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For COVID-19 plus diabetes, glycemic control tops treatment list
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.
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.
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.
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.”
Three-drug combo promising against high-risk CLL
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.
FROM EHA CONGRESS
Secondary infections common in COVID-19, implications unclear
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.
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.
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.
Organoid model unveils response to Shiga toxin
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.
Limited therapies exist to mitigate the life-threatening sequelae of Shiga toxin (Stx)–producing Escherichia coli (STEC) infections. Stx continues to be a leading cause of hemolytic uremic syndrome and can devastate the kidneys, central nervous system, and other vital organs. Conflicting results from animal models and cell lines have left important questions unanswered, slowing therapy development. This study by Pradhan et al. takes advantage of the human intestinal organoid system to provide insight to questions pertinent to understanding Stx mechanism of action. Importantly, the authors find that intestinal epithelial cells (IECs) are a direct target of Stx and express the Stx receptor, Gb3, a point that had not been previously well established. They further confirm that IECs efficiently transport Stx from the apical to basolateral surface, before barrier integrity is compromised. This likely allows Stx to rapidly access circulation and other affected organs to cause disease.
Nicole Maloney Belle, MD, PhD, is an instructor of medicine, division of gastroenterology and hepatology, at the University of Pennsylvania, Philadelphia. She has no conflicts.
Limited therapies exist to mitigate the life-threatening sequelae of Shiga toxin (Stx)–producing Escherichia coli (STEC) infections. Stx continues to be a leading cause of hemolytic uremic syndrome and can devastate the kidneys, central nervous system, and other vital organs. Conflicting results from animal models and cell lines have left important questions unanswered, slowing therapy development. This study by Pradhan et al. takes advantage of the human intestinal organoid system to provide insight to questions pertinent to understanding Stx mechanism of action. Importantly, the authors find that intestinal epithelial cells (IECs) are a direct target of Stx and express the Stx receptor, Gb3, a point that had not been previously well established. They further confirm that IECs efficiently transport Stx from the apical to basolateral surface, before barrier integrity is compromised. This likely allows Stx to rapidly access circulation and other affected organs to cause disease.
Nicole Maloney Belle, MD, PhD, is an instructor of medicine, division of gastroenterology and hepatology, at the University of Pennsylvania, Philadelphia. She has no conflicts.
Limited therapies exist to mitigate the life-threatening sequelae of Shiga toxin (Stx)–producing Escherichia coli (STEC) infections. Stx continues to be a leading cause of hemolytic uremic syndrome and can devastate the kidneys, central nervous system, and other vital organs. Conflicting results from animal models and cell lines have left important questions unanswered, slowing therapy development. This study by Pradhan et al. takes advantage of the human intestinal organoid system to provide insight to questions pertinent to understanding Stx mechanism of action. Importantly, the authors find that intestinal epithelial cells (IECs) are a direct target of Stx and express the Stx receptor, Gb3, a point that had not been previously well established. They further confirm that IECs efficiently transport Stx from the apical to basolateral surface, before barrier integrity is compromised. This likely allows Stx to rapidly access circulation and other affected organs to cause disease.
Nicole Maloney Belle, MD, PhD, is an instructor of medicine, division of gastroenterology and hepatology, at the University of Pennsylvania, Philadelphia. She has no conflicts.
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.
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.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Snail mucus in skin care
Although it is not glamorous, .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
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, .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
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, .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
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.
Diabetes hospitalizations halved with FreeStyle Libre glucose monitor
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.
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.
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.
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.
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.
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.
FROM ADA 2020
CV outcomes of SGLT2 inhibitors and GLP-1 agonists compared in real-world study
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.
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.
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.
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
FROM ADA 2020
High-frequency spinal cord stimulation eases painful diabetic neuropathy
For patients with painful diabetic neuropathy that doesn’t resolve with standard treatment, use of a 10-kHz spinal cord stimulation device may relieve pain and improve sensation, initial results of a large randomized controlled trial suggest.
Some 79% of patients had substantial pain relief 3 months after starting treatment, compared with 5% of patients managed with conventional medical treatment, according to results of SENZA-PDN, which investigators say is the largest-ever randomized, controlled trial of spinal cord stimulation for managing painful diabetic neuropathy.
Although this was not a comparative trial, investigator Erika Petersen, MD, said in an interview that results seen with the 10-kHz spinal cord stimulator (Nevro Corp.) exceed what has been seen in previous studies of spinal cord stimulation devices operating at lower frequencies, where response rates have been in the 40%-55% range.
New option for front line providers?
“My overall takeaway here is that these initial 3-month results are very promising,” said Dr. Petersen, who is Director of Functional & Restorative Neurosurgery and Neuromodulation at the University of Arkansas for Medical Sciences in Little Rock.
Patient-perceived numbness and sensory assessments by investigators also improved following implantation of the spinal cord stimulator, according to Dr. Peterson, who added that measurements of sleep and activity also seemed to improve in these patients with painful diabetic neuropathy.
“Spinal cord stimulation has been established for chronic back and leg pain, but being able to innovate in this population with diabetic neuropathy is really something that we anticipate will improve quality of life and functional benefit for a large number of patients who currently have been stuck with the options that are currently available,” Dr. Petersen said in an interview.
Natalie H. Strand, MD, assistant professor of pain medicine at Mayo Clinic, Scottsdale, Ariz., said that while the findings of this randomized study may require corroboration, they do suggest that this neuromodulation device may provide another option for front line diabetes providers when patients have persistent pain despite appropriately medication management.
