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MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
Myeloma: Daratumumab Plus Lenalidomide Improves MRD Outcomes
“To date, no randomized trial has directly compared daratumumab-based maintenance therapy vs standard of care lenalidomide maintenance, which is the focus of our trial,” said first author Ashraf Z. Badros, MD, a professor of medicine at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, in presenting the findings at the International Myeloma Society (IMS) 2024.
“These results support the addition of daratumumab not only to induction/consolidation but also to standard of care lenalidomide maintenance for these patients,” he said of the study, which was published concurrently in the journal Blood.
Despite ongoing advancements in regimens for induction, consolidation, and maintenance posttransplant, most patients with MM eventually relapse, driving continuing efforts to optimize treatment strategies and improve long-term outcomes.
While daratumumab, an anti-CD38 monoclonal antibody, is approved in induction and consolidation with ASCT for patients with newly diagnosed MM, the authors sought to investigate the potential benefits of adding it to the standard-of-care therapy lenalidomide in maintenance therapy.
For the phase 3 AURIGA trial, they recruited 200 patients with newly diagnosed MM within 12 months of induction therapy and 6 months of ASCT.
The patients, who were all anti-CD38 naive, received at least four induction cycles, had at least a very good partial response, and were MRD positive following ASCT.
They were randomized 1:1 to receive 28-day lenalidomide maintenance cycles either with (n = 99) or without (n = 101) subcutaneous daratumumab for at least 36 cycles or until disease progression, unacceptable toxicity, or withdrawal.
The patients had similar baseline demographic characteristics; their median age was about 62 years, and 25.3% in the daratumumab and 23.5% in the no-daratumumab group had ISS stage III disease. At the time of diagnosis, 23.9% and 16.9%, respectively, had high cytogenic risk.
Overall, patients received a median of five induction cycles prior to entering the study.
For the primary endpoint, the rate of conversion from MRD positive to MRD negative (at a sensitivity of 10-5 using next-generation sequencing) by 12 months was significantly higher in the daratumumab group than in the lenalidomide-only group, at 50.5% vs 18.8% (odds ratio [OR], 4.51; P < .0001).
A similar benefit with the daratumumab group was observed across all clinically relevant subgroups, including patients with high-risk disease.
The MRD-negative conversion rate was similar at the 10-6 threshold (23.2% vs 5%; OR, 5.97; P = .0002).
At a median follow-up of 32.3 months, the overall rates of MRD negativity were 60.6% and 27.7%, with and without daratumumab, respectively (OR, 4.12; P < .0001)
The achievement of complete response or better also was significantly greater with daratumumab (75.8% vs 61.4%; OR, 2.00; P = .0255).
Likewise, PFS favored daratumumab (hazard ratio, 0.53), and the estimated 30-month PFS rates were 82.7% and 66.4%, respectively.
The daratumumab group received more maintenance cycles than the lenalidomide-only group (median of 33 vs 21.5), and it had higher rates of completion of 12 cycles (88.5% vs 78.6%). Dr. Badros noted that the main reason for discontinuation of therapy in the no-daratumumab arm was disease progression.
Consistent with previous studies, daratumumab was associated with more grade 3/4 treatment-emergent adverse events (TEAEs), occurring in 74.0% patients vs 67.3% patients not receiving daratumumab, including infections (18.8% vs 13.3%), cytopenia (54.2% vs 46.9%), and neutropenia (46.9% vs 41.8%). Dr. Badros noted the significantly longer time of treatment in the daratumumab arm (30 months vs 20 months).
Serious TEAEs occurred in 30.2% daratumumab patients and 22.4% no-daratumumab patients, and fatal TEAEs occurred in 2.1% and 1.0% patients, respectively.
“Overall, there were no new safety concerns for daratumumab,” he said.
The authors noted that the requirement that patients be anti-CD38 naive was partially because of “the D-VRd [daratumumab combined with bortezomib, lenalidomide, and dexamethasone] regimen gaining popularity and increased utilization in the myeloma community for transplant-eligible patients with NDMM, even before the publication of the long-term results of the randomized GRIFFIN and PERSEUS studies.”
A key question, remarked Joseph Mikhael, MD, who is chief medical officer of the International Myeloma Foundation, from the audience, is how applicable the findings are in the modern environment, where most patients now have indeed had prior anti-CD38 treatment.
