and one at cycle 9 from cardiac failure), and the third patient withdrew consent at cycle 10.

In all, 33 patients (80.5%) were MRD-negative in peripheral blood, 4 remained MRD positive, and 4 were not assessed. Per protocol, 22 patients with undetectable MRD and a CR or CRi discontinued therapy at week 15. An additional 13 patients also discontinued therapy because of adverse events or other reasons, and 6 remained on therapy beyond cycle 15.

The most frequent adverse events of any grade through the end of cycle 14 were gastrointestinal disorders in 83%, none higher than grade 2; infections and infestations in 70.7%, of which 19.5% were grade 3 or greater in severity; and blood and lymphatic system disorders in 58.5%, most of which (53.7%) were grade 3 or greater.

Cardiac disorders were reported in 19.5% of all patients, including 12.2% with atrial fibrillation; grade 3 or greater atrial fibrillation occurred in 2.4% of patients.

There was one case each of cerebral aspergillosis, progressive multifocal leukoencephalopathy (without PCR testing), urosepsis, staphylococcal sepsis and febrile infection.

Laboratory confirmed tumor lysis syndrome, all grade 3 or greater, was reported in 9.8% of patients. Infusion-related reactions were reported in 29.3% of patients, with a total of 7.3% being grade 3 or greater.

The trial was supported by Janssen-Cilag and Roche. Dr. Huber disclosed travel reimbursement from Novartis. Dr. Danilov disclosed consulting for AbbVie, Janssen, and Genentech.

SOURCE: Huber H et al. EHA Congress. Abstract S157.

Secondary respiratory infections appear to be highly prevalent among patients with severe COVID-19, but at this point, most pulmonologists aren’t sure what to make of this understudied phenomenon.

“We really do not understand the implications of secondary infections on outcomes in COVID-19 patients,” David L. Bowton, MD, FCCP, said in an interview. “In most early reports the incidence of secondary infections was much higher in patients dying from COVID-19, compared to survivors, but it isn’t clear whether this indicates that the secondary infection itself led to excess mortality or was more a marker of the severity of the COVID-19 infection.

“Further, details of the diagnostic criteria used, the microbiology, and the appropriateness of treatment of these secondary infections has not generally been included in these reports,” added Dr. Bowton, a pulmonologist and professor emeritus of critical care anesthesiology at Wake Forest University, Winston-Salem, N.C.

One such early retrospective cohort study included 191 COVID-19 patients in Wuhan, China. Of the 54 who died in hospital, half had secondary bacterial lung infections (Lancet. 2020 Mar 28;395[10229]:1054-62). That comes as no surprise to U.S. pulmonologists, who learned back in their training that many deaths during the so-called Spanish influenza epidemic of 1918-1920 were actually caused by secondary pneumonia involving Staphylococcus aureus, commented Daniel L. Ouellette, MD, FCCP, associate director of medical critical care at Henry Ford Hospital, Detroit.

“Critically ill patients are highly susceptible to secondary infections regardless of the cause of the patient’s critical illness,” he noted in an interview. “Recent reports of secondary infections in patients critically ill from COVID-19 are interesting but should be considered in this context. To confirm that COVID-19 patients have a different, or increased, risk of infection at specific sites or from specific agents will require careful study.”

That will be no easy matter given the challenges of obtaining bronchoalveolar lavage samples in mechanically ventilated patients with COVID-19, according to Eric J. Gartman, MD, FCCP, a pulmonologist at Brown University, Providence, R.I., and director of the pulmonary function laboratory at the Providence Veterans Affairs Medical Center.

“Unfortunately, many of the invasive modalities that are typically employed to help diagnose secondary infections in critically ill patients are being severely limited or even prohibited in COVID-19 patients due to infection control measures,” he said. As a result, Dr. Gartman noted, intensivists are often resorting to empiric broad-spectrum antimicrobial therapy in patients with severe COVID-19 and are without ready access to the bacterial cultures which might otherwise permit later treatment de-escalation or retargeting.

Among the myriad areas of uncertainty regarding COVID-19 is the proportion of bacterial coinfections that are hospital acquired. Given the lengthy duration of invasive mechanical ventilation in patients with severe COVID-19 – a mean of 9.1 days in the United Kingdom – the chances of hospital-acquired infection are likely substantial. Moreover, a recent single-center U.K. study involving microbiologic testing in 195 consecutive patients newly hospitalized for COVID-19 reported that community-acquired bacterial infection was uncommon: Just 4% of patients had pneumococcal coinfection at hospital admission, and S. aureus wasn’t detected in anyone (Lancet. 2020;1:362. doi:10.1016/S2666-5247[20]30036-7). French investigators have reported detecting putative invasive pulmonary aspergillosis in nearly one-third of a small series of 27 consecutive mechanically ventilated COVID-19 patients (Lancet Resp Med. 2020; 8[6]:e48-9). Dr. Gartman said the diagnostic testing methods utilized in this and similar reports haven’t been prospectively validated in COVID-19. The testing methods may not indicate invasive Aspergillus infection in this population with a high degree of certainty, since they have previously been performed mainly in patients with hematologic malignancies.

“Although there is nothing definitive regarding this research, as a practicing critical care doctor one should respect these findings and consider this secondary diagnosis if the supporting clinical data is positive, especially given that the mortality risk in this population is high,” he advised.

Dr. Bowton said that he and his fellow intensivists at Wake Forest Baptist Health don’t routinely screen COVID-19 patients for secondary bacterial or fungal infections. And in talking with colleagues around the country, it’s his impression that most have similarly elected not to do so.

“However, our clinical index of suspicion for secondary infections is heightened and, if triggered, will initiate a search for and treatment of these secondary infections,” Dr. Bowton said.
 

bjancin@mdedge.com

Secondary respiratory infections appear to be highly prevalent among patients with severe COVID-19, but at this point, most pulmonologists aren’t sure what to make of this understudied phenomenon.

“We really do not understand the implications of secondary infections on outcomes in COVID-19 patients,” David L. Bowton, MD, FCCP, said in an interview. “In most early reports the incidence of secondary infections was much higher in patients dying from COVID-19, compared to survivors, but it isn’t clear whether this indicates that the secondary infection itself led to excess mortality or was more a marker of the severity of the COVID-19 infection.

“Further, details of the diagnostic criteria used, the microbiology, and the appropriateness of treatment of these secondary infections has not generally been included in these reports,” added Dr. Bowton, a pulmonologist and professor emeritus of critical care anesthesiology at Wake Forest University, Winston-Salem, N.C.

One such early retrospective cohort study included 191 COVID-19 patients in Wuhan, China. Of the 54 who died in hospital, half had secondary bacterial lung infections (Lancet. 2020 Mar 28;395[10229]:1054-62). That comes as no surprise to U.S. pulmonologists, who learned back in their training that many deaths during the so-called Spanish influenza epidemic of 1918-1920 were actually caused by secondary pneumonia involving Staphylococcus aureus, commented Daniel L. Ouellette, MD, FCCP, associate director of medical critical care at Henry Ford Hospital, Detroit.

“Critically ill patients are highly susceptible to secondary infections regardless of the cause of the patient’s critical illness,” he noted in an interview. “Recent reports of secondary infections in patients critically ill from COVID-19 are interesting but should be considered in this context. To confirm that COVID-19 patients have a different, or increased, risk of infection at specific sites or from specific agents will require careful study.”

That will be no easy matter given the challenges of obtaining bronchoalveolar lavage samples in mechanically ventilated patients with COVID-19, according to Eric J. Gartman, MD, FCCP, a pulmonologist at Brown University, Providence, R.I., and director of the pulmonary function laboratory at the Providence Veterans Affairs Medical Center.

“Unfortunately, many of the invasive modalities that are typically employed to help diagnose secondary infections in critically ill patients are being severely limited or even prohibited in COVID-19 patients due to infection control measures,” he said. As a result, Dr. Gartman noted, intensivists are often resorting to empiric broad-spectrum antimicrobial therapy in patients with severe COVID-19 and are without ready access to the bacterial cultures which might otherwise permit later treatment de-escalation or retargeting.

Among the myriad areas of uncertainty regarding COVID-19 is the proportion of bacterial coinfections that are hospital acquired. Given the lengthy duration of invasive mechanical ventilation in patients with severe COVID-19 – a mean of 9.1 days in the United Kingdom – the chances of hospital-acquired infection are likely substantial. Moreover, a recent single-center U.K. study involving microbiologic testing in 195 consecutive patients newly hospitalized for COVID-19 reported that community-acquired bacterial infection was uncommon: Just 4% of patients had pneumococcal coinfection at hospital admission, and S. aureus wasn’t detected in anyone (Lancet. 2020;1:362. doi:10.1016/S2666-5247[20]30036-7). French investigators have reported detecting putative invasive pulmonary aspergillosis in nearly one-third of a small series of 27 consecutive mechanically ventilated COVID-19 patients (Lancet Resp Med. 2020; 8[6]:e48-9). Dr. Gartman said the diagnostic testing methods utilized in this and similar reports haven’t been prospectively validated in COVID-19. The testing methods may not indicate invasive Aspergillus infection in this population with a high degree of certainty, since they have previously been performed mainly in patients with hematologic malignancies.

“Although there is nothing definitive regarding this research, as a practicing critical care doctor one should respect these findings and consider this secondary diagnosis if the supporting clinical data is positive, especially given that the mortality risk in this population is high,” he advised.

Dr. Bowton said that he and his fellow intensivists at Wake Forest Baptist Health don’t routinely screen COVID-19 patients for secondary bacterial or fungal infections. And in talking with colleagues around the country, it’s his impression that most have similarly elected not to do so.

“However, our clinical index of suspicion for secondary infections is heightened and, if triggered, will initiate a search for and treatment of these secondary infections,” Dr. Bowton said.
 

bjancin@mdedge.com

Secondary respiratory infections appear to be highly prevalent among patients with severe COVID-19, but at this point, most pulmonologists aren’t sure what to make of this understudied phenomenon.

“We really do not understand the implications of secondary infections on outcomes in COVID-19 patients,” David L. Bowton, MD, FCCP, said in an interview. “In most early reports the incidence of secondary infections was much higher in patients dying from COVID-19, compared to survivors, but it isn’t clear whether this indicates that the secondary infection itself led to excess mortality or was more a marker of the severity of the COVID-19 infection.

“Further, details of the diagnostic criteria used, the microbiology, and the appropriateness of treatment of these secondary infections has not generally been included in these reports,” added Dr. Bowton, a pulmonologist and professor emeritus of critical care anesthesiology at Wake Forest University, Winston-Salem, N.C.

One such early retrospective cohort study included 191 COVID-19 patients in Wuhan, China. Of the 54 who died in hospital, half had secondary bacterial lung infections (Lancet. 2020 Mar 28;395[10229]:1054-62). That comes as no surprise to U.S. pulmonologists, who learned back in their training that many deaths during the so-called Spanish influenza epidemic of 1918-1920 were actually caused by secondary pneumonia involving Staphylococcus aureus, commented Daniel L. Ouellette, MD, FCCP, associate director of medical critical care at Henry Ford Hospital, Detroit.