“These patients are probably under-referred to interventional pain specialists,” said Dr. Strand in an interview. “The primary care physicians and endocrinologists may not think of neuromodulation as an appropriate treatment, and they may not know that it can be so effective.”
“Anything that we can add as physicians to help decrease the burden of diabetes is going to be very impactful,” Dr. Strand added. “While this is focused on pain, what we’re really trying to treat is the entire patient – improve their quality of life and make diabetes more manageable.”
Nearly 80% of treated patients responded at 3 months
The SENZA-PDN study results were presented as a late-breaking poster presentation at the virtual annual scientific sessions of the American Diabetes Association. Those results included 103 patients randomized to conventional medical management alone, and 113 who received medical management plus the spinal cord stimulator, which Dr. Strand described as a minimally invasive, reversibly implanted epidural device designed to stimulate the spinal cord and reverse pain sensations.
The median age was about 61 years and roughly two-thirds were male. All patients had to have lower extremity pain with an average intensity of at least 5 out of 10 cm on the visual analog scale (VAS) at enrollment, according to published inclusion criteria for the study (NCT03228420).
Three months after device implantation, 75 out of 95 evaluable patients (79%) had a response, defined as 50% or greater pain relief plus no worsening of neurological deficit related to painful diabetic neuropathy. By contrast, only 5 of 94 medically managed patients (5%) met those response criteria (P < 0.001), according to reported data.
The mean VAS score in the device group dropped from 7.6 at baseline to 2.4 at 1 month and 1.7 at 3 months, data show. In the medical management group, mean VAS scores were 7.0 at baseline, 6.7 at 1 month, and 6.5 at 3 months.
Sensory assessment of monofilament and pinprick perception, performed by investigators at 3 months, indicated a 72% improvement in the device arm versus 7% improvement in the medical management arm, while analysis of patient-drawn diagrams additionally suggested improvement in perceived numbness, according to investigators.
Quality-of-life improvements related to sleep and activity were also apparent at 3 months in the device group, Dr. Petersen said, with investigators noting substantial reductions in trouble falling asleep because of pain and awakening due to pain. Likewise, data at this initial report suggested improvements in 6-minute walk test that were apparent in the device group but not the medical management group.
While the spinal cord stimulator under investigation is already approved by the U.S. Food and Drug Administration, Dr. Petersen said a lack of data specific to painful diabetic neuropathy has been a hurdle to insurance coverage for some patients.
“I’ve had patients who clearly have every suggestion that they match the characteristics of our research population here, but the insurance will decline the procedure as being experimental,” she said. “My hope is that randomized, controlled trial results in a research study such as this is something that will improve the access of the therapy to patients who would not be able to afford it without having insurance cover the procedure.”
Follow-up of the study will continue for 24 months and will include assessment of health economics and use of pain medication, Dr. Petersen said.
The SENZA-PDN study is funded by Nevro Corp. Dr. Petersen said that she receives research funding and consulting fees from Nevro Corp. and other device manufacturers. Dr. Strand said she had no disclosures related to the research.
SOURCE: Petersen E. ADA 2020, Late-breaking poster 31-LB.
For patients with painful diabetic neuropathy that doesn’t resolve with standard treatment, use of a 10-kHz spinal cord stimulation device may relieve pain and improve sensation, initial results of a large randomized controlled trial suggest.
Some 79% of patients had substantial pain relief 3 months after starting treatment, compared with 5% of patients managed with conventional medical treatment, according to results of SENZA-PDN, which investigators say is the largest-ever randomized, controlled trial of spinal cord stimulation for managing painful diabetic neuropathy.
Although this was not a comparative trial, investigator Erika Petersen, MD, said in an interview that results seen with the 10-kHz spinal cord stimulator (Nevro Corp.) exceed what has been seen in previous studies of spinal cord stimulation devices operating at lower frequencies, where response rates have been in the 40%-55% range.
New option for front line providers?
“My overall takeaway here is that these initial 3-month results are very promising,” said Dr. Petersen, who is Director of Functional & Restorative Neurosurgery and Neuromodulation at the University of Arkansas for Medical Sciences in Little Rock.
Patient-perceived numbness and sensory assessments by investigators also improved following implantation of the spinal cord stimulator, according to Dr. Peterson, who added that measurements of sleep and activity also seemed to improve in these patients with painful diabetic neuropathy.
“Spinal cord stimulation has been established for chronic back and leg pain, but being able to innovate in this population with diabetic neuropathy is really something that we anticipate will improve quality of life and functional benefit for a large number of patients who currently have been stuck with the options that are currently available,” Dr. Petersen said in an interview.
Natalie H. Strand, MD, assistant professor of pain medicine at Mayo Clinic, Scottsdale, Ariz., said that while the findings of this randomized study may require corroboration, they do suggest that this neuromodulation device may provide another option for front line diabetes providers when patients have persistent pain despite appropriately medication management.
“These patients are probably under-referred to interventional pain specialists,” said Dr. Strand in an interview. “The primary care physicians and endocrinologists may not think of neuromodulation as an appropriate treatment, and they may not know that it can be so effective.”
“Anything that we can add as physicians to help decrease the burden of diabetes is going to be very impactful,” Dr. Strand added. “While this is focused on pain, what we’re really trying to treat is the entire patient – improve their quality of life and make diabetes more manageable.”