In response, Dr. Badros explained that “I think this is an important study because it is probably one of the few studies that separates the impact of daratumumab-lenalidomide without prior daratumumab use.”
Dr. Badros noted that results from the PERSEUS trial, of D-VRd, show MRD-positive to MRD-negative conversion rates that are similar to the current trial; “therefore, I really don’t think that using daratumumab up front will prevent using it as maintenance,” he said. “If anything, it actually improves outcomes.”
The findings from continuous treatment “are an important reminder that high-risk patients do not do well if you stop treatment,” he said.
Further commenting on the research at the meeting, María-Victoria Mateos, MD, PhD, an associate professor of medicine at the University of Salamanca in Spain, noted that “the unmet need in maintenance is to upgrade the quality of the response and to increase the conversion of MRD-positivity to MRD negative in order to delay the progression of the disease and prolong the overall survival.”
Regarding the AURIGA trial, “this is very interesting data about the role of daratumumab-lenalidomide maintenance in patients who are MRD positive after autologous stem cell transplantation.”
“What is more important is we are progressing in response-adaptive therapy, and we are generating very useful information to possibly make the majority of patients become MRD negative.
“Developing early endpoints as surrogate markers for long-term outcomes and overall survival is critically important,” she added. “Otherwise, trials may continue for more than 15 years.”
The study was sponsored by Janssen Biotech. Dr. Badros reported relationships with Bristol-Myers Squibb, BeiGene, Roche, Jansen, and GSK. Mateos disclosed ties with AbbVie, Amgen, Bristol-Myers Squibb, GSK, Kite, Johnson & Johnson, Oncopeptides, Pfizer, Regeneron, Roche, and Sanofi.
A version of this article first appeared on Medscape.com.
“To date, no randomized trial has directly compared daratumumab-based maintenance therapy vs standard of care lenalidomide maintenance, which is the focus of our trial,” said first author Ashraf Z. Badros, MD, a professor of medicine at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, in presenting the findings at the International Myeloma Society (IMS) 2024.
“These results support the addition of daratumumab not only to induction/consolidation but also to standard of care lenalidomide maintenance for these patients,” he said of the study, which was published concurrently in the journal Blood.
Despite ongoing advancements in regimens for induction, consolidation, and maintenance posttransplant, most patients with MM eventually relapse, driving continuing efforts to optimize treatment strategies and improve long-term outcomes.
While daratumumab, an anti-CD38 monoclonal antibody, is approved in induction and consolidation with ASCT for patients with newly diagnosed MM, the authors sought to investigate the potential benefits of adding it to the standard-of-care therapy lenalidomide in maintenance therapy.
For the phase 3 AURIGA trial, they recruited 200 patients with newly diagnosed MM within 12 months of induction therapy and 6 months of ASCT.
The patients, who were all anti-CD38 naive, received at least four induction cycles, had at least a very good partial response, and were MRD positive following ASCT.
They were randomized 1:1 to receive 28-day lenalidomide maintenance cycles either with (n = 99) or without (n = 101) subcutaneous daratumumab for at least 36 cycles or until disease progression, unacceptable toxicity, or withdrawal.
The patients had similar baseline demographic characteristics; their median age was about 62 years, and 25.3% in the daratumumab and 23.5% in the no-daratumumab group had ISS stage III disease. At the time of diagnosis, 23.9% and 16.9%, respectively, had high cytogenic risk.
Overall, patients received a median of five induction cycles prior to entering the study.
For the primary endpoint, the rate of conversion from MRD positive to MRD negative (at a sensitivity of 10-5 using next-generation sequencing) by 12 months was significantly higher in the daratumumab group than in the lenalidomide-only group, at 50.5% vs 18.8% (odds ratio [OR], 4.51; P < .0001).
A similar benefit with the daratumumab group was observed across all clinically relevant subgroups, including patients with high-risk disease.
The MRD-negative conversion rate was similar at the 10-6 threshold (23.2% vs 5%; OR, 5.97; P = .0002).
At a median follow-up of 32.3 months, the overall rates of MRD negativity were 60.6% and 27.7%, with and without daratumumab, respectively (OR, 4.12; P < .0001)
The achievement of complete response or better also was significantly greater with daratumumab (75.8% vs 61.4%; OR, 2.00; P = .0255).