“Critically ill patients are highly susceptible to secondary infections regardless of the cause of the patient’s critical illness,” he noted in an interview. “Recent reports of secondary infections in patients critically ill from COVID-19 are interesting but should be considered in this context. To confirm that COVID-19 patients have a different, or increased, risk of infection at specific sites or from specific agents will require careful study.”

That will be no easy matter given the challenges of obtaining bronchoalveolar lavage samples in mechanically ventilated patients with COVID-19, according to Eric J. Gartman, MD, FCCP, a pulmonologist at Brown University, Providence, R.I., and director of the pulmonary function laboratory at the Providence Veterans Affairs Medical Center.

“Unfortunately, many of the invasive modalities that are typically employed to help diagnose secondary infections in critically ill patients are being severely limited or even prohibited in COVID-19 patients due to infection control measures,” he said. As a result, Dr. Gartman noted, intensivists are often resorting to empiric broad-spectrum antimicrobial therapy in patients with severe COVID-19 and are without ready access to the bacterial cultures which might otherwise permit later treatment de-escalation or retargeting.

Among the myriad areas of uncertainty regarding COVID-19 is the proportion of bacterial coinfections that are hospital acquired. Given the lengthy duration of invasive mechanical ventilation in patients with severe COVID-19 – a mean of 9.1 days in the United Kingdom – the chances of hospital-acquired infection are likely substantial. Moreover, a recent single-center U.K. study involving microbiologic testing in 195 consecutive patients newly hospitalized for COVID-19 reported that community-acquired bacterial infection was uncommon: Just 4% of patients had pneumococcal coinfection at hospital admission, and S. aureus wasn’t detected in anyone (Lancet. 2020;1:362. doi:10.1016/S2666-5247[20]30036-7). French investigators have reported detecting putative invasive pulmonary aspergillosis in nearly one-third of a small series of 27 consecutive mechanically ventilated COVID-19 patients (Lancet Resp Med. 2020; 8[6]:e48-9). Dr. Gartman said the diagnostic testing methods utilized in this and similar reports haven’t been prospectively validated in COVID-19. The testing methods may not indicate invasive Aspergillus infection in this population with a high degree of certainty, since they have previously been performed mainly in patients with hematologic malignancies.

“Although there is nothing definitive regarding this research, as a practicing critical care doctor one should respect these findings and consider this secondary diagnosis if the supporting clinical data is positive, especially given that the mortality risk in this population is high,” he advised.

Dr. Bowton said that he and his fellow intensivists at Wake Forest Baptist Health don’t routinely screen COVID-19 patients for secondary bacterial or fungal infections. And in talking with colleagues around the country, it’s his impression that most have similarly elected not to do so.

“However, our clinical index of suspicion for secondary infections is heightened and, if triggered, will initiate a search for and treatment of these secondary infections,” Dr. Bowton said.
 

bjancin@mdedge.com

Exposure to Shiga toxin induces a complex intestinal response involving transcriptional changes, necrosis, apoptotic cell death, cellular proliferation, and cross-talk between epithelial and mesenchymal cells, according to investigators.

The study explored new territory in Shiga toxin research, enabled by the use of human intestinal organoids (HIOs), reported lead author Suman Pradhan, PhD, of the University of Cincinnati, and colleagues.

Each year, Shiga toxin–producing Escherichia coli infections cause approximately 3 million cases of bloody diarrheal disease, with about 4,000 of those patients developing the life-threatening complication of hemolytic uremic syndrome (HUS), the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.

But little is known about the underlying biological processes driving Shiga-induced disease.

“Developing effective interventions for disease resulting from Shiga toxin is exacerbated by a lack of tractable model systems,” the investigators wrote. “Mice do not develop the symptoms characteristic of HUS, and the murine intestinal tract is resistant to Shiga toxin.”

To overcome this obstacle, Dr. Pradhan and colleagues turned to HIOs, which are grown in culture by directing differentiation of pluripotent stem cells. HIOs represent the small bowel, complete with a lumen surrounded by epithelial and mesenchymal layers that include typical cell types, such as goblet cells and myofibroblasts. The model is made more realistic by transplantation into mice, where it grows under the kidney capsule to form crypts, structured villi, and proliferating progenitor zones. And HIOs grown with neuronal precursors develop an enteric nervous system, complete with functional peristalsis.

For the present study, the investigators evaluated the effect of Shiga toxin on HIOs both in culture and after transplantation into mice.

First, they demonstrated that HIOs in culture expressed glycolipid Gb3, the Shiga toxin receptor. “Reports regarding expression of glycolipid Gb3 ... on human intestine have been inconsistent,” the investigators noted. “For negative reports, the inability to detect Gb3 could be owing to technical limitations.”

Next, Dr. Pradhan and colleagues showed that HIOs were susceptible to Shiga toxin whether it be delivered lumenally or basolaterally, which respectively represent intestinal exposure and exposure via circulating toxin or after breakdown of the epithelial barrier. Leakage from the lumen was observed with both Shiga toxin 1 (Stx1) and 2 (Stx2). Subsequent testing involved only Stx2, as this form is more relevant to human disease.

In addition to lumenal leakage, Stx2 exposure caused significant transcriptional up-regulation of multiple gene families, including those involved in cellular transport and metabolic processes. Increased expression also was observed for epithelial structural proteins, lineage-specific proteins, factors involved in mucus layer formation and stabilization, and cytokines interleukin-18 and CCL15.

In both epithelial and mesenchymal layers, transcriptional changes were accompanied by cellular necrosis and apoptosis, and, to a greater degree with interstitial exposure, cellular proliferation.

With lumenal exposure, mesenchymal necrosis was observed before loss of epithelial barrier function, indicating toxin access to mesenchymal cells. This phenomenon was explained by transcytosis, which the investigators observed in two-dimensional monolayers of enteroids grown in Transwells.

“[Shiga toxin] was transferred from the apical to the basolateral surface in the absence of loss of epithelial barrier function,” the investigators wrote, noting that this finding explains how Shiga toxin can quickly access the circulatory system, and from there damage the kidneys and brain, as seen in cases of HUS.

Mice with transplanted HIOs, and those receiving HIOs with an enteric nervous system (HIO + ENS), lost weight when organoids were injected with 10 ng of Stx2. Mice with HIO + ENS transplants developed more severe responses, prompting closer analysis.

Postmortem histologic examination of HIO + ENS transplants revealed epithelial damage and blood accumulation in the mesenchyme and villi. Additional staining showed signs of apoptosis and mesenchymal-epithelial transition.

Dr. Pradham and colleagues suggested that their findings could inform therapeutic research.

“If preventing cellular death is to be an effective intervention, it is likely that both necrosis and apoptosis need to be targeted,” the investigators wrote.

More generally, the study supports the use of HIOs as a disease model for future investigations.

“The advent of stem cell–derived human tissue models, both in vitro and in vivo, has a tremendous potential to increase our understanding of Shiga toxin disease and lead to development of therapeutic interventions,” the investigators concluded.

The study was funded by the National Institutes of Health, the Center for Clinical and Translational Science, the National Institute of Diabetes and Digestive and Kidney Diseases, and others. The investigators disclosed no conflicts of interest.

SOURCE: Pradhan S et al. Cell Mol Gastroenterol Hepatol. 2020 Mar 5. doi: 10.1016/j.jcmgh.2020.02.006.

Exposure to Shiga toxin induces a complex intestinal response involving transcriptional changes, necrosis, apoptotic cell death, cellular proliferation, and cross-talk between epithelial and mesenchymal cells, according to investigators.

The study explored new territory in Shiga toxin research, enabled by the use of human intestinal organoids (HIOs), reported lead author Suman Pradhan, PhD, of the University of Cincinnati, and colleagues.

Each year, Shiga toxin–producing Escherichia coli infections cause approximately 3 million cases of bloody diarrheal disease, with about 4,000 of those patients developing the life-threatening complication of hemolytic uremic syndrome (HUS), the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.

But little is known about the underlying biological processes driving Shiga-induced disease.

“Developing effective interventions for disease resulting from Shiga toxin is exacerbated by a lack of tractable model systems,” the investigators wrote. “Mice do not develop the symptoms characteristic of HUS, and the murine intestinal tract is resistant to Shiga toxin.”

To overcome this obstacle, Dr. Pradhan and colleagues turned to HIOs, which are grown in culture by directing differentiation of pluripotent stem cells. HIOs represent the small bowel, complete with a lumen surrounded by epithelial and mesenchymal layers that include typical cell types, such as goblet cells and myofibroblasts. The model is made more realistic by transplantation into mice, where it grows under the kidney capsule to form crypts, structured villi, and proliferating progenitor zones. And HIOs grown with neuronal precursors develop an enteric nervous system, complete with functional peristalsis.

For the present study, the investigators evaluated the effect of Shiga toxin on HIOs both in culture and after transplantation into mice.

First, they demonstrated that HIOs in culture expressed glycolipid Gb3, the Shiga toxin receptor. “Reports regarding expression of glycolipid Gb3 ... on human intestine have been inconsistent,” the investigators noted. “For negative reports, the inability to detect Gb3 could be owing to technical limitations.”

Next, Dr. Pradhan and colleagues showed that HIOs were susceptible to Shiga toxin whether it be delivered lumenally or basolaterally, which respectively represent intestinal exposure and exposure via circulating toxin or after breakdown of the epithelial barrier. Leakage from the lumen was observed with both Shiga toxin 1 (Stx1) and 2 (Stx2). Subsequent testing involved only Stx2, as this form is more relevant to human disease.

In addition to lumenal leakage, Stx2 exposure caused significant transcriptional up-regulation of multiple gene families, including those involved in cellular transport and metabolic processes. Increased expression also was observed for epithelial structural proteins, lineage-specific proteins, factors involved in mucus layer formation and stabilization, and cytokines interleukin-18 and CCL15.

In both epithelial and mesenchymal layers, transcriptional changes were accompanied by cellular necrosis and apoptosis, and, to a greater degree with interstitial exposure, cellular proliferation.

With lumenal exposure, mesenchymal necrosis was observed before loss of epithelial barrier function, indicating toxin access to mesenchymal cells. This phenomenon was explained by transcytosis, which the investigators observed in two-dimensional monolayers of enteroids grown in Transwells.

“[Shiga toxin] was transferred from the apical to the basolateral surface in the absence of loss of epithelial barrier function,” the investigators wrote, noting that this finding explains how Shiga toxin can quickly access the circulatory system, and from there damage the kidneys and brain, as seen in cases of HUS.

Mice with transplanted HIOs, and those receiving HIOs with an enteric nervous system (HIO + ENS), lost weight when organoids were injected with 10 ng of Stx2. Mice with HIO + ENS transplants developed more severe responses, prompting closer analysis.

Postmortem histologic examination of HIO + ENS transplants revealed epithelial damage and blood accumulation in the mesenchyme and villi. Additional staining showed signs of apoptosis and mesenchymal-epithelial transition.

Dr. Pradham and colleagues suggested that their findings could inform therapeutic research.

“If preventing cellular death is to be an effective intervention, it is likely that both necrosis and apoptosis need to be targeted,” the investigators wrote.

More generally, the study supports the use of HIOs as a disease model for future investigations.