Nearly 80% of treated patients responded at 3 months
The SENZA-PDN study results were presented as a late-breaking poster presentation at the virtual annual scientific sessions of the American Diabetes Association. Those results included 103 patients randomized to conventional medical management alone, and 113 who received medical management plus the spinal cord stimulator, which Dr. Strand described as a minimally invasive, reversibly implanted epidural device designed to stimulate the spinal cord and reverse pain sensations.
The median age was about 61 years and roughly two-thirds were male. All patients had to have lower extremity pain with an average intensity of at least 5 out of 10 cm on the visual analog scale (VAS) at enrollment, according to published inclusion criteria for the study (NCT03228420).
Three months after device implantation, 75 out of 95 evaluable patients (79%) had a response, defined as 50% or greater pain relief plus no worsening of neurological deficit related to painful diabetic neuropathy. By contrast, only 5 of 94 medically managed patients (5%) met those response criteria (P < 0.001), according to reported data.
The mean VAS score in the device group dropped from 7.6 at baseline to 2.4 at 1 month and 1.7 at 3 months, data show. In the medical management group, mean VAS scores were 7.0 at baseline, 6.7 at 1 month, and 6.5 at 3 months.
Sensory assessment of monofilament and pinprick perception, performed by investigators at 3 months, indicated a 72% improvement in the device arm versus 7% improvement in the medical management arm, while analysis of patient-drawn diagrams additionally suggested improvement in perceived numbness, according to investigators.
Quality-of-life improvements related to sleep and activity were also apparent at 3 months in the device group, Dr. Petersen said, with investigators noting substantial reductions in trouble falling asleep because of pain and awakening due to pain. Likewise, data at this initial report suggested improvements in 6-minute walk test that were apparent in the device group but not the medical management group.
While the spinal cord stimulator under investigation is already approved by the U.S. Food and Drug Administration, Dr. Petersen said a lack of data specific to painful diabetic neuropathy has been a hurdle to insurance coverage for some patients.
“I’ve had patients who clearly have every suggestion that they match the characteristics of our research population here, but the insurance will decline the procedure as being experimental,” she said. “My hope is that randomized, controlled trial results in a research study such as this is something that will improve the access of the therapy to patients who would not be able to afford it without having insurance cover the procedure.”
Follow-up of the study will continue for 24 months and will include assessment of health economics and use of pain medication, Dr. Petersen said.
The SENZA-PDN study is funded by Nevro Corp. Dr. Petersen said that she receives research funding and consulting fees from Nevro Corp. and other device manufacturers. Dr. Strand said she had no disclosures related to the research.
SOURCE: Petersen E. ADA 2020, Late-breaking poster 31-LB.
For patients with painful diabetic neuropathy that doesn’t resolve with standard treatment, use of a 10-kHz spinal cord stimulation device may relieve pain and improve sensation, initial results of a large randomized controlled trial suggest.
Some 79% of patients had substantial pain relief 3 months after starting treatment, compared with 5% of patients managed with conventional medical treatment, according to results of SENZA-PDN, which investigators say is the largest-ever randomized, controlled trial of spinal cord stimulation for managing painful diabetic neuropathy.
Although this was not a comparative trial, investigator Erika Petersen, MD, said in an interview that results seen with the 10-kHz spinal cord stimulator (Nevro Corp.) exceed what has been seen in previous studies of spinal cord stimulation devices operating at lower frequencies, where response rates have been in the 40%-55% range.
New option for front line providers?
“My overall takeaway here is that these initial 3-month results are very promising,” said Dr. Petersen, who is Director of Functional & Restorative Neurosurgery and Neuromodulation at the University of Arkansas for Medical Sciences in Little Rock.
Patient-perceived numbness and sensory assessments by investigators also improved following implantation of the spinal cord stimulator, according to Dr. Peterson, who added that measurements of sleep and activity also seemed to improve in these patients with painful diabetic neuropathy.
“Spinal cord stimulation has been established for chronic back and leg pain, but being able to innovate in this population with diabetic neuropathy is really something that we anticipate will improve quality of life and functional benefit for a large number of patients who currently have been stuck with the options that are currently available,” Dr. Petersen said in an interview.
Natalie H. Strand, MD, assistant professor of pain medicine at Mayo Clinic, Scottsdale, Ariz., said that while the findings of this randomized study may require corroboration, they do suggest that this neuromodulation device may provide another option for front line diabetes providers when patients have persistent pain despite appropriately medication management.
“These patients are probably under-referred to interventional pain specialists,” said Dr. Strand in an interview. “The primary care physicians and endocrinologists may not think of neuromodulation as an appropriate treatment, and they may not know that it can be so effective.”
“Anything that we can add as physicians to help decrease the burden of diabetes is going to be very impactful,” Dr. Strand added. “While this is focused on pain, what we’re really trying to treat is the entire patient – improve their quality of life and make diabetes more manageable.”
Nearly 80% of treated patients responded at 3 months
The SENZA-PDN study results were presented as a late-breaking poster presentation at the virtual annual scientific sessions of the American Diabetes Association. Those results included 103 patients randomized to conventional medical management alone, and 113 who received medical management plus the spinal cord stimulator, which Dr. Strand described as a minimally invasive, reversibly implanted epidural device designed to stimulate the spinal cord and reverse pain sensations.
The median age was about 61 years and roughly two-thirds were male. All patients had to have lower extremity pain with an average intensity of at least 5 out of 10 cm on the visual analog scale (VAS) at enrollment, according to published inclusion criteria for the study (NCT03228420).