Likewise, PFS favored daratumumab (hazard ratio, 0.53), and the estimated 30-month PFS rates were 82.7% and 66.4%, respectively.
The daratumumab group received more maintenance cycles than the lenalidomide-only group (median of 33 vs 21.5), and it had higher rates of completion of 12 cycles (88.5% vs 78.6%). Dr. Badros noted that the main reason for discontinuation of therapy in the no-daratumumab arm was disease progression.
Consistent with previous studies, daratumumab was associated with more grade 3/4 treatment-emergent adverse events (TEAEs), occurring in 74.0% patients vs 67.3% patients not receiving daratumumab, including infections (18.8% vs 13.3%), cytopenia (54.2% vs 46.9%), and neutropenia (46.9% vs 41.8%). Dr. Badros noted the significantly longer time of treatment in the daratumumab arm (30 months vs 20 months).
Serious TEAEs occurred in 30.2% daratumumab patients and 22.4% no-daratumumab patients, and fatal TEAEs occurred in 2.1% and 1.0% patients, respectively.
“Overall, there were no new safety concerns for daratumumab,” he said.
The authors noted that the requirement that patients be anti-CD38 naive was partially because of “the D-VRd [daratumumab combined with bortezomib, lenalidomide, and dexamethasone] regimen gaining popularity and increased utilization in the myeloma community for transplant-eligible patients with NDMM, even before the publication of the long-term results of the randomized GRIFFIN and PERSEUS studies.”
A key question, remarked Joseph Mikhael, MD, who is chief medical officer of the International Myeloma Foundation, from the audience, is how applicable the findings are in the modern environment, where most patients now have indeed had prior anti-CD38 treatment.
In response, Dr. Badros explained that “I think this is an important study because it is probably one of the few studies that separates the impact of daratumumab-lenalidomide without prior daratumumab use.”
Dr. Badros noted that results from the PERSEUS trial, of D-VRd, show MRD-positive to MRD-negative conversion rates that are similar to the current trial; “therefore, I really don’t think that using daratumumab up front will prevent using it as maintenance,” he said. “If anything, it actually improves outcomes.”
The findings from continuous treatment “are an important reminder that high-risk patients do not do well if you stop treatment,” he said.
Further commenting on the research at the meeting, María-Victoria Mateos, MD, PhD, an associate professor of medicine at the University of Salamanca in Spain, noted that “the unmet need in maintenance is to upgrade the quality of the response and to increase the conversion of MRD-positivity to MRD negative in order to delay the progression of the disease and prolong the overall survival.”
Regarding the AURIGA trial, “this is very interesting data about the role of daratumumab-lenalidomide maintenance in patients who are MRD positive after autologous stem cell transplantation.”
“What is more important is we are progressing in response-adaptive therapy, and we are generating very useful information to possibly make the majority of patients become MRD negative.
“Developing early endpoints as surrogate markers for long-term outcomes and overall survival is critically important,” she added. “Otherwise, trials may continue for more than 15 years.”
The study was sponsored by Janssen Biotech. Dr. Badros reported relationships with Bristol-Myers Squibb, BeiGene, Roche, Jansen, and GSK. Mateos disclosed ties with AbbVie, Amgen, Bristol-Myers Squibb, GSK, Kite, Johnson & Johnson, Oncopeptides, Pfizer, Regeneron, Roche, and Sanofi.
A version of this article first appeared on Medscape.com.
“To date, no randomized trial has directly compared daratumumab-based maintenance therapy vs standard of care lenalidomide maintenance, which is the focus of our trial,” said first author Ashraf Z. Badros, MD, a professor of medicine at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, in presenting the findings at the International Myeloma Society (IMS) 2024.
“These results support the addition of daratumumab not only to induction/consolidation but also to standard of care lenalidomide maintenance for these patients,” he said of the study, which was published concurrently in the journal Blood.
Despite ongoing advancements in regimens for induction, consolidation, and maintenance posttransplant, most patients with MM eventually relapse, driving continuing efforts to optimize treatment strategies and improve long-term outcomes.
While daratumumab, an anti-CD38 monoclonal antibody, is approved in induction and consolidation with ASCT for patients with newly diagnosed MM, the authors sought to investigate the potential benefits of adding it to the standard-of-care therapy lenalidomide in maintenance therapy.