“The advent of stem cell–derived human tissue models, both in vitro and in vivo, has a tremendous potential to increase our understanding of Shiga toxin disease and lead to development of therapeutic interventions,” the investigators concluded.

The study was funded by the National Institutes of Health, the Center for Clinical and Translational Science, the National Institute of Diabetes and Digestive and Kidney Diseases, and others. The investigators disclosed no conflicts of interest.

SOURCE: Pradhan S et al. Cell Mol Gastroenterol Hepatol. 2020 Mar 5. doi: 10.1016/j.jcmgh.2020.02.006.

Exposure to Shiga toxin induces a complex intestinal response involving transcriptional changes, necrosis, apoptotic cell death, cellular proliferation, and cross-talk between epithelial and mesenchymal cells, according to investigators.

The study explored new territory in Shiga toxin research, enabled by the use of human intestinal organoids (HIOs), reported lead author Suman Pradhan, PhD, of the University of Cincinnati, and colleagues.

Each year, Shiga toxin–producing Escherichia coli infections cause approximately 3 million cases of bloody diarrheal disease, with about 4,000 of those patients developing the life-threatening complication of hemolytic uremic syndrome (HUS), the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.

But little is known about the underlying biological processes driving Shiga-induced disease.

“Developing effective interventions for disease resulting from Shiga toxin is exacerbated by a lack of tractable model systems,” the investigators wrote. “Mice do not develop the symptoms characteristic of HUS, and the murine intestinal tract is resistant to Shiga toxin.”

To overcome this obstacle, Dr. Pradhan and colleagues turned to HIOs, which are grown in culture by directing differentiation of pluripotent stem cells. HIOs represent the small bowel, complete with a lumen surrounded by epithelial and mesenchymal layers that include typical cell types, such as goblet cells and myofibroblasts. The model is made more realistic by transplantation into mice, where it grows under the kidney capsule to form crypts, structured villi, and proliferating progenitor zones. And HIOs grown with neuronal precursors develop an enteric nervous system, complete with functional peristalsis.

For the present study, the investigators evaluated the effect of Shiga toxin on HIOs both in culture and after transplantation into mice.

First, they demonstrated that HIOs in culture expressed glycolipid Gb3, the Shiga toxin receptor. “Reports regarding expression of glycolipid Gb3 ... on human intestine have been inconsistent,” the investigators noted. “For negative reports, the inability to detect Gb3 could be owing to technical limitations.”

Next, Dr. Pradhan and colleagues showed that HIOs were susceptible to Shiga toxin whether it be delivered lumenally or basolaterally, which respectively represent intestinal exposure and exposure via circulating toxin or after breakdown of the epithelial barrier. Leakage from the lumen was observed with both Shiga toxin 1 (Stx1) and 2 (Stx2). Subsequent testing involved only Stx2, as this form is more relevant to human disease.

In addition to lumenal leakage, Stx2 exposure caused significant transcriptional up-regulation of multiple gene families, including those involved in cellular transport and metabolic processes. Increased expression also was observed for epithelial structural proteins, lineage-specific proteins, factors involved in mucus layer formation and stabilization, and cytokines interleukin-18 and CCL15.

In both epithelial and mesenchymal layers, transcriptional changes were accompanied by cellular necrosis and apoptosis, and, to a greater degree with interstitial exposure, cellular proliferation.

With lumenal exposure, mesenchymal necrosis was observed before loss of epithelial barrier function, indicating toxin access to mesenchymal cells. This phenomenon was explained by transcytosis, which the investigators observed in two-dimensional monolayers of enteroids grown in Transwells.

“[Shiga toxin] was transferred from the apical to the basolateral surface in the absence of loss of epithelial barrier function,” the investigators wrote, noting that this finding explains how Shiga toxin can quickly access the circulatory system, and from there damage the kidneys and brain, as seen in cases of HUS.

Mice with transplanted HIOs, and those receiving HIOs with an enteric nervous system (HIO + ENS), lost weight when organoids were injected with 10 ng of Stx2. Mice with HIO + ENS transplants developed more severe responses, prompting closer analysis.

Postmortem histologic examination of HIO + ENS transplants revealed epithelial damage and blood accumulation in the mesenchyme and villi. Additional staining showed signs of apoptosis and mesenchymal-epithelial transition.

Dr. Pradham and colleagues suggested that their findings could inform therapeutic research.

“If preventing cellular death is to be an effective intervention, it is likely that both necrosis and apoptosis need to be targeted,” the investigators wrote.

More generally, the study supports the use of HIOs as a disease model for future investigations.

“The advent of stem cell–derived human tissue models, both in vitro and in vivo, has a tremendous potential to increase our understanding of Shiga toxin disease and lead to development of therapeutic interventions,” the investigators concluded.

The study was funded by the National Institutes of Health, the Center for Clinical and Translational Science, the National Institute of Diabetes and Digestive and Kidney Diseases, and others. The investigators disclosed no conflicts of interest.

SOURCE: Pradhan S et al. Cell Mol Gastroenterol Hepatol. 2020 Mar 5. doi: 10.1016/j.jcmgh.2020.02.006.

Although it is not glamorous, snail mucus is a popular ingredient in skin care products. Its use dates back to ancient Greece, where Hippocrates reportedly applied crushed snails to treat skin inflammations.¹ The modern consideration of using snail secretions in skin care arose serendipitously in the 1990s when Chilean farmers observed accelerated healing of their skin lesions without scarring after handling snails.¹

valentinrussanov/E+

Today, snail mucin is among the increasingly wide array of bioactive ingredients undergoing scientific validation and inclusion in the burgeoning Korean cosmeceutical market.^2,3 In fact, a variety of Korean cosmeceuticals incorporate the mucus derived from Achatina fulica (African giant land snail) and Cryptomphalus (Helix) aspersa (common brown garden snail) based on their demonstrated antimicrobial and skin regenerative activity.^1,3,4 The antioxidant properties also attributed to snail mucus are thought to originate in constituents such as glycosaminoglycans, as well as growth factors, and may justify the use of these ingredients in novel cosmeceuticals.⁵ The focus of this discussion is recent research into the novel use of this animal-derived product for dermatologic purposes.
 

Antioxidant activity, skin rejuvenation, and wound healing

In 2008, Brieva et al. reported on a screen for natural products yielding a molecular basis for the secretions of the mollusk Cryptomphalus aspersa, which displays skin-regenerative activity. Specifically, they found that the secretion exerts antioxidant superoxide dismutase and glutathione S-transferase, and spurred fibroblast proliferation and extracellular matrix assembly while regulating metalloproteinase function. The researchers concluded that such activities may support wound regeneration.⁵

Four years later, Cruz et al. found that secretions of C. aspersa promote in vitro cell proliferation and migration by localizing beta-catenin to the nuclei of human fibroblasts and keratinocytes, augment phosphorylated focal adhesion kinase, and thereby enhance cell survival. The investigators concluded that snail secretions may therefore impart regenerative and wound healing activity.3,6

Antimicrobial properties

In 2015, Pitt et al. investigated the antimicrobial properties of the mucus of the brown garden snail C. or H. aspersa, which had a reputation for exhibiting skin regeneration capabilities. Their results revealed that snail mucus displayed a strong antibacterial effect against multiple strains of Pseudomonas aeruginosa and a weak effect against Staphylococcus aureus.⁴

Indications for the use of snail mucin

Radiation-induced dermatitis and burns represented the first indication for the initial use of snail mucin as a cutaneous therapy.⁷ Experimental and clinical studies have since been performed to assess its applicability to treat acute radiation dermatitis, atopic dermatitis, partial-thickness burns, and photoaging.^8-11

A 2017 in vitro investigation by Ellijimi et al. revealed that snail mucin displayed antimelanogenic and antitumoral activity against human melanoma cells, suggesting another possible application of this product.¹²

Human studies on photoaging

In a 2009 study by Tsoutsos et al. of an open, moist burn management protocol in deep partial-thickness facial burns, a cream containing H. aspersa secretions was identified to be an effective treatment option. For 14 days or until full epithelialization, 27 adult patients were treated with snail extract cream twice daily. Comparisons were made to 16 patients treated with moist exposure burn ointment. Visual analog scale pain scores were significantly lower in the group that received the H. aspersa cream, compared with the moist exposure burn group. The researchers concluded that the H. aspersa cream is a safe, effective, and natural option for treating partial-thickness burns in adults that acts by facilitating debris removal and accelerating reepithelialization.¹⁰

Also that year, Tribo-Boixareu et al. treated 15 patients with chronic photodamage with secretions of C. aspersa over a 3-month period, yielding significant amelioration in the clinical and histologic markers of photoaging.¹¹

Four years later, a double-blind, split-face, randomized, controlled clinical study conducted by Fabi et al. over 12 weeks demonstrated that the topical application of an antiphotoaging formulation containing C. aspersa mucus diminished periocular and fine facial rhytides and enhanced skin texture within 8 weeks of treatment initiation.⁷

Snail eggs and photoaging

In 2015, Espada et al. determined in vitro that an extract derived from C. aspersa eggs could reorganize the cytoskeleton of keratinocytes and fibroblasts, as well as trigger the synthesis of the extracellular proteins collagen and fibronectin. They also found that gene expression declined in age-related genes including p53 and b-Gal. The researchers concluded that C. aspersa egg extract has the potential to reduce the signs of photoaging.^3,13

Antiaging cosmeceuticals

In a 2017 assessment of the antiaging and skin-whitening activity of the nine most popular ingredients in the South Korean skin care product market, Quay et al. considered industry profit data from Euromonitor and conducted a comprehensive literature search. They identified licorice, niacinamide, green tea, soy, beta-glucan, snail mucus, ginkgo biloba, ginseng, and pomegranate as the nine most popular ingredients, with the first four associated with the most supportive data. They found a paucity of cogent evidence on the use of the other ingredients in antiaging and skin-whitening formulations.¹⁴

Conclusion

The use of snail mucin to treat skin dates back at least to the time of Hippocrates. Recent research suggests reasons for optimism, and further investigation, as this ingredient appears to have potential across various cutaneous conditions. As is often the case, though, much more research is necessary to ascertain what enduring benefits may be derived from the use of snail mucin. Nevertheless, this product has been available on the market for the last 20 years and is associated with anecdotal reports of efficacy.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mdedge.com. She has no relevant disclosures.