Three months after device implantation, 75 out of 95 evaluable patients (79%) had a response, defined as 50% or greater pain relief plus no worsening of neurological deficit related to painful diabetic neuropathy. By contrast, only 5 of 94 medically managed patients (5%) met those response criteria (P < 0.001), according to reported data.
The mean VAS score in the device group dropped from 7.6 at baseline to 2.4 at 1 month and 1.7 at 3 months, data show. In the medical management group, mean VAS scores were 7.0 at baseline, 6.7 at 1 month, and 6.5 at 3 months.
Sensory assessment of monofilament and pinprick perception, performed by investigators at 3 months, indicated a 72% improvement in the device arm versus 7% improvement in the medical management arm, while analysis of patient-drawn diagrams additionally suggested improvement in perceived numbness, according to investigators.
Quality-of-life improvements related to sleep and activity were also apparent at 3 months in the device group, Dr. Petersen said, with investigators noting substantial reductions in trouble falling asleep because of pain and awakening due to pain. Likewise, data at this initial report suggested improvements in 6-minute walk test that were apparent in the device group but not the medical management group.
While the spinal cord stimulator under investigation is already approved by the U.S. Food and Drug Administration, Dr. Petersen said a lack of data specific to painful diabetic neuropathy has been a hurdle to insurance coverage for some patients.
“I’ve had patients who clearly have every suggestion that they match the characteristics of our research population here, but the insurance will decline the procedure as being experimental,” she said. “My hope is that randomized, controlled trial results in a research study such as this is something that will improve the access of the therapy to patients who would not be able to afford it without having insurance cover the procedure.”
Follow-up of the study will continue for 24 months and will include assessment of health economics and use of pain medication, Dr. Petersen said.
The SENZA-PDN study is funded by Nevro Corp. Dr. Petersen said that she receives research funding and consulting fees from Nevro Corp. and other device manufacturers. Dr. Strand said she had no disclosures related to the research.
SOURCE: Petersen E. ADA 2020, Late-breaking poster 31-LB.
FROM ADA 2020
Half of young adults with diabetes have diastolic dysfunction
Roughly half of adolescents and young adults with either type 1 or type 2 diabetes for about a decade had diastolic dysfunction, a direct precursor to heart failure, in a multicenter echocardiography survey of 479 American patients.
Using tissue Doppler echocardiography findings from 258 adolescents and young adults with type 1 diabetes, and 221 with type 2 diabetes, the study found at least one imaging marker of ventricular stiffness – diastolic dysfunction – in 58% of the patients with type 2 diabetes and in 47% of those with type 1 diabetes. The type 1 patients averaged 21 years of age with a median 12 years of diagnosed disease, while the type 2 patients had an average age of 25 years and a median 11 years disease duration.
The analysis also identified several measures that significantly linked with the presence of diastolic dysfunction: older age, female sex, nonwhite race, type 2 diabetes, higher heart rate, higher body mass index, higher systolic blood pressure, and higher hemoglobin A1c.
“Our data suggest targeting modifiable risk factors” in these patients in an effort to slow the process causing the diastolic dysfunction, Amy S. Shah, MD, said at the virtual annual scientific sessions of the American Diabetes Association. She particularly cited interventions aimed at reducing body mass index, lowering blood pressure, and improving glycemic control, as well as preventing type 2 diabetes in the first place.
Prevention of type 2 diabetes, as well as prevention of diastolic dysfunction development and progression, are key steps because of the substantial clinical consequences of diastolic dysfunction, triggered by stiffening of the left ventricle. Diastolic dysfunction leads to increased left ventricular diastolic pressure, left atrial dysfunction, and ultimately heart failure with preserved ejection fraction, a common diabetes complication that currently has no treatment with proven efficacy, said Dr. Shah, a pediatric endocrinologist and director of the Adolescent Type 2 Diabetes Program at Cincinnati Children’s Hospital Medical Center.
“It’s very concerning that diastolic dysfunction is so prevalent in this age group,” commented Robert A. Gabbay, MD, Chief Science & Medical Officer of the American Diabetes Association. “An important question is whether you can see an improvement by reversing risk factors.” He noted the importance of confirming the finding in additional cohorts as well as running prospective studies looking at the impact of risk factor modification.
Dr. Shah and her associates used data collected at four U.S. centers from patients enrolled in the SEARCH for Diabetes in Youth study who underwent a tissue Doppler examination during 2016-2019, and used three measures derived from the scans to identify diastolic dysfunction:
- The E/A ratio, which compares the early flow wave across the mitral valve (E) with the atrial flow wave (A) that occurs after atrial contraction. Lower values reflect worse pathology.
- The E/e’ ratio, which compares the early flow wave across the mitral valve (E) with the rate of cardiac wall relaxation in early diastole (e’). Higher values reflect worse pathology.
- The e’/a’ ratio, which compares the rate of cardiac wall relaxation in early diastole (e’) with the rate of cardiac wall relaxation in late diastole (a’). Lower values reflect worse pathology.
The most common abnormality involved the e’/a’ measure, which occurred in roughly 38% of the patients with type 2 diabetes and in about 23% of those with type 1 diabetes. Next most common was an abnormally high E/e’ ratio, and fewer than 10% of patients had an abnormally low E/A ratio. Both the E/A and E/e’ values were significantly worse among patients with type 2 diabetes compared with type 1 patients, while no statistically significant difference separated the two subgroups for prevalence of an e’/a’ abnormality after adjustment for body mass index, blood pressure, and HbA1c values.