For the phase 3 AURIGA trial, they recruited 200 patients with newly diagnosed MM within 12 months of induction therapy and 6 months of ASCT.
The patients, who were all anti-CD38 naive, received at least four induction cycles, had at least a very good partial response, and were MRD positive following ASCT.
They were randomized 1:1 to receive 28-day lenalidomide maintenance cycles either with (n = 99) or without (n = 101) subcutaneous daratumumab for at least 36 cycles or until disease progression, unacceptable toxicity, or withdrawal.
The patients had similar baseline demographic characteristics; their median age was about 62 years, and 25.3% in the daratumumab and 23.5% in the no-daratumumab group had ISS stage III disease. At the time of diagnosis, 23.9% and 16.9%, respectively, had high cytogenic risk.
Overall, patients received a median of five induction cycles prior to entering the study.
For the primary endpoint, the rate of conversion from MRD positive to MRD negative (at a sensitivity of 10-5 using next-generation sequencing) by 12 months was significantly higher in the daratumumab group than in the lenalidomide-only group, at 50.5% vs 18.8% (odds ratio [OR], 4.51; P < .0001).
A similar benefit with the daratumumab group was observed across all clinically relevant subgroups, including patients with high-risk disease.
The MRD-negative conversion rate was similar at the 10-6 threshold (23.2% vs 5%; OR, 5.97; P = .0002).
At a median follow-up of 32.3 months, the overall rates of MRD negativity were 60.6% and 27.7%, with and without daratumumab, respectively (OR, 4.12; P < .0001)
The achievement of complete response or better also was significantly greater with daratumumab (75.8% vs 61.4%; OR, 2.00; P = .0255).
Likewise, PFS favored daratumumab (hazard ratio, 0.53), and the estimated 30-month PFS rates were 82.7% and 66.4%, respectively.
The daratumumab group received more maintenance cycles than the lenalidomide-only group (median of 33 vs 21.5), and it had higher rates of completion of 12 cycles (88.5% vs 78.6%). Dr. Badros noted that the main reason for discontinuation of therapy in the no-daratumumab arm was disease progression.
Consistent with previous studies, daratumumab was associated with more grade 3/4 treatment-emergent adverse events (TEAEs), occurring in 74.0% patients vs 67.3% patients not receiving daratumumab, including infections (18.8% vs 13.3%), cytopenia (54.2% vs 46.9%), and neutropenia (46.9% vs 41.8%). Dr. Badros noted the significantly longer time of treatment in the daratumumab arm (30 months vs 20 months).
Serious TEAEs occurred in 30.2% daratumumab patients and 22.4% no-daratumumab patients, and fatal TEAEs occurred in 2.1% and 1.0% patients, respectively.
“Overall, there were no new safety concerns for daratumumab,” he said.
The authors noted that the requirement that patients be anti-CD38 naive was partially because of “the D-VRd [daratumumab combined with bortezomib, lenalidomide, and dexamethasone] regimen gaining popularity and increased utilization in the myeloma community for transplant-eligible patients with NDMM, even before the publication of the long-term results of the randomized GRIFFIN and PERSEUS studies.”
A key question, remarked Joseph Mikhael, MD, who is chief medical officer of the International Myeloma Foundation, from the audience, is how applicable the findings are in the modern environment, where most patients now have indeed had prior anti-CD38 treatment.
In response, Dr. Badros explained that “I think this is an important study because it is probably one of the few studies that separates the impact of daratumumab-lenalidomide without prior daratumumab use.”
Dr. Badros noted that results from the PERSEUS trial, of D-VRd, show MRD-positive to MRD-negative conversion rates that are similar to the current trial; “therefore, I really don’t think that using daratumumab up front will prevent using it as maintenance,” he said. “If anything, it actually improves outcomes.”
The findings from continuous treatment “are an important reminder that high-risk patients do not do well if you stop treatment,” he said.
Further commenting on the research at the meeting, María-Victoria Mateos, MD, PhD, an associate professor of medicine at the University of Salamanca in Spain, noted that “the unmet need in maintenance is to upgrade the quality of the response and to increase the conversion of MRD-positivity to MRD negative in order to delay the progression of the disease and prolong the overall survival.”