References

1. Liu L et al. Snails and skin care – an uncovered combination. JAMA Dermatol. 2017 Jul 1;153(7):650.

2. Nguyen JK et al. J Cosmet Dermatol. 2020 Feb 26. doi: 10.1111/jocd.13344.

3. Juhász ML et al. J Cosmet Dermatol. 2018;17(3):305-12.

4. Pitt SJ et al. Br J Biomed Sci. 2015;72(4):174-81.

5. Brieva A et al. Skin Pharmacol Physiol. 2008;21(1):15-22.

6. Cruz MC et al. Int J Cosmet Sci. 2012 Apr;34(2):183-9.

7. Fabi SG et al. J Drugs Dermatol. 2013; Apr;12(4):453-7.

8. Ledo E et al. Radioproteccion. 1999;23(7):34-8.

9. Oh M-Jet al. J Korean Med Ophthalmol Otolaryngol Dermatol. 2010; Dec,23(3):138-53.

10. Tsoutsos D et al. J Dermatolog Treat. 2009;20(4):219-22.

11. Tribo-Boixareu MJ et al. Cosmet Dermatol. 2009;22(5):247-52.

12. Ellijimi C et al. Biomed Pharmacother. 2018 May;101:871-80.

13. Espada J et al. Int J Cosmet Sci. 2015 Feb;37(1):41-55.

14. Quay ER et al. J Drugs Dermatol. 2017 Apr 1;16(4):358-63.
 

Although it is not glamorous, snail mucus is a popular ingredient in skin care products. Its use dates back to ancient Greece, where Hippocrates reportedly applied crushed snails to treat skin inflammations.¹ The modern consideration of using snail secretions in skin care arose serendipitously in the 1990s when Chilean farmers observed accelerated healing of their skin lesions without scarring after handling snails.¹

valentinrussanov/E+

Today, snail mucin is among the increasingly wide array of bioactive ingredients undergoing scientific validation and inclusion in the burgeoning Korean cosmeceutical market.^2,3 In fact, a variety of Korean cosmeceuticals incorporate the mucus derived from Achatina fulica (African giant land snail) and Cryptomphalus (Helix) aspersa (common brown garden snail) based on their demonstrated antimicrobial and skin regenerative activity.^1,3,4 The antioxidant properties also attributed to snail mucus are thought to originate in constituents such as glycosaminoglycans, as well as growth factors, and may justify the use of these ingredients in novel cosmeceuticals.⁵ The focus of this discussion is recent research into the novel use of this animal-derived product for dermatologic purposes.
 

Antioxidant activity, skin rejuvenation, and wound healing

In 2008, Brieva et al. reported on a screen for natural products yielding a molecular basis for the secretions of the mollusk Cryptomphalus aspersa, which displays skin-regenerative activity. Specifically, they found that the secretion exerts antioxidant superoxide dismutase and glutathione S-transferase, and spurred fibroblast proliferation and extracellular matrix assembly while regulating metalloproteinase function. The researchers concluded that such activities may support wound regeneration.⁵

Four years later, Cruz et al. found that secretions of C. aspersa promote in vitro cell proliferation and migration by localizing beta-catenin to the nuclei of human fibroblasts and keratinocytes, augment phosphorylated focal adhesion kinase, and thereby enhance cell survival. The investigators concluded that snail secretions may therefore impart regenerative and wound healing activity.3,6

Antimicrobial properties

In 2015, Pitt et al. investigated the antimicrobial properties of the mucus of the brown garden snail C. or H. aspersa, which had a reputation for exhibiting skin regeneration capabilities. Their results revealed that snail mucus displayed a strong antibacterial effect against multiple strains of Pseudomonas aeruginosa and a weak effect against Staphylococcus aureus.⁴

Indications for the use of snail mucin

Radiation-induced dermatitis and burns represented the first indication for the initial use of snail mucin as a cutaneous therapy.⁷ Experimental and clinical studies have since been performed to assess its applicability to treat acute radiation dermatitis, atopic dermatitis, partial-thickness burns, and photoaging.^8-11

A 2017 in vitro investigation by Ellijimi et al. revealed that snail mucin displayed antimelanogenic and antitumoral activity against human melanoma cells, suggesting another possible application of this product.¹²

Human studies on photoaging

In a 2009 study by Tsoutsos et al. of an open, moist burn management protocol in deep partial-thickness facial burns, a cream containing H. aspersa secretions was identified to be an effective treatment option. For 14 days or until full epithelialization, 27 adult patients were treated with snail extract cream twice daily. Comparisons were made to 16 patients treated with moist exposure burn ointment. Visual analog scale pain scores were significantly lower in the group that received the H. aspersa cream, compared with the moist exposure burn group. The researchers concluded that the H. aspersa cream is a safe, effective, and natural option for treating partial-thickness burns in adults that acts by facilitating debris removal and accelerating reepithelialization.¹⁰

Also that year, Tribo-Boixareu et al. treated 15 patients with chronic photodamage with secretions of C. aspersa over a 3-month period, yielding significant amelioration in the clinical and histologic markers of photoaging.¹¹

Four years later, a double-blind, split-face, randomized, controlled clinical study conducted by Fabi et al. over 12 weeks demonstrated that the topical application of an antiphotoaging formulation containing C. aspersa mucus diminished periocular and fine facial rhytides and enhanced skin texture within 8 weeks of treatment initiation.⁷

Snail eggs and photoaging

In 2015, Espada et al. determined in vitro that an extract derived from C. aspersa eggs could reorganize the cytoskeleton of keratinocytes and fibroblasts, as well as trigger the synthesis of the extracellular proteins collagen and fibronectin. They also found that gene expression declined in age-related genes including p53 and b-Gal. The researchers concluded that C. aspersa egg extract has the potential to reduce the signs of photoaging.^3,13

Antiaging cosmeceuticals

In a 2017 assessment of the antiaging and skin-whitening activity of the nine most popular ingredients in the South Korean skin care product market, Quay et al. considered industry profit data from Euromonitor and conducted a comprehensive literature search. They identified licorice, niacinamide, green tea, soy, beta-glucan, snail mucus, ginkgo biloba, ginseng, and pomegranate as the nine most popular ingredients, with the first four associated with the most supportive data. They found a paucity of cogent evidence on the use of the other ingredients in antiaging and skin-whitening formulations.¹⁴

Conclusion

The use of snail mucin to treat skin dates back at least to the time of Hippocrates. Recent research suggests reasons for optimism, and further investigation, as this ingredient appears to have potential across various cutaneous conditions. As is often the case, though, much more research is necessary to ascertain what enduring benefits may be derived from the use of snail mucin. Nevertheless, this product has been available on the market for the last 20 years and is associated with anecdotal reports of efficacy.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mdedge.com. She has no relevant disclosures.

References

1. Liu L et al. Snails and skin care – an uncovered combination. JAMA Dermatol. 2017 Jul 1;153(7):650.

2. Nguyen JK et al. J Cosmet Dermatol. 2020 Feb 26. doi: 10.1111/jocd.13344.

3. Juhász ML et al. J Cosmet Dermatol. 2018;17(3):305-12.

4. Pitt SJ et al. Br J Biomed Sci. 2015;72(4):174-81.

5. Brieva A et al. Skin Pharmacol Physiol. 2008;21(1):15-22.

6. Cruz MC et al. Int J Cosmet Sci. 2012 Apr;34(2):183-9.

7. Fabi SG et al. J Drugs Dermatol. 2013; Apr;12(4):453-7.

8. Ledo E et al. Radioproteccion. 1999;23(7):34-8.

9. Oh M-Jet al. J Korean Med Ophthalmol Otolaryngol Dermatol. 2010; Dec,23(3):138-53.

10. Tsoutsos D et al. J Dermatolog Treat. 2009;20(4):219-22.

11. Tribo-Boixareu MJ et al. Cosmet Dermatol. 2009;22(5):247-52.

12. Ellijimi C et al. Biomed Pharmacother. 2018 May;101:871-80.

13. Espada J et al. Int J Cosmet Sci. 2015 Feb;37(1):41-55.

14. Quay ER et al. J Drugs Dermatol. 2017 Apr 1;16(4):358-63.
 

Although it is not glamorous, snail mucus is a popular ingredient in skin care products. Its use dates back to ancient Greece, where Hippocrates reportedly applied crushed snails to treat skin inflammations.¹ The modern consideration of using snail secretions in skin care arose serendipitously in the 1990s when Chilean farmers observed accelerated healing of their skin lesions without scarring after handling snails.¹

valentinrussanov/E+

Today, snail mucin is among the increasingly wide array of bioactive ingredients undergoing scientific validation and inclusion in the burgeoning Korean cosmeceutical market.^2,3 In fact, a variety of Korean cosmeceuticals incorporate the mucus derived from Achatina fulica (African giant land snail) and Cryptomphalus (Helix) aspersa (common brown garden snail) based on their demonstrated antimicrobial and skin regenerative activity.^1,3,4 The antioxidant properties also attributed to snail mucus are thought to originate in constituents such as glycosaminoglycans, as well as growth factors, and may justify the use of these ingredients in novel cosmeceuticals.⁵ The focus of this discussion is recent research into the novel use of this animal-derived product for dermatologic purposes.
 

Antioxidant activity, skin rejuvenation, and wound healing

In 2008, Brieva et al. reported on a screen for natural products yielding a molecular basis for the secretions of the mollusk Cryptomphalus aspersa, which displays skin-regenerative activity. Specifically, they found that the secretion exerts antioxidant superoxide dismutase and glutathione S-transferase, and spurred fibroblast proliferation and extracellular matrix assembly while regulating metalloproteinase function. The researchers concluded that such activities may support wound regeneration.⁵

Four years later, Cruz et al. found that secretions of C. aspersa promote in vitro cell proliferation and migration by localizing beta-catenin to the nuclei of human fibroblasts and keratinocytes, augment phosphorylated focal adhesion kinase, and thereby enhance cell survival. The investigators concluded that snail secretions may therefore impart regenerative and wound healing activity.3,6

Antimicrobial properties

In 2015, Pitt et al. investigated the antimicrobial properties of the mucus of the brown garden snail C. or H. aspersa, which had a reputation for exhibiting skin regeneration capabilities. Their results revealed that snail mucus displayed a strong antibacterial effect against multiple strains of Pseudomonas aeruginosa and a weak effect against Staphylococcus aureus.⁴

Indications for the use of snail mucin

Radiation-induced dermatitis and burns represented the first indication for the initial use of snail mucin as a cutaneous therapy.⁷ Experimental and clinical studies have since been performed to assess its applicability to treat acute radiation dermatitis, atopic dermatitis, partial-thickness burns, and photoaging.^8-11

A 2017 in vitro investigation by Ellijimi et al. revealed that snail mucin displayed antimelanogenic and antitumoral activity against human melanoma cells, suggesting another possible application of this product.¹²

Human studies on photoaging

In a 2009 study by Tsoutsos et al. of an open, moist burn management protocol in deep partial-thickness facial burns, a cream containing H. aspersa secretions was identified to be an effective treatment option. For 14 days or until full epithelialization, 27 adult patients were treated with snail extract cream twice daily. Comparisons were made to 16 patients treated with moist exposure burn ointment. Visual analog scale pain scores were significantly lower in the group that received the H. aspersa cream, compared with the moist exposure burn group. The researchers concluded that the H. aspersa cream is a safe, effective, and natural option for treating partial-thickness burns in adults that acts by facilitating debris removal and accelerating reepithelialization.¹⁰

Also that year, Tribo-Boixareu et al. treated 15 patients with chronic photodamage with secretions of C. aspersa over a 3-month period, yielding significant amelioration in the clinical and histologic markers of photoaging.¹¹

Four years later, a double-blind, split-face, randomized, controlled clinical study conducted by Fabi et al. over 12 weeks demonstrated that the topical application of an antiphotoaging formulation containing C. aspersa mucus diminished periocular and fine facial rhytides and enhanced skin texture within 8 weeks of treatment initiation.⁷

Snail eggs and photoaging

In 2015, Espada et al. determined in vitro that an extract derived from C. aspersa eggs could reorganize the cytoskeleton of keratinocytes and fibroblasts, as well as trigger the synthesis of the extracellular proteins collagen and fibronectin. They also found that gene expression declined in age-related genes including p53 and b-Gal. The researchers concluded that C. aspersa egg extract has the potential to reduce the signs of photoaging.^3,13

Antiaging cosmeceuticals

In a 2017 assessment of the antiaging and skin-whitening activity of the nine most popular ingredients in the South Korean skin care product market, Quay et al. considered industry profit data from Euromonitor and conducted a comprehensive literature search. They identified licorice, niacinamide, green tea, soy, beta-glucan, snail mucus, ginkgo biloba, ginseng, and pomegranate as the nine most popular ingredients, with the first four associated with the most supportive data. They found a paucity of cogent evidence on the use of the other ingredients in antiaging and skin-whitening formulations.¹⁴

Conclusion

The use of snail mucin to treat skin dates back at least to the time of Hippocrates. Recent research suggests reasons for optimism, and further investigation, as this ingredient appears to have potential across various cutaneous conditions. As is often the case, though, much more research is necessary to ascertain what enduring benefits may be derived from the use of snail mucin. Nevertheless, this product has been available on the market for the last 20 years and is associated with anecdotal reports of efficacy.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mdedge.com. She has no relevant disclosures.