Average body mass index among the 221 studied patients with type 2 diabetes was 38 kg/m2, 74% were girls or women, and 57% were non-Hispanic black and 24% non-Hispanic white. Mean blood pressure among the patients with type 2 diabetes was 123/80 mm Hg, while it was 110/72 mm Hg among the 258 patients with type 1 diabetes.
SEARCH for Diabetes in Youth receives no commercial funding. Dr. Shah had no disclosures.
SOURCE: Shah AS et al. ADA 2020 abstract 58-OR.
Roughly half of adolescents and young adults with either type 1 or type 2 diabetes for about a decade had diastolic dysfunction, a direct precursor to heart failure, in a multicenter echocardiography survey of 479 American patients.
Using tissue Doppler echocardiography findings from 258 adolescents and young adults with type 1 diabetes, and 221 with type 2 diabetes, the study found at least one imaging marker of ventricular stiffness – diastolic dysfunction – in 58% of the patients with type 2 diabetes and in 47% of those with type 1 diabetes. The type 1 patients averaged 21 years of age with a median 12 years of diagnosed disease, while the type 2 patients had an average age of 25 years and a median 11 years disease duration.
The analysis also identified several measures that significantly linked with the presence of diastolic dysfunction: older age, female sex, nonwhite race, type 2 diabetes, higher heart rate, higher body mass index, higher systolic blood pressure, and higher hemoglobin A1c.
“Our data suggest targeting modifiable risk factors” in these patients in an effort to slow the process causing the diastolic dysfunction, Amy S. Shah, MD, said at the virtual annual scientific sessions of the American Diabetes Association. She particularly cited interventions aimed at reducing body mass index, lowering blood pressure, and improving glycemic control, as well as preventing type 2 diabetes in the first place.
Prevention of type 2 diabetes, as well as prevention of diastolic dysfunction development and progression, are key steps because of the substantial clinical consequences of diastolic dysfunction, triggered by stiffening of the left ventricle. Diastolic dysfunction leads to increased left ventricular diastolic pressure, left atrial dysfunction, and ultimately heart failure with preserved ejection fraction, a common diabetes complication that currently has no treatment with proven efficacy, said Dr. Shah, a pediatric endocrinologist and director of the Adolescent Type 2 Diabetes Program at Cincinnati Children’s Hospital Medical Center.
“It’s very concerning that diastolic dysfunction is so prevalent in this age group,” commented Robert A. Gabbay, MD, Chief Science & Medical Officer of the American Diabetes Association. “An important question is whether you can see an improvement by reversing risk factors.” He noted the importance of confirming the finding in additional cohorts as well as running prospective studies looking at the impact of risk factor modification.
Dr. Shah and her associates used data collected at four U.S. centers from patients enrolled in the SEARCH for Diabetes in Youth study who underwent a tissue Doppler examination during 2016-2019, and used three measures derived from the scans to identify diastolic dysfunction:
- The E/A ratio, which compares the early flow wave across the mitral valve (E) with the atrial flow wave (A) that occurs after atrial contraction. Lower values reflect worse pathology.
- The E/e’ ratio, which compares the early flow wave across the mitral valve (E) with the rate of cardiac wall relaxation in early diastole (e’). Higher values reflect worse pathology.
- The e’/a’ ratio, which compares the rate of cardiac wall relaxation in early diastole (e’) with the rate of cardiac wall relaxation in late diastole (a’). Lower values reflect worse pathology.
The most common abnormality involved the e’/a’ measure, which occurred in roughly 38% of the patients with type 2 diabetes and in about 23% of those with type 1 diabetes. Next most common was an abnormally high E/e’ ratio, and fewer than 10% of patients had an abnormally low E/A ratio. Both the E/A and E/e’ values were significantly worse among patients with type 2 diabetes compared with type 1 patients, while no statistically significant difference separated the two subgroups for prevalence of an e’/a’ abnormality after adjustment for body mass index, blood pressure, and HbA1c values.
Average body mass index among the 221 studied patients with type 2 diabetes was 38 kg/m2, 74% were girls or women, and 57% were non-Hispanic black and 24% non-Hispanic white. Mean blood pressure among the patients with type 2 diabetes was 123/80 mm Hg, while it was 110/72 mm Hg among the 258 patients with type 1 diabetes.
SEARCH for Diabetes in Youth receives no commercial funding. Dr. Shah had no disclosures.
SOURCE: Shah AS et al. ADA 2020 abstract 58-OR.
Roughly half of adolescents and young adults with either type 1 or type 2 diabetes for about a decade had diastolic dysfunction, a direct precursor to heart failure, in a multicenter echocardiography survey of 479 American patients.
Using tissue Doppler echocardiography findings from 258 adolescents and young adults with type 1 diabetes, and 221 with type 2 diabetes, the study found at least one imaging marker of ventricular stiffness – diastolic dysfunction – in 58% of the patients with type 2 diabetes and in 47% of those with type 1 diabetes. The type 1 patients averaged 21 years of age with a median 12 years of diagnosed disease, while the type 2 patients had an average age of 25 years and a median 11 years disease duration.
The analysis also identified several measures that significantly linked with the presence of diastolic dysfunction: older age, female sex, nonwhite race, type 2 diabetes, higher heart rate, higher body mass index, higher systolic blood pressure, and higher hemoglobin A1c.
“Our data suggest targeting modifiable risk factors” in these patients in an effort to slow the process causing the diastolic dysfunction, Amy S. Shah, MD, said at the virtual annual scientific sessions of the American Diabetes Association. She particularly cited interventions aimed at reducing body mass index, lowering blood pressure, and improving glycemic control, as well as preventing type 2 diabetes in the first place.