Regarding the AURIGA trial, “this is very interesting data about the role of daratumumab-lenalidomide maintenance in patients who are MRD positive after autologous stem cell transplantation.”
“What is more important is we are progressing in response-adaptive therapy, and we are generating very useful information to possibly make the majority of patients become MRD negative.
“Developing early endpoints as surrogate markers for long-term outcomes and overall survival is critically important,” she added. “Otherwise, trials may continue for more than 15 years.”
The study was sponsored by Janssen Biotech. Dr. Badros reported relationships with Bristol-Myers Squibb, BeiGene, Roche, Jansen, and GSK. Mateos disclosed ties with AbbVie, Amgen, Bristol-Myers Squibb, GSK, Kite, Johnson & Johnson, Oncopeptides, Pfizer, Regeneron, Roche, and Sanofi.
A version of this article first appeared on Medscape.com.
FROM IMS 2024
Diabetic Kidney Disease Therapies Keep on FLOWing
Further data from the FLOW study were presented during the 2024 congress of the European Association for the Study of Diabetes (EASD) in Madrid. The FLOW study was originally presented in May at the European Renal Association’s 2024 congress in Stockholm. It was the first dedicated kidney outcomes trial to examine a GLP-1 receptor agonist.
The FLOW study demonstrated significant kidney, cardiovascular, and mortality benefits with semaglutide 1 mg once weekly in patients with type 2 diabetes and chronic kidney disease (CKD). This study has elevated semaglutide to a new pillar of care for the management of diabetic kidney disease (DKD) alongside RAAS inhibitors, SGLT2 inhibitors, and finerenone.
At first, whether the benefits of semaglutide were independent of baseline SGLT2 inhibitor use was uncertain. The data presented at the EASD congress, however, appeared to confirm the additive benefits of semaglutide, when combined with SGLT2 inhibitor use, in patients with DKD. The authors did acknowledge that study power was limited, given the low use of SGLT2 inhibitors at trial recruitment (no licensed SGLT2 inhibitor was available for CKD at that point), so small, clinically relevant interactions may not have been detected.
So, what are the implications of the FLOW study for primary care?
DKD is a common clinical challenge in primary care; a national diabetes audit in the United Kingdom suggested that over 40% of patients with type 2 diabetes had kidney disease. Moreover, DKD is the most common cause of kidney failure in adults starting renal replacement therapy in the United Kingdom.
Residual renal risk in patients with DKD persists despite optimal use of guideline-directed medical therapy (GDMT) with RAAS inhibitors, SGLT2 inhibitors, and finerenone, as demonstrated in the many landmark kidney outcomes trials over the past 25 years.
So, a new pillar of GDMT is welcome, but I am worried that this widened choice of therapies may worsen therapeutic inertia; baseline use of the newer DKD therapies (specifically SGLT2 inhibitors and finerenone) remains low.
In addition, during the EASD FLOW session, Katherine Tuttle, MD, executive director for research at Providence Inland Northwest Health Services in Spokane, Washington, presented data from the US CURE-CKD registry study showing that baseline ACE inhibitor/ARB use of about 70% dropped to 50% after just 90 days. Baseline use of SGLT2 inhibitors was only about 6% and dropped to 5% after 90 days.
I suspect that much of this reduction in prescribing of ACE inhibitors/ARBs will have been in response to an acute dip in estimated glomerular filtration rate (eGFR) or hyperkalemia, which has been a perennial challenge with RAAS inhibitor use in primary care. Ongoing education in primary care is required to manage hyperkalemia and reductions in eGFR after RAAS inhibitor initiation to prevent premature cessation of these foundational therapies.
On a positive note, there was no acute dip in eGFR after prescribing semaglutide in DKD. This observation will be reassuring for primary care and hopefully prevent unnecessary cessation of therapy.
Also reassuring was the lack of difference in diabetic retinopathy adverse events between the semaglutide and placebo groups. These events raised concerns about semaglutide following the SUSTAIN-6 CVOT study and have affected attitudes in primary care. But the rapidity and magnitude of improvement in glycemic control with semaglutide was believed to be the underlying issue, rather than semaglutide itself. A similar phenomenon has been observed with insulin. The ongoing FOCUS study is exploring the long-term effects of semaglutide on diabetic retinopathy in patients with type 2 diabetes. This study will hopefully provide a definite answer to this issue.