References

1. Liu L et al. Snails and skin care – an uncovered combination. JAMA Dermatol. 2017 Jul 1;153(7):650.

2. Nguyen JK et al. J Cosmet Dermatol. 2020 Feb 26. doi: 10.1111/jocd.13344.

3. Juhász ML et al. J Cosmet Dermatol. 2018;17(3):305-12.

4. Pitt SJ et al. Br J Biomed Sci. 2015;72(4):174-81.

5. Brieva A et al. Skin Pharmacol Physiol. 2008;21(1):15-22.

6. Cruz MC et al. Int J Cosmet Sci. 2012 Apr;34(2):183-9.

7. Fabi SG et al. J Drugs Dermatol. 2013; Apr;12(4):453-7.

8. Ledo E et al. Radioproteccion. 1999;23(7):34-8.

9. Oh M-Jet al. J Korean Med Ophthalmol Otolaryngol Dermatol. 2010; Dec,23(3):138-53.

10. Tsoutsos D et al. J Dermatolog Treat. 2009;20(4):219-22.

11. Tribo-Boixareu MJ et al. Cosmet Dermatol. 2009;22(5):247-52.

12. Ellijimi C et al. Biomed Pharmacother. 2018 May;101:871-80.

13. Espada J et al. Int J Cosmet Sci. 2015 Feb;37(1):41-55.

14. Quay ER et al. J Drugs Dermatol. 2017 Apr 1;16(4):358-63.
 

The Abbott FreeStyle Libre glucose monitoring system significantly reduced hospitalizations for diabetic ketoacidosis (DKA), diabetes-related emergencies, and all-cause hospitalizations among patients with diabetes, data from two new studies indicate.

The results were presented June 13 during the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

One large database analysis, from France, revealed that use of the Libre system halved hospitalization rates for DKA among people with type 1 or type 2 diabetes.

In the other study, a retrospective analysis of data from over 1200 insulin-treated individuals with type 2 diabetes in the United States, use of the Libre was associated with significant reductions in both hospitalizations for acute diabetes-related emergency events and all-cause hospitalizations.

The Libre system reads glucose levels through a sensor worn on the back of the upper arm for up to 14 days. Users wave a scanner over the device to obtain a reading.

Asked to comment, Nicholas Argento, MD, diabetes technology director at Maryland Endocrine and Diabetes, Columbia, told Medscape Medical News: “One of the biggest problems with access to continuous glucose monitoring is cost. Payers need to see that there’s some cost-saving to offset the cost of paying for these devices. I think both of these studies are important for that reason.”

However, Argento also said he recommends that people with type 1 diabetes use the Dexcom continuous glucose monitor (CGM) if possible rather than the Libre, despite the former’s higher cost, because it has an alarm feature that the Libre doesn’t and is more accurate in the hypoglycemic range.

Large French study: Libre cuts DKA hospitalizations by 50%

The FreeStyle Libre system has been reimbursed in France since June 1, 2017 for patients over 4 years of age with type 1 or type 2 diabetes who take at least 3 insulin injections per day or use an insulin pump.

Sara Freeman/MDedge News

The new results were presented by Ronan Roussel, MD, PhD, chief of the endocrinology, diabetes, and nutrition department at Hôpital Bichat, Fédération de Diabétologie, AP-HP, Paris, France.

The DKA hospitalization data Roussel reported were part of a larger longitudinal retrospective cohort study looking at overall prescribing and use of the Libre system, and its impact on healthcare outcomes and associated costs in standard practice in France. The data came from a large nationwide claims database containing all healthcare expenses for over 66 million people.

The current study participants were 74,076 individuals with at least a full year of follow-up beginning in 2017 with the date of first reimbursement for the FreeStyle Libre system. Of those, 44.8% (33,203) had type 1 diabetes and 55.2% (40,955) had type 2 diabetes.

Prior to initiation of Libre use, about a quarter of each group was using 0 fingerstick test strips per day, about 19% of the type 1 diabetes group and 28% of the type 2 diabetes group were using 1-3 strips per day, and about half of both groups were using 4 or more strips per day.

Compared with the year prior to the date of first reimbursement for the Libre, hospitalization rates for DKA during the first year of Libre use fell by 52% in the type 1 diabetes group, from 5.46 to 2.59 per 100 patient-years, and by 47% in the type 2 diabetes group, from 1.70 to 0.90 per 100 patient-years.

The impact of Libre on DKA hospitalizations was most dramatic among those not using any test strips prior to Libre use, with a 60% reduction for the type 1 diabetes group (8.31 to 3.31 per 100 patient-years) and a 51% reduction in the type 2 diabetes group (2.51 to 1.23 per 100 patient-years).

But interestingly, the next-biggest impact was among those who had been using more than 5 test strips per day, with drops of 59% among those with type 1 diabetes (5.55 to 2.26 per 100 patient-years) and 52% in the type 2 diabetes group (1.88 to 0.90 per 100 patient-years).

This finding is important for the United States, Argento said, because some insurers, including Medicare, require that the patient performs at least 4 fingerstick glucose measurements per day to qualify for reimbursement for the Libre or any CGM system.

“I think that speaks to the importance of not requiring that patients first show they’re frequently doing self-blood glucose monitoring before they can get these devices,” he observed.

The large benefit in the high strip use group is interesting too, Argento said. “It’s a different group of people. They’re more engaged in their care...This U-shaped curve they showed is fascinating.”

Reductions in DKA hospitalizations were also similar between patients using insulin pumps and those using multiple daily injections of insulin, Roussel reported.

“It is plausible that use of the FreeStyle Libre system allowed people to detect and limit persistent hyperglycemia, and subsequently ketoacidosis,” Roussel said.

“This analysis has significant implications for patient-centered clinical care in diabetes and also for long-term health economic outcomes in the treatment of diabetes at a national level.”

All-cause hospitalizations drop 30% with Libre in type 2 diabetes

Richard M. Bergenstal, MD, executive director of the International Diabetes Center at Park Nicollet, Minneapolis, Minnesota, presented the US results, obtained from the IBM Watson Health MarketScan, a database of commercial and Medicare supplemental insurance claims for over 30 million Americans.

The study population included 2463 patients with type 2 diabetes using basal-bolus daily insulin injections but who had not previously used Libre or any other CGM, and for whom data were available 6 months prior to and after Libre initiation.

Compared with 6 months prior to Libre use, the number of acute diabetes-related events — including hyperglycemia, hypoglycemia, DKA, hypoglycemic coma, and hyperosmolarity — in the subsequent 6 months dropped by 60%, from 0.180 to 0.072 events per patient-year (P < .001).

Similarly significant reductions were seen between males and females, and among those aged ≥ 50 years or < 50 years.

All-cause hospitalizations also significantly dropped by 33% (P < 0.001), from 0.420 to 0.283 events per patient-year. Among diagnostic codes for the hospitalizations, circulatory system causes remained number one during both time periods, with little change from pre-Libre to during Libre use.

However, “endocrine, nutritional, and metabolism system” codes dropped from the second position pre-Libre (6.4 events/100 patient-years) down to the fifth position (2.6 events/100 patient-years).

And, Bergenstal noted, other major diagnostic categories that also dropped included respiratory (3.5 to 2.1 events/100 patient-years), kidney and urinary tract (3.3 to 1.7 events/100 patient-years), and hepatobiliary system and pancreas (2.4 to 1.4 events/100 patient-years).

“We’re seeing a resurgence of certain types of complications, but all of these were reduced in the 6 months after Libre,” Bergenstal pointed out.

And, pertinent to the current COVID-19 situation, “infectious and parasitic disease and disorders” dropped as well, from 4.8 to 2.8 per 100 patient-years.

Argento commented: “The fact that infections went down speaks to something that is important right now. Hyperglycemia impairs immune function chronically, but also acutely...so patients who become ill and their blood glucose deteriorates rapidly are much more likely to have a poor outcome regardless of infection. There are data for COVID-19 now.”

“These findings provide compelling support for use of [Libre] to improve both clinical outcomes and potentially reduce costs in this patient population,” Bergenstal concluded.

Roussel has reported being on advisory panels for Abbott, AstraZeneca, Diabnext, Eli Lilly, Merck, Mundipharma International, Novo Nordisk, and Sanofi-Aventis. Bergenstal has reported being a consultant for Ascensia Diabetes Care, Johnson & Johnson, and has other relationships with Abbott, Dexcom, Hygieia, Lilly Diabetes, Medtronic, Novo Nordisk, Onduo, Roche Diabetes Care, Sanofi, and UnitedHealth Group. Argento has reported consulting and being on speaker bureaus for Omnipod, Eli Lilly, Novo Nordisk, Dexcom, and Boehringer Ingelheim.

This article first appeared on Medscape.com.
 

The Abbott FreeStyle Libre glucose monitoring system significantly reduced hospitalizations for diabetic ketoacidosis (DKA), diabetes-related emergencies, and all-cause hospitalizations among patients with diabetes, data from two new studies indicate.

The results were presented June 13 during the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

One large database analysis, from France, revealed that use of the Libre system halved hospitalization rates for DKA among people with type 1 or type 2 diabetes.

In the other study, a retrospective analysis of data from over 1200 insulin-treated individuals with type 2 diabetes in the United States, use of the Libre was associated with significant reductions in both hospitalizations for acute diabetes-related emergency events and all-cause hospitalizations.

The Libre system reads glucose levels through a sensor worn on the back of the upper arm for up to 14 days. Users wave a scanner over the device to obtain a reading.

Asked to comment, Nicholas Argento, MD, diabetes technology director at Maryland Endocrine and Diabetes, Columbia, told Medscape Medical News: “One of the biggest problems with access to continuous glucose monitoring is cost. Payers need to see that there’s some cost-saving to offset the cost of paying for these devices. I think both of these studies are important for that reason.”