Prevention of type 2 diabetes, as well as prevention of diastolic dysfunction development and progression, are key steps because of the substantial clinical consequences of diastolic dysfunction, triggered by stiffening of the left ventricle. Diastolic dysfunction leads to increased left ventricular diastolic pressure, left atrial dysfunction, and ultimately heart failure with preserved ejection fraction, a common diabetes complication that currently has no treatment with proven efficacy, said Dr. Shah, a pediatric endocrinologist and director of the Adolescent Type 2 Diabetes Program at Cincinnati Children’s Hospital Medical Center.
“It’s very concerning that diastolic dysfunction is so prevalent in this age group,” commented Robert A. Gabbay, MD, Chief Science & Medical Officer of the American Diabetes Association. “An important question is whether you can see an improvement by reversing risk factors.” He noted the importance of confirming the finding in additional cohorts as well as running prospective studies looking at the impact of risk factor modification.
Dr. Shah and her associates used data collected at four U.S. centers from patients enrolled in the SEARCH for Diabetes in Youth study who underwent a tissue Doppler examination during 2016-2019, and used three measures derived from the scans to identify diastolic dysfunction:
- The E/A ratio, which compares the early flow wave across the mitral valve (E) with the atrial flow wave (A) that occurs after atrial contraction. Lower values reflect worse pathology.
- The E/e’ ratio, which compares the early flow wave across the mitral valve (E) with the rate of cardiac wall relaxation in early diastole (e’). Higher values reflect worse pathology.
- The e’/a’ ratio, which compares the rate of cardiac wall relaxation in early diastole (e’) with the rate of cardiac wall relaxation in late diastole (a’). Lower values reflect worse pathology.
The most common abnormality involved the e’/a’ measure, which occurred in roughly 38% of the patients with type 2 diabetes and in about 23% of those with type 1 diabetes. Next most common was an abnormally high E/e’ ratio, and fewer than 10% of patients had an abnormally low E/A ratio. Both the E/A and E/e’ values were significantly worse among patients with type 2 diabetes compared with type 1 patients, while no statistically significant difference separated the two subgroups for prevalence of an e’/a’ abnormality after adjustment for body mass index, blood pressure, and HbA1c values.
Average body mass index among the 221 studied patients with type 2 diabetes was 38 kg/m2, 74% were girls or women, and 57% were non-Hispanic black and 24% non-Hispanic white. Mean blood pressure among the patients with type 2 diabetes was 123/80 mm Hg, while it was 110/72 mm Hg among the 258 patients with type 1 diabetes.
SEARCH for Diabetes in Youth receives no commercial funding. Dr. Shah had no disclosures.
SOURCE: Shah AS et al. ADA 2020 abstract 58-OR.
FROM ADA 2020
Key clinical point: .
Major finding: Tissue Doppler echocardiography detected diastolic dysfunction in 58% of patients with type 2 diabetes and 47% of type 1 patients.
Study details: SEARCH for Diabetes in Youth study, with 479 American adolescents and young adults with diabetes.
Disclosures: SEARCH for Diabetes in Youth receives no commercial funding. Dr. Shah had no disclosures.
Source: Shah AS et al. ADA 2020, Abstract 58-OR.
Starting new diabetes drugs less likely for racial minorities, Medicare Advantage beneficiaries
, according to researchers at the virtual annual scientific sessions of the American Diabetes Association.
Initiation of DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors was less likely among racial/ethnic minorities and Medicare Advantage beneficiaries in the retrospective analyses, leading the investigators to call for a better understanding of nonclinical factors that may be influencing treatment decisions.
Odds of new diabetes medication use were 55%-69% lower in patients in Medicare Advantage (MA) as compared to patients in commercial health plans, according to results of a separate study presented by Rozalina McCoy, MD, endocrinologist and researcher with Mayo Clinic, Rochester, Minn.
“The rates of use are increasing over time, but not enough in MA beneficiaries,” she said in her virtual presentation. “I think it really calls for more to be done to ensure access to and use of evidence based medications, by all people with type 2 diabetes.”
The likelihood of initiating a new diabetes drug was 29% lower among African Americans and 49% lower among Native Americans in a study of enrollees in the Look AHEAD (Action for Health in Diabetes) randomized trial, according to researcher Ahmed Elhussein, BMBCh, MPH, of the Johns Hopkins Bloomberg School of Public Health.
“This is particularly concerning, because they might have a greater need for these new diabetes medications, but reduced access,” Dr. Elhussein said in his presentation.
Disparities by race in diabetes drug use
The prevalence of type 2 diabetes in the United States is higher among racial and ethnic minorities, at about 12%-15%, versus about 7% in whites, according to Dr. Elhussein,
While the newer classes of diabetes medications have a lower risk of hyperglycemia and have cardiovascular and renal benefits, they also come at a higher cost, he added.
“This has created some concerns about access in particular for underserved groups,” he said in his presentation.
In their retrospective analysis, based on 4,892 patients enrolled in the Look AHEAD (Action for Health in Diabetes) randomized trial, Dr. Elhussein and coinvestigators identified 44% who had initiated a newer diabetes medication over a median follow-up of about 8 years.
They found black race was associated with significantly lower initiation of newer medications compared to whites, with a hazard ratio of 0.81 (95% confidence interval 0.80-0.94; P = 0.019), after adjustment for socioeconomic status.