Another useful message from the FLOW study for primary care is the utility of semaglutide for glucose-lowering in the context of CKD. A1c was 0.81% lower in the semaglutide group compared with the placebo group in participants with eGFRs as low as 25 mL/min/1.73 m2. It is well established that SGLT2 inhibitors have negligible glucose-lowering effects once eGFR drops below 45 mL/min/1.73 m2. Indeed, my usual practice in CKD, if additional glucose-lowering is required once renal protection has been established with an SGLT2 inhibitor, was to add a GLP-1 receptor agonist. It is reassuring to have my clinical practice ratified by the FLOW study.
Semaglutide also helpfully provides an alternative therapeutic option for patients who do not tolerate SGLT2 inhibitors because of, for example, recurrent mycotic genital infections or polyuria, or for those in whom SGLT2 inhibitors are contraindicated, such as patients who have experienced an unprovoked episode of diabetic ketoacidosis. Many of these patients still require cardiovascular and kidney protection, so the FLOW study gives me a viable evidence-based alternative.
As a class, semaglutide and GLP-1 receptor agonists are, of course, not without side effects. Gastrointestinal side effects are the most common, and this finding was echoed in the FLOW study. Gastrointestinal disorders led to permanent treatment discontinuation in 4.5% of the semaglutide group compared with 1.1% of the placebo group. The overall safety profile of semaglutide was favorable, however.
Gastrointestinal side effects can be particularly concerning in the context of CKD because of the possibility of clinical dehydration and acute kidney injury with persistent vomiting or diarrhea. Patient education is particularly important when using GLP-1 receptor agonists in this group of individuals. Reassuringly, there was no imbalance in dehydration and acute kidney injury between trial arms in the FLOW study.
Notably, past studies have suggested that patients with CKD are more likely to experience gastrointestinal side effects with GLP-1 receptor agonists; in these patients, the usual mantra of GLP-1 receptor agonist prescribing is particularly important: Start low, go slow.
Finally, medication adherence is a challenge with multiple pillars of GDMT: These evidence-based disease-modifying therapies work only if our patients take them regularly. My senior partner had a lovely turn of phrase when reviewing patients with multiple long-term conditions; he would always start the consultation by asking individuals which medications they were not taking regularly.
Overall, the FLOW study confirms semaglutide’s position as a new therapeutic pillar for DKD. This treatment will help address the residual renal risk for patients with DKD despite optimal use of GDMT. However, education and support will be required in primary care to prevent worsening therapeutic inertia.
Kevin Fernando, general practitioner partner, North Berwick Health Centre, North Berwick, UK, has disclosed the following relevant financial relationships: Received speaker fees from: Amarin; Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Dexcom; Daiichi Sankyo; Lilly; Menarini; Novartis; Novo Nordisk; Roche Diagnostics; Embecta; Roche Diabetes Care. Received honoraria for participation in advisory boards from: Amarin; Amgen; AstraZen
A version of this article first appeared on Medscape.com.
Further data from the FLOW study were presented during the 2024 congress of the European Association for the Study of Diabetes (EASD) in Madrid. The FLOW study was originally presented in May at the European Renal Association’s 2024 congress in Stockholm. It was the first dedicated kidney outcomes trial to examine a GLP-1 receptor agonist.
The FLOW study demonstrated significant kidney, cardiovascular, and mortality benefits with semaglutide 1 mg once weekly in patients with type 2 diabetes and chronic kidney disease (CKD). This study has elevated semaglutide to a new pillar of care for the management of diabetic kidney disease (DKD) alongside RAAS inhibitors, SGLT2 inhibitors, and finerenone.
At first, whether the benefits of semaglutide were independent of baseline SGLT2 inhibitor use was uncertain. The data presented at the EASD congress, however, appeared to confirm the additive benefits of semaglutide, when combined with SGLT2 inhibitor use, in patients with DKD. The authors did acknowledge that study power was limited, given the low use of SGLT2 inhibitors at trial recruitment (no licensed SGLT2 inhibitor was available for CKD at that point), so small, clinically relevant interactions may not have been detected.
So, what are the implications of the FLOW study for primary care?