However, Argento also said he recommends that people with type 1 diabetes use the Dexcom continuous glucose monitor (CGM) if possible rather than the Libre, despite the former’s higher cost, because it has an alarm feature that the Libre doesn’t and is more accurate in the hypoglycemic range.

Large French study: Libre cuts DKA hospitalizations by 50%

The FreeStyle Libre system has been reimbursed in France since June 1, 2017 for patients over 4 years of age with type 1 or type 2 diabetes who take at least 3 insulin injections per day or use an insulin pump.

Sara Freeman/MDedge News

The new results were presented by Ronan Roussel, MD, PhD, chief of the endocrinology, diabetes, and nutrition department at Hôpital Bichat, Fédération de Diabétologie, AP-HP, Paris, France.

The DKA hospitalization data Roussel reported were part of a larger longitudinal retrospective cohort study looking at overall prescribing and use of the Libre system, and its impact on healthcare outcomes and associated costs in standard practice in France. The data came from a large nationwide claims database containing all healthcare expenses for over 66 million people.

The current study participants were 74,076 individuals with at least a full year of follow-up beginning in 2017 with the date of first reimbursement for the FreeStyle Libre system. Of those, 44.8% (33,203) had type 1 diabetes and 55.2% (40,955) had type 2 diabetes.

Prior to initiation of Libre use, about a quarter of each group was using 0 fingerstick test strips per day, about 19% of the type 1 diabetes group and 28% of the type 2 diabetes group were using 1-3 strips per day, and about half of both groups were using 4 or more strips per day.

Compared with the year prior to the date of first reimbursement for the Libre, hospitalization rates for DKA during the first year of Libre use fell by 52% in the type 1 diabetes group, from 5.46 to 2.59 per 100 patient-years, and by 47% in the type 2 diabetes group, from 1.70 to 0.90 per 100 patient-years.

The impact of Libre on DKA hospitalizations was most dramatic among those not using any test strips prior to Libre use, with a 60% reduction for the type 1 diabetes group (8.31 to 3.31 per 100 patient-years) and a 51% reduction in the type 2 diabetes group (2.51 to 1.23 per 100 patient-years).

But interestingly, the next-biggest impact was among those who had been using more than 5 test strips per day, with drops of 59% among those with type 1 diabetes (5.55 to 2.26 per 100 patient-years) and 52% in the type 2 diabetes group (1.88 to 0.90 per 100 patient-years).

This finding is important for the United States, Argento said, because some insurers, including Medicare, require that the patient performs at least 4 fingerstick glucose measurements per day to qualify for reimbursement for the Libre or any CGM system.

“I think that speaks to the importance of not requiring that patients first show they’re frequently doing self-blood glucose monitoring before they can get these devices,” he observed.

The large benefit in the high strip use group is interesting too, Argento said. “It’s a different group of people. They’re more engaged in their care...This U-shaped curve they showed is fascinating.”

Reductions in DKA hospitalizations were also similar between patients using insulin pumps and those using multiple daily injections of insulin, Roussel reported.

“It is plausible that use of the FreeStyle Libre system allowed people to detect and limit persistent hyperglycemia, and subsequently ketoacidosis,” Roussel said.

“This analysis has significant implications for patient-centered clinical care in diabetes and also for long-term health economic outcomes in the treatment of diabetes at a national level.”

All-cause hospitalizations drop 30% with Libre in type 2 diabetes

Richard M. Bergenstal, MD, executive director of the International Diabetes Center at Park Nicollet, Minneapolis, Minnesota, presented the US results, obtained from the IBM Watson Health MarketScan, a database of commercial and Medicare supplemental insurance claims for over 30 million Americans.

The study population included 2463 patients with type 2 diabetes using basal-bolus daily insulin injections but who had not previously used Libre or any other CGM, and for whom data were available 6 months prior to and after Libre initiation.

Compared with 6 months prior to Libre use, the number of acute diabetes-related events — including hyperglycemia, hypoglycemia, DKA, hypoglycemic coma, and hyperosmolarity — in the subsequent 6 months dropped by 60%, from 0.180 to 0.072 events per patient-year (P < .001).

Similarly significant reductions were seen between males and females, and among those aged ≥ 50 years or < 50 years.

All-cause hospitalizations also significantly dropped by 33% (P < 0.001), from 0.420 to 0.283 events per patient-year. Among diagnostic codes for the hospitalizations, circulatory system causes remained number one during both time periods, with little change from pre-Libre to during Libre use.

However, “endocrine, nutritional, and metabolism system” codes dropped from the second position pre-Libre (6.4 events/100 patient-years) down to the fifth position (2.6 events/100 patient-years).

And, Bergenstal noted, other major diagnostic categories that also dropped included respiratory (3.5 to 2.1 events/100 patient-years), kidney and urinary tract (3.3 to 1.7 events/100 patient-years), and hepatobiliary system and pancreas (2.4 to 1.4 events/100 patient-years).

“We’re seeing a resurgence of certain types of complications, but all of these were reduced in the 6 months after Libre,” Bergenstal pointed out.

And, pertinent to the current COVID-19 situation, “infectious and parasitic disease and disorders” dropped as well, from 4.8 to 2.8 per 100 patient-years.

Argento commented: “The fact that infections went down speaks to something that is important right now. Hyperglycemia impairs immune function chronically, but also acutely...so patients who become ill and their blood glucose deteriorates rapidly are much more likely to have a poor outcome regardless of infection. There are data for COVID-19 now.”

“These findings provide compelling support for use of [Libre] to improve both clinical outcomes and potentially reduce costs in this patient population,” Bergenstal concluded.

Roussel has reported being on advisory panels for Abbott, AstraZeneca, Diabnext, Eli Lilly, Merck, Mundipharma International, Novo Nordisk, and Sanofi-Aventis. Bergenstal has reported being a consultant for Ascensia Diabetes Care, Johnson & Johnson, and has other relationships with Abbott, Dexcom, Hygieia, Lilly Diabetes, Medtronic, Novo Nordisk, Onduo, Roche Diabetes Care, Sanofi, and UnitedHealth Group. Argento has reported consulting and being on speaker bureaus for Omnipod, Eli Lilly, Novo Nordisk, Dexcom, and Boehringer Ingelheim.

This article first appeared on Medscape.com.
 

The Abbott FreeStyle Libre glucose monitoring system significantly reduced hospitalizations for diabetic ketoacidosis (DKA), diabetes-related emergencies, and all-cause hospitalizations among patients with diabetes, data from two new studies indicate.

The results were presented June 13 during the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

One large database analysis, from France, revealed that use of the Libre system halved hospitalization rates for DKA among people with type 1 or type 2 diabetes.

In the other study, a retrospective analysis of data from over 1200 insulin-treated individuals with type 2 diabetes in the United States, use of the Libre was associated with significant reductions in both hospitalizations for acute diabetes-related emergency events and all-cause hospitalizations.

The Libre system reads glucose levels through a sensor worn on the back of the upper arm for up to 14 days. Users wave a scanner over the device to obtain a reading.

Asked to comment, Nicholas Argento, MD, diabetes technology director at Maryland Endocrine and Diabetes, Columbia, told Medscape Medical News: “One of the biggest problems with access to continuous glucose monitoring is cost. Payers need to see that there’s some cost-saving to offset the cost of paying for these devices. I think both of these studies are important for that reason.”

However, Argento also said he recommends that people with type 1 diabetes use the Dexcom continuous glucose monitor (CGM) if possible rather than the Libre, despite the former’s higher cost, because it has an alarm feature that the Libre doesn’t and is more accurate in the hypoglycemic range.

Large French study: Libre cuts DKA hospitalizations by 50%

The FreeStyle Libre system has been reimbursed in France since June 1, 2017 for patients over 4 years of age with type 1 or type 2 diabetes who take at least 3 insulin injections per day or use an insulin pump.

Sara Freeman/MDedge News

The new results were presented by Ronan Roussel, MD, PhD, chief of the endocrinology, diabetes, and nutrition department at Hôpital Bichat, Fédération de Diabétologie, AP-HP, Paris, France.

The DKA hospitalization data Roussel reported were part of a larger longitudinal retrospective cohort study looking at overall prescribing and use of the Libre system, and its impact on healthcare outcomes and associated costs in standard practice in France. The data came from a large nationwide claims database containing all healthcare expenses for over 66 million people.

The current study participants were 74,076 individuals with at least a full year of follow-up beginning in 2017 with the date of first reimbursement for the FreeStyle Libre system. Of those, 44.8% (33,203) had type 1 diabetes and 55.2% (40,955) had type 2 diabetes.

Prior to initiation of Libre use, about a quarter of each group was using 0 fingerstick test strips per day, about 19% of the type 1 diabetes group and 28% of the type 2 diabetes group were using 1-3 strips per day, and about half of both groups were using 4 or more strips per day.

Compared with the year prior to the date of first reimbursement for the Libre, hospitalization rates for DKA during the first year of Libre use fell by 52% in the type 1 diabetes group, from 5.46 to 2.59 per 100 patient-years, and by 47% in the type 2 diabetes group, from 1.70 to 0.90 per 100 patient-years.

The impact of Libre on DKA hospitalizations was most dramatic among those not using any test strips prior to Libre use, with a 60% reduction for the type 1 diabetes group (8.31 to 3.31 per 100 patient-years) and a 51% reduction in the type 2 diabetes group (2.51 to 1.23 per 100 patient-years).

But interestingly, the next-biggest impact was among those who had been using more than 5 test strips per day, with drops of 59% among those with type 1 diabetes (5.55 to 2.26 per 100 patient-years) and 52% in the type 2 diabetes group (1.88 to 0.90 per 100 patient-years).

This finding is important for the United States, Argento said, because some insurers, including Medicare, require that the patient performs at least 4 fingerstick glucose measurements per day to qualify for reimbursement for the Libre or any CGM system.

“I think that speaks to the importance of not requiring that patients first show they’re frequently doing self-blood glucose monitoring before they can get these devices,” he observed.

The large benefit in the high strip use group is interesting too, Argento said. “It’s a different group of people. They’re more engaged in their care...This U-shaped curve they showed is fascinating.”

Reductions in DKA hospitalizations were also similar between patients using insulin pumps and those using multiple daily injections of insulin, Roussel reported.

“It is plausible that use of the FreeStyle Libre system allowed people to detect and limit persistent hyperglycemia, and subsequently ketoacidosis,” Roussel said.

“This analysis has significant implications for patient-centered clinical care in diabetes and also for long-term health economic outcomes in the treatment of diabetes at a national level.”

All-cause hospitalizations drop 30% with Libre in type 2 diabetes

Richard M. Bergenstal, MD, executive director of the International Diabetes Center at Park Nicollet, Minneapolis, Minnesota, presented the US results, obtained from the IBM Watson Health MarketScan, a database of commercial and Medicare supplemental insurance claims for over 30 million Americans.

The study population included 2463 patients with type 2 diabetes using basal-bolus daily insulin injections but who had not previously used Libre or any other CGM, and for whom data were available 6 months prior to and after Libre initiation.