New diabetes medication use was also significantly lower among American Indian/Alaskan Natives, with an HR of 0.51 and a confidence interval that did not include the null value of 1, according to the investigator.
No significant differences in new diabetes drug use were seen in Hispanics or those classified as other race/ethnicity, he added.
“We’d advocate for more study to try to understand what are the drivers of this disparity,” he said. “This would let us develop interventions that might help to increase access in these patient groups that might need them the most.”
Insurance type and diabetes drugs
Second-line medications, including GLP-1 receptor agonists and SGLT2 inhibitors, have “preferred” efficacy and side effect profiles, but are more costly than older, generic options such as sulfonylureas, which may affect the likelihood of their use, said Dr. McCoy, the Mayo Clinic researcher and lead author of the study on diabetes medication use by insurance type.
They analyzed 1.7 million individuals in a de-identified dataset (OptumLabs Data Warehouse) who were either privately insured or beneficiaries of Medicare Advantage, the private health plan alternative to fee-for-service Medicare.
After adjusting for race/ethnicity, baseline medications, age, gender, and other factors, odds of new medication use were significantly lower in the Medicare Advantage group, according to Dr. McCoy.
Odds ratios ranged from 0.61 (95% CI, 0.60-0.63) for DPP-4 inhibitors, to 0.45 (95% CI, 0.44-0.46) for GLP-1 receptor agonists, and to 0.31 (95% CI, 0.30-0.31) for SGLT2 inhibitors, she reported.
“This may be driven by affordability, because patients with Medicare Advantage plans are not able to access prescription savings cards (as compared to Medicare beneficiaries) and they also are more likely to have fixed incomes and not be able to afford the high costs of these drugs,” she said.
Dr. Elhussein reported no disclosures related to the research, while co-authors provided disclosures related to Abbott, Bigfoot Biomedical, Boehringer Ingelheim, Eli Lilly, MannKind, Medscape, Novo Nordisk, Sanofi US, and others. Dr McCoy likewise had no disclosures, while co-authors indicated disclosures related to Janssen Pharmaceuticals, the Centers for Medicare and Medicaid Services, and the U.S. Food and Drug Administration.
SOURCES: ADA 2020. Authors: McCoy R et al (38-OR), and Elhussein A, et al (37-OR).
, according to researchers at the virtual annual scientific sessions of the American Diabetes Association.
Initiation of DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors was less likely among racial/ethnic minorities and Medicare Advantage beneficiaries in the retrospective analyses, leading the investigators to call for a better understanding of nonclinical factors that may be influencing treatment decisions.
Odds of new diabetes medication use were 55%-69% lower in patients in Medicare Advantage (MA) as compared to patients in commercial health plans, according to results of a separate study presented by Rozalina McCoy, MD, endocrinologist and researcher with Mayo Clinic, Rochester, Minn.
“The rates of use are increasing over time, but not enough in MA beneficiaries,” she said in her virtual presentation. “I think it really calls for more to be done to ensure access to and use of evidence based medications, by all people with type 2 diabetes.”
The likelihood of initiating a new diabetes drug was 29% lower among African Americans and 49% lower among Native Americans in a study of enrollees in the Look AHEAD (Action for Health in Diabetes) randomized trial, according to researcher Ahmed Elhussein, BMBCh, MPH, of the Johns Hopkins Bloomberg School of Public Health.
“This is particularly concerning, because they might have a greater need for these new diabetes medications, but reduced access,” Dr. Elhussein said in his presentation.
Disparities by race in diabetes drug use
The prevalence of type 2 diabetes in the United States is higher among racial and ethnic minorities, at about 12%-15%, versus about 7% in whites, according to Dr. Elhussein,
While the newer classes of diabetes medications have a lower risk of hyperglycemia and have cardiovascular and renal benefits, they also come at a higher cost, he added.
“This has created some concerns about access in particular for underserved groups,” he said in his presentation.
In their retrospective analysis, based on 4,892 patients enrolled in the Look AHEAD (Action for Health in Diabetes) randomized trial, Dr. Elhussein and coinvestigators identified 44% who had initiated a newer diabetes medication over a median follow-up of about 8 years.
They found black race was associated with significantly lower initiation of newer medications compared to whites, with a hazard ratio of 0.81 (95% confidence interval 0.80-0.94; P = 0.019), after adjustment for socioeconomic status.
New diabetes medication use was also significantly lower among American Indian/Alaskan Natives, with an HR of 0.51 and a confidence interval that did not include the null value of 1, according to the investigator.
No significant differences in new diabetes drug use were seen in Hispanics or those classified as other race/ethnicity, he added.
“We’d advocate for more study to try to understand what are the drivers of this disparity,” he said. “This would let us develop interventions that might help to increase access in these patient groups that might need them the most.”
Insurance type and diabetes drugs
Second-line medications, including GLP-1 receptor agonists and SGLT2 inhibitors, have “preferred” efficacy and side effect profiles, but are more costly than older, generic options such as sulfonylureas, which may affect the likelihood of their use, said Dr. McCoy, the Mayo Clinic researcher and lead author of the study on diabetes medication use by insurance type.
They analyzed 1.7 million individuals in a de-identified dataset (OptumLabs Data Warehouse) who were either privately insured or beneficiaries of Medicare Advantage, the private health plan alternative to fee-for-service Medicare.
After adjusting for race/ethnicity, baseline medications, age, gender, and other factors, odds of new medication use were significantly lower in the Medicare Advantage group, according to Dr. McCoy.