Compared with 6 months prior to Libre use, the number of acute diabetes-related events — including hyperglycemia, hypoglycemia, DKA, hypoglycemic coma, and hyperosmolarity — in the subsequent 6 months dropped by 60%, from 0.180 to 0.072 events per patient-year (P < .001).

Similarly significant reductions were seen between males and females, and among those aged ≥ 50 years or < 50 years.

All-cause hospitalizations also significantly dropped by 33% (P < 0.001), from 0.420 to 0.283 events per patient-year. Among diagnostic codes for the hospitalizations, circulatory system causes remained number one during both time periods, with little change from pre-Libre to during Libre use.

However, “endocrine, nutritional, and metabolism system” codes dropped from the second position pre-Libre (6.4 events/100 patient-years) down to the fifth position (2.6 events/100 patient-years).

And, Bergenstal noted, other major diagnostic categories that also dropped included respiratory (3.5 to 2.1 events/100 patient-years), kidney and urinary tract (3.3 to 1.7 events/100 patient-years), and hepatobiliary system and pancreas (2.4 to 1.4 events/100 patient-years).

“We’re seeing a resurgence of certain types of complications, but all of these were reduced in the 6 months after Libre,” Bergenstal pointed out.

And, pertinent to the current COVID-19 situation, “infectious and parasitic disease and disorders” dropped as well, from 4.8 to 2.8 per 100 patient-years.

Argento commented: “The fact that infections went down speaks to something that is important right now. Hyperglycemia impairs immune function chronically, but also acutely...so patients who become ill and their blood glucose deteriorates rapidly are much more likely to have a poor outcome regardless of infection. There are data for COVID-19 now.”

“These findings provide compelling support for use of [Libre] to improve both clinical outcomes and potentially reduce costs in this patient population,” Bergenstal concluded.

Roussel has reported being on advisory panels for Abbott, AstraZeneca, Diabnext, Eli Lilly, Merck, Mundipharma International, Novo Nordisk, and Sanofi-Aventis. Bergenstal has reported being a consultant for Ascensia Diabetes Care, Johnson & Johnson, and has other relationships with Abbott, Dexcom, Hygieia, Lilly Diabetes, Medtronic, Novo Nordisk, Onduo, Roche Diabetes Care, Sanofi, and UnitedHealth Group. Argento has reported consulting and being on speaker bureaus for Omnipod, Eli Lilly, Novo Nordisk, Dexcom, and Boehringer Ingelheim.

This article first appeared on Medscape.com.
 

Drug adherence, healthcare use, medical costs, and heart failure rates were better among patients with type 2 diabetes who were newly prescribed a sodium-glucose cotransporter 2 (SGLT2) inhibitor than a glucagon-like peptide 1 (GLP-1) receptor agonist in a real-world, observational study.

Composite cardiovascular (CV) outcomes were similar between the two drug classes.

Insiya Poonawalla, PhD, a researcher at Humana Healthcare Research, Flower Mound, Texas, reported the study results in an oral presentation on June 12 at the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

The investigators matched more than 10,000 patients with type 2 diabetes — half initiated on an SGLT2 inhibitor and half initiated on a GLP-1 agonist — from the Humana database of insurance claims data.

“These findings suggest potential benefits” of SGLT2 inhibitors, “particularly where risk related to heart failure is an important consideration,” Poonawalla said, but as always, any benefits need to be weighed against any risks.

And “while this study provides a pretty complete and current picture of claims until 2018,” it has limitations inherent to observational data (such as possible errors or omissions in the claims data), she conceded.

Mitchel L. Zoler/MDedge News

Mikhail Kosiborod, MD, invited to comment on the research, said this preliminary study was likely too short and small to definitively demonstrate differences in composite CV outcomes between the two drug classes, but he noted that the overall findings are not unexpected.

And often, the particular CV risk profile of an individual patient will point to one or the other of these drug classes as a best fit, he noted.

Too soon to alter clinical practice

Kosiborod, from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, said he nevertheless feels “it would be a bit premature to use these findings as a guide to change clinical practice.”

“The study is relatively small in scope and likely underpowered to examine CV outcomes,” he said in an email interview.

Larger population-based studies and ideally head-to-head randomized controlled trials of various type 2 diabetes agents could compare these two drug classes more definitively, he asserted.

In the meantime, safety profiles of both medication classes “have been well established — in tens of thousands of patients in clinical trials and millions of patients prescribed these therapies in clinical practice,” he noted.

In general, the drugs in both classes are well-tolerated and safe for most patients with type 2 diabetes when used appropriately.

“Certainly, patients with type 2 diabetes and established CV disease (or at high risk for CV complications) are ideal candidates for either an SGLT2 inhibitor or a GLP-1 receptor agonist,” Kosiborod said.

“Given the data we have from outcome trials, an SGLT2 inhibitor would be a better initial strategy in a patient with type 2 diabetes and heart failure (especially heart failure with reduced ejection fraction) and/or diabetic kidney disease,” he continued.

On the other hand, “a GLP-1 receptor agonist may be a better initial strategy in a type 2 diabetes patient with (or at very high risk for) atherosclerotic cardiovascular disease (ASCVD), especially if there is concomitant obesity contributing to the disease process.”

Limited comparisons of these two newer drug classes

“Real-world evidence comparing these two therapeutic classes based on CV outcomes is limited,” Poonawalla said at the start of her presentation, and relative treatment persistence, utilization, and cost data are even less well studied.

To investigate this, the researchers identified patients aged 19 to 89 years who were newly prescribed one of these two types of antidiabetic agents during January 1, 2015 through June 30, 2017.

Poonawalla and senior study author Phil Schwab, PhD, research lead, Humana Healthcare Research, Louisville, Kentucky, clarified the study design and findings in an email to this new organization.

The team matched 5507 patients initiated on a GLP-1 agonist with 5507 patients newly prescribed an SGLT2 inhibitor.

Patients were a mean age of 65 years and 53% were women.

More than a third (37%) had established ASCVD, including myocardial infarction (MI) (7.9%) and stroke (9.8%), and 11.5% had heart failure.

About two thirds were receiving metformin and about a third were receiving insulin.

In the GLP-1 agonist group, more than half of patients were prescribed liraglutide (57%), followed by dulaglutide (33%), exenatide, and lixisenatide (two patients).

In the SGLT2 inhibitor group, close to 70% received canagliflozin, about a quarter received empagliflozin, and the rest received dapagliflozin.

During up to 3.5 years of follow-up, a similar percentage of patients in each group had either an MI, stroke, or died (the primary composite CV outcome) (hazard ratio [HR], 0.98; 95% CI, 0.89 - 1.07).

However, more patients in the GLP-1 agonist group had heart failure or died (the secondary composite CV outcome), driven by a higher rate of heart failure in this group.

But after adjusting for time to events there was no significant between-group difference in the secondary composite CV outcome (HR, 1.09; 95% CI, 0.99 - 1.21).

During the 12-months after the initial prescription, patients who were started on a GLP-1 agonist versus an SGLT2 inhibitor had higher mean monthly medical costs, which included hospitalizations, emergency department (ED) visits, and outpatient visits ($904 vs $834; P < .001).

They also had higher pharmacy costs, which covered all drugs ($891 vs $783; P < .001).

And they were more likely to discontinue treatment (HR, 1.15; 95% CI, 1.10 - 1.21), be hospitalized (14.4% vs 11.9%; P < .001), or visit the ED (27.4% vs 23.5%; P < .001).

“Not too surprising” and “somewhat reassuring”

Overall, Kosiborod did not find the results surprising.

Given the sample size and follow-up time, event rates were probably quite low and insufficient to draw firm conclusions about the composite CV outcomes, he reiterated.

However, given the comparable effects of these two drug types on major adverse cardiac events (MACE) in similar patient populations with type 2 diabetes, it is not too surprising that there were no significant differences in these outcomes.

It was also “somewhat reassuring” to see that heart failure rates were lower with SGLT2 inhibitors, “as one would expect,” he said, because these agents “have been shown to significantly reduce the risk of hospitalization for heart failure in multiple outcome trials, whereas GLP-1 receptor agonists’ beneficial CV effects appear to be more limited to MACE reduction.”

The higher rates of discontinuation with GLP-1 receptor agonists “is also not a surprise, since patients experience more gastrointestinal tolerability issues with these agents (mainly nausea),” which can be mitigated in the majority of patients with appropriate education and close follow up — but is not done consistently.

Similarly, “the cost differences are also expected, since GLP-1 receptor agonists tend to be more expensive.”

On the other hand, the higher rates of hospitalizations with GLP-1 agonists compared to SGLT2 inhibitors “requires further exploration and confirmation,” Kosiborod said.

But he suspects this may be due to residual confounding, “since GLP-1 agonists are typically initiated later in the type 2 diabetes treatment algorithm,” so these patients could have lengthier, more difficult-to-manage type 2 diabetes with more comorbidities despite the propensity matching.

Poonawalla and Schwab are employed by Humana. Kosiborod has disclosed research support from AstraZeneca and Boehringer Ingelheim; honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and consulting fees from Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec, Intarcia, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi Aventis .



This article first appeared on Medscape.com

Drug adherence, healthcare use, medical costs, and heart failure rates were better among patients with type 2 diabetes who were newly prescribed a sodium-glucose cotransporter 2 (SGLT2) inhibitor than a glucagon-like peptide 1 (GLP-1) receptor agonist in a real-world, observational study.

Composite cardiovascular (CV) outcomes were similar between the two drug classes.

Insiya Poonawalla, PhD, a researcher at Humana Healthcare Research, Flower Mound, Texas, reported the study results in an oral presentation on June 12 at the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

The investigators matched more than 10,000 patients with type 2 diabetes — half initiated on an SGLT2 inhibitor and half initiated on a GLP-1 agonist — from the Humana database of insurance claims data.

“These findings suggest potential benefits” of SGLT2 inhibitors, “particularly where risk related to heart failure is an important consideration,” Poonawalla said, but as always, any benefits need to be weighed against any risks.

And “while this study provides a pretty complete and current picture of claims until 2018,” it has limitations inherent to observational data (such as possible errors or omissions in the claims data), she conceded.

Mitchel L. Zoler/MDedge News

Mikhail Kosiborod, MD, invited to comment on the research, said this preliminary study was likely too short and small to definitively demonstrate differences in composite CV outcomes between the two drug classes, but he noted that the overall findings are not unexpected.

And often, the particular CV risk profile of an individual patient will point to one or the other of these drug classes as a best fit, he noted.

Too soon to alter clinical practice

Kosiborod, from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, said he nevertheless feels “it would be a bit premature to use these findings as a guide to change clinical practice.”

“The study is relatively small in scope and likely underpowered to examine CV outcomes,” he said in an email interview.

Larger population-based studies and ideally head-to-head randomized controlled trials of various type 2 diabetes agents could compare these two drug classes more definitively, he asserted.

In the meantime, safety profiles of both medication classes “have been well established — in tens of thousands of patients in clinical trials and millions of patients prescribed these therapies in clinical practice,” he noted.

In general, the drugs in both classes are well-tolerated and safe for most patients with type 2 diabetes when used appropriately.

“Certainly, patients with type 2 diabetes and established CV disease (or at high risk for CV complications) are ideal candidates for either an SGLT2 inhibitor or a GLP-1 receptor agonist,” Kosiborod said.

“Given the data we have from outcome trials, an SGLT2 inhibitor would be a better initial strategy in a patient with type 2 diabetes and heart failure (especially heart failure with reduced ejection fraction) and/or diabetic kidney disease,” he continued.

On the other hand, “a GLP-1 receptor agonist may be a better initial strategy in a type 2 diabetes patient with (or at very high risk for) atherosclerotic cardiovascular disease (ASCVD), especially if there is concomitant obesity contributing to the disease process.”

Limited comparisons of these two newer drug classes

“Real-world evidence comparing these two therapeutic classes based on CV outcomes is limited,” Poonawalla said at the start of her presentation, and relative treatment persistence, utilization, and cost data are even less well studied.

To investigate this, the researchers identified patients aged 19 to 89 years who were newly prescribed one of these two types of antidiabetic agents during January 1, 2015 through June 30, 2017.

Poonawalla and senior study author Phil Schwab, PhD, research lead, Humana Healthcare Research, Louisville, Kentucky, clarified the study design and findings in an email to this new organization.

The team matched 5507 patients initiated on a GLP-1 agonist with 5507 patients newly prescribed an SGLT2 inhibitor.

Patients were a mean age of 65 years and 53% were women.

More than a third (37%) had established ASCVD, including myocardial infarction (MI) (7.9%) and stroke (9.8%), and 11.5% had heart failure.

About two thirds were receiving metformin and about a third were receiving insulin.

In the GLP-1 agonist group, more than half of patients were prescribed liraglutide (57%), followed by dulaglutide (33%), exenatide, and lixisenatide (two patients).

In the SGLT2 inhibitor group, close to 70% received canagliflozin, about a quarter received empagliflozin, and the rest received dapagliflozin.

During up to 3.5 years of follow-up, a similar percentage of patients in each group had either an MI, stroke, or died (the primary composite CV outcome) (hazard ratio [HR], 0.98; 95% CI, 0.89 - 1.07).

However, more patients in the GLP-1 agonist group had heart failure or died (the secondary composite CV outcome), driven by a higher rate of heart failure in this group.

But after adjusting for time to events there was no significant between-group difference in the secondary composite CV outcome (HR, 1.09; 95% CI, 0.99 - 1.21).

During the 12-months after the initial prescription, patients who were started on a GLP-1 agonist versus an SGLT2 inhibitor had higher mean monthly medical costs, which included hospitalizations, emergency department (ED) visits, and outpatient visits ($904 vs $834; P < .001).

They also had higher pharmacy costs, which covered all drugs ($891 vs $783; P < .001).

And they were more likely to discontinue treatment (HR, 1.15; 95% CI, 1.10 - 1.21), be hospitalized (14.4% vs 11.9%; P < .001), or visit the ED (27.4% vs 23.5%; P < .001).

“Not too surprising” and “somewhat reassuring”

Overall, Kosiborod did not find the results surprising.

Given the sample size and follow-up time, event rates were probably quite low and insufficient to draw firm conclusions about the composite CV outcomes, he reiterated.

However, given the comparable effects of these two drug types on major adverse cardiac events (MACE) in similar patient populations with type 2 diabetes, it is not too surprising that there were no significant differences in these outcomes.

It was also “somewhat reassuring” to see that heart failure rates were lower with SGLT2 inhibitors, “as one would expect,” he said, because these agents “have been shown to significantly reduce the risk of hospitalization for heart failure in multiple outcome trials, whereas GLP-1 receptor agonists’ beneficial CV effects appear to be more limited to MACE reduction.”

The higher rates of discontinuation with GLP-1 receptor agonists “is also not a surprise, since patients experience more gastrointestinal tolerability issues with these agents (mainly nausea),” which can be mitigated in the majority of patients with appropriate education and close follow up — but is not done consistently.

Similarly, “the cost differences are also expected, since GLP-1 receptor agonists tend to be more expensive.”

On the other hand, the higher rates of hospitalizations with GLP-1 agonists compared to SGLT2 inhibitors “requires further exploration and confirmation,” Kosiborod said.

But he suspects this may be due to residual confounding, “since GLP-1 agonists are typically initiated later in the type 2 diabetes treatment algorithm,” so these patients could have lengthier, more difficult-to-manage type 2 diabetes with more comorbidities despite the propensity matching.

Poonawalla and Schwab are employed by Humana. Kosiborod has disclosed research support from AstraZeneca and Boehringer Ingelheim; honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and consulting fees from Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec, Intarcia, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi Aventis .



This article first appeared on Medscape.com

Drug adherence, healthcare use, medical costs, and heart failure rates were better among patients with type 2 diabetes who were newly prescribed a sodium-glucose cotransporter 2 (SGLT2) inhibitor than a glucagon-like peptide 1 (GLP-1) receptor agonist in a real-world, observational study.

Composite cardiovascular (CV) outcomes were similar between the two drug classes.

Insiya Poonawalla, PhD, a researcher at Humana Healthcare Research, Flower Mound, Texas, reported the study results in an oral presentation on June 12 at the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

The investigators matched more than 10,000 patients with type 2 diabetes — half initiated on an SGLT2 inhibitor and half initiated on a GLP-1 agonist — from the Humana database of insurance claims data.

“These findings suggest potential benefits” of SGLT2 inhibitors, “particularly where risk related to heart failure is an important consideration,” Poonawalla said, but as always, any benefits need to be weighed against any risks.

And “while this study provides a pretty complete and current picture of claims until 2018,” it has limitations inherent to observational data (such as possible errors or omissions in the claims data), she conceded.

Mitchel L. Zoler/MDedge News

Mikhail Kosiborod, MD, invited to comment on the research, said this preliminary study was likely too short and small to definitively demonstrate differences in composite CV outcomes between the two drug classes, but he noted that the overall findings are not unexpected.

And often, the particular CV risk profile of an individual patient will point to one or the other of these drug classes as a best fit, he noted.

Too soon to alter clinical practice

Kosiborod, from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, said he nevertheless feels “it would be a bit premature to use these findings as a guide to change clinical practice.”

“The study is relatively small in scope and likely underpowered to examine CV outcomes,” he said in an email interview.

Larger population-based studies and ideally head-to-head randomized controlled trials of various type 2 diabetes agents could compare these two drug classes more definitively, he asserted.

In the meantime, safety profiles of both medication classes “have been well established — in tens of thousands of patients in clinical trials and millions of patients prescribed these therapies in clinical practice,” he noted.

In general, the drugs in both classes are well-tolerated and safe for most patients with type 2 diabetes when used appropriately.

“Certainly, patients with type 2 diabetes and established CV disease (or at high risk for CV complications) are ideal candidates for either an SGLT2 inhibitor or a GLP-1 receptor agonist,” Kosiborod said.

“Given the data we have from outcome trials, an SGLT2 inhibitor would be a better initial strategy in a patient with type 2 diabetes and heart failure (especially heart failure with reduced ejection fraction) and/or diabetic kidney disease,” he continued.

On the other hand, “a GLP-1 receptor agonist may be a better initial strategy in a type 2 diabetes patient with (or at very high risk for) atherosclerotic cardiovascular disease (ASCVD), especially if there is concomitant obesity contributing to the disease process.”

Limited comparisons of these two newer drug classes

“Real-world evidence comparing these two therapeutic classes based on CV outcomes is limited,” Poonawalla said at the start of her presentation, and relative treatment persistence, utilization, and cost data are even less well studied.

To investigate this, the researchers identified patients aged 19 to 89 years who were newly prescribed one of these two types of antidiabetic agents during January 1, 2015 through June 30, 2017.

Poonawalla and senior study author Phil Schwab, PhD, research lead, Humana Healthcare Research, Louisville, Kentucky, clarified the study design and findings in an email to this new organization.

The team matched 5507 patients initiated on a GLP-1 agonist with 5507 patients newly prescribed an SGLT2 inhibitor.

Patients were a mean age of 65 years and 53% were women.

More than a third (37%) had established ASCVD, including myocardial infarction (MI) (7.9%) and stroke (9.8%), and 11.5% had heart failure.

About two thirds were receiving metformin and about a third were receiving insulin.

In the GLP-1 agonist group, more than half of patients were prescribed liraglutide (57%), followed by dulaglutide (33%), exenatide, and lixisenatide (two patients).

In the SGLT2 inhibitor group, close to 70% received canagliflozin, about a quarter received empagliflozin, and the rest received dapagliflozin.

During up to 3.5 years of follow-up, a similar percentage of patients in each group had either an MI, stroke, or died (the primary composite CV outcome) (hazard ratio [HR], 0.98; 95% CI, 0.89 - 1.07).

However, more patients in the GLP-1 agonist group had heart failure or died (the secondary composite CV outcome), driven by a higher rate of heart failure in this group.

But after adjusting for time to events there was no significant between-group difference in the secondary composite CV outcome (HR, 1.09; 95% CI, 0.99 - 1.21).

During the 12-months after the initial prescription, patients who were started on a GLP-1 agonist versus an SGLT2 inhibitor had higher mean monthly medical costs, which included hospitalizations, emergency department (ED) visits, and outpatient visits ($904 vs $834; P < .001).

They also had higher pharmacy costs, which covered all drugs ($891 vs $783; P < .001).

And they were more likely to discontinue treatment (HR, 1.15; 95% CI, 1.10 - 1.21), be hospitalized (14.4% vs 11.9%; P < .001), or visit the ED (27.4% vs 23.5%; P < .001).

“Not too surprising” and “somewhat reassuring”

Overall, Kosiborod did not find the results surprising.

Given the sample size and follow-up time, event rates were probably quite low and insufficient to draw firm conclusions about the composite CV outcomes, he reiterated.

However, given the comparable effects of these two drug types on major adverse cardiac events (MACE) in similar patient populations with type 2 diabetes, it is not too surprising that there were no significant differences in these outcomes.

It was also “somewhat reassuring” to see that heart failure rates were lower with SGLT2 inhibitors, “as one would expect,” he said, because these agents “have been shown to significantly reduce the risk of hospitalization for heart failure in multiple outcome trials, whereas GLP-1 receptor agonists’ beneficial CV effects appear to be more limited to MACE reduction.”

The higher rates of discontinuation with GLP-1 receptor agonists “is also not a surprise, since patients experience more gastrointestinal tolerability issues with these agents (mainly nausea),” which can be mitigated in the majority of patients with appropriate education and close follow up — but is not done consistently.

Similarly, “the cost differences are also expected, since GLP-1 receptor agonists tend to be more expensive.”

On the other hand, the higher rates of hospitalizations with GLP-1 agonists compared to SGLT2 inhibitors “requires further exploration and confirmation,” Kosiborod said.

But he suspects this may be due to residual confounding, “since GLP-1 agonists are typically initiated later in the type 2 diabetes treatment algorithm,” so these patients could have lengthier, more difficult-to-manage type 2 diabetes with more comorbidities despite the propensity matching.

Poonawalla and Schwab are employed by Humana. Kosiborod has disclosed research support from AstraZeneca and Boehringer Ingelheim; honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and consulting fees from Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec, Intarcia, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi Aventis .



This article first appeared on Medscape.com