Odds ratios ranged from 0.61 (95% CI, 0.60-0.63) for DPP-4 inhibitors, to 0.45 (95% CI, 0.44-0.46) for GLP-1 receptor agonists, and to 0.31 (95% CI, 0.30-0.31) for SGLT2 inhibitors, she reported.
“This may be driven by affordability, because patients with Medicare Advantage plans are not able to access prescription savings cards (as compared to Medicare beneficiaries) and they also are more likely to have fixed incomes and not be able to afford the high costs of these drugs,” she said.
Dr. Elhussein reported no disclosures related to the research, while co-authors provided disclosures related to Abbott, Bigfoot Biomedical, Boehringer Ingelheim, Eli Lilly, MannKind, Medscape, Novo Nordisk, Sanofi US, and others. Dr McCoy likewise had no disclosures, while co-authors indicated disclosures related to Janssen Pharmaceuticals, the Centers for Medicare and Medicaid Services, and the U.S. Food and Drug Administration.
SOURCES: ADA 2020. Authors: McCoy R et al (38-OR), and Elhussein A, et al (37-OR).
, according to researchers at the virtual annual scientific sessions of the American Diabetes Association.
Initiation of DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors was less likely among racial/ethnic minorities and Medicare Advantage beneficiaries in the retrospective analyses, leading the investigators to call for a better understanding of nonclinical factors that may be influencing treatment decisions.
Odds of new diabetes medication use were 55%-69% lower in patients in Medicare Advantage (MA) as compared to patients in commercial health plans, according to results of a separate study presented by Rozalina McCoy, MD, endocrinologist and researcher with Mayo Clinic, Rochester, Minn.
“The rates of use are increasing over time, but not enough in MA beneficiaries,” she said in her virtual presentation. “I think it really calls for more to be done to ensure access to and use of evidence based medications, by all people with type 2 diabetes.”
The likelihood of initiating a new diabetes drug was 29% lower among African Americans and 49% lower among Native Americans in a study of enrollees in the Look AHEAD (Action for Health in Diabetes) randomized trial, according to researcher Ahmed Elhussein, BMBCh, MPH, of the Johns Hopkins Bloomberg School of Public Health.
“This is particularly concerning, because they might have a greater need for these new diabetes medications, but reduced access,” Dr. Elhussein said in his presentation.
Disparities by race in diabetes drug use
The prevalence of type 2 diabetes in the United States is higher among racial and ethnic minorities, at about 12%-15%, versus about 7% in whites, according to Dr. Elhussein,
While the newer classes of diabetes medications have a lower risk of hyperglycemia and have cardiovascular and renal benefits, they also come at a higher cost, he added.
“This has created some concerns about access in particular for underserved groups,” he said in his presentation.
In their retrospective analysis, based on 4,892 patients enrolled in the Look AHEAD (Action for Health in Diabetes) randomized trial, Dr. Elhussein and coinvestigators identified 44% who had initiated a newer diabetes medication over a median follow-up of about 8 years.
They found black race was associated with significantly lower initiation of newer medications compared to whites, with a hazard ratio of 0.81 (95% confidence interval 0.80-0.94; P = 0.019), after adjustment for socioeconomic status.
New diabetes medication use was also significantly lower among American Indian/Alaskan Natives, with an HR of 0.51 and a confidence interval that did not include the null value of 1, according to the investigator.
No significant differences in new diabetes drug use were seen in Hispanics or those classified as other race/ethnicity, he added.
“We’d advocate for more study to try to understand what are the drivers of this disparity,” he said. “This would let us develop interventions that might help to increase access in these patient groups that might need them the most.”
Insurance type and diabetes drugs
Second-line medications, including GLP-1 receptor agonists and SGLT2 inhibitors, have “preferred” efficacy and side effect profiles, but are more costly than older, generic options such as sulfonylureas, which may affect the likelihood of their use, said Dr. McCoy, the Mayo Clinic researcher and lead author of the study on diabetes medication use by insurance type.
They analyzed 1.7 million individuals in a de-identified dataset (OptumLabs Data Warehouse) who were either privately insured or beneficiaries of Medicare Advantage, the private health plan alternative to fee-for-service Medicare.
After adjusting for race/ethnicity, baseline medications, age, gender, and other factors, odds of new medication use were significantly lower in the Medicare Advantage group, according to Dr. McCoy.
Odds ratios ranged from 0.61 (95% CI, 0.60-0.63) for DPP-4 inhibitors, to 0.45 (95% CI, 0.44-0.46) for GLP-1 receptor agonists, and to 0.31 (95% CI, 0.30-0.31) for SGLT2 inhibitors, she reported.
“This may be driven by affordability, because patients with Medicare Advantage plans are not able to access prescription savings cards (as compared to Medicare beneficiaries) and they also are more likely to have fixed incomes and not be able to afford the high costs of these drugs,” she said.
Dr. Elhussein reported no disclosures related to the research, while co-authors provided disclosures related to Abbott, Bigfoot Biomedical, Boehringer Ingelheim, Eli Lilly, MannKind, Medscape, Novo Nordisk, Sanofi US, and others. Dr McCoy likewise had no disclosures, while co-authors indicated disclosures related to Janssen Pharmaceuticals, the Centers for Medicare and Medicaid Services, and the U.S. Food and Drug Administration.
SOURCES: ADA 2020. Authors: McCoy R et al (38-OR), and Elhussein A, et al (37-OR).
FROM ADA 2020