DKD is a common clinical challenge in primary care; a national diabetes audit in the United Kingdom suggested that over 40% of patients with type 2 diabetes had kidney disease. Moreover, DKD is the most common cause of kidney failure in adults starting renal replacement therapy in the United Kingdom.
Residual renal risk in patients with DKD persists despite optimal use of guideline-directed medical therapy (GDMT) with RAAS inhibitors, SGLT2 inhibitors, and finerenone, as demonstrated in the many landmark kidney outcomes trials over the past 25 years.
So, a new pillar of GDMT is welcome, but I am worried that this widened choice of therapies may worsen therapeutic inertia; baseline use of the newer DKD therapies (specifically SGLT2 inhibitors and finerenone) remains low.
In addition, during the EASD FLOW session, Katherine Tuttle, MD, executive director for research at Providence Inland Northwest Health Services in Spokane, Washington, presented data from the US CURE-CKD registry study showing that baseline ACE inhibitor/ARB use of about 70% dropped to 50% after just 90 days. Baseline use of SGLT2 inhibitors was only about 6% and dropped to 5% after 90 days.
I suspect that much of this reduction in prescribing of ACE inhibitors/ARBs will have been in response to an acute dip in estimated glomerular filtration rate (eGFR) or hyperkalemia, which has been a perennial challenge with RAAS inhibitor use in primary care. Ongoing education in primary care is required to manage hyperkalemia and reductions in eGFR after RAAS inhibitor initiation to prevent premature cessation of these foundational therapies.
On a positive note, there was no acute dip in eGFR after prescribing semaglutide in DKD. This observation will be reassuring for primary care and hopefully prevent unnecessary cessation of therapy.
Also reassuring was the lack of difference in diabetic retinopathy adverse events between the semaglutide and placebo groups. These events raised concerns about semaglutide following the SUSTAIN-6 CVOT study and have affected attitudes in primary care. But the rapidity and magnitude of improvement in glycemic control with semaglutide was believed to be the underlying issue, rather than semaglutide itself. A similar phenomenon has been observed with insulin. The ongoing FOCUS study is exploring the long-term effects of semaglutide on diabetic retinopathy in patients with type 2 diabetes. This study will hopefully provide a definite answer to this issue.
Another useful message from the FLOW study for primary care is the utility of semaglutide for glucose-lowering in the context of CKD. A1c was 0.81% lower in the semaglutide group compared with the placebo group in participants with eGFRs as low as 25 mL/min/1.73 m2. It is well established that SGLT2 inhibitors have negligible glucose-lowering effects once eGFR drops below 45 mL/min/1.73 m2. Indeed, my usual practice in CKD, if additional glucose-lowering is required once renal protection has been established with an SGLT2 inhibitor, was to add a GLP-1 receptor agonist. It is reassuring to have my clinical practice ratified by the FLOW study.
Semaglutide also helpfully provides an alternative therapeutic option for patients who do not tolerate SGLT2 inhibitors because of, for example, recurrent mycotic genital infections or polyuria, or for those in whom SGLT2 inhibitors are contraindicated, such as patients who have experienced an unprovoked episode of diabetic ketoacidosis. Many of these patients still require cardiovascular and kidney protection, so the FLOW study gives me a viable evidence-based alternative.
As a class, semaglutide and GLP-1 receptor agonists are, of course, not without side effects. Gastrointestinal side effects are the most common, and this finding was echoed in the FLOW study. Gastrointestinal disorders led to permanent treatment discontinuation in 4.5% of the semaglutide group compared with 1.1% of the placebo group. The overall safety profile of semaglutide was favorable, however.
Gastrointestinal side effects can be particularly concerning in the context of CKD because of the possibility of clinical dehydration and acute kidney injury with persistent vomiting or diarrhea. Patient education is particularly important when using GLP-1 receptor agonists in this group of individuals. Reassuringly, there was no imbalance in dehydration and acute kidney injury between trial arms in the FLOW study.
Notably, past studies have suggested that patients with CKD are more likely to experience gastrointestinal side effects with GLP-1 receptor agonists; in these patients, the usual mantra of GLP-1 receptor agonist prescribing is particularly important: Start low, go slow.
Finally, medication adherence is a challenge with multiple pillars of GDMT: These evidence-based disease-modifying therapies work only if our patients take them regularly. My senior partner had a lovely turn of phrase when reviewing patients with multiple long-term conditions; he would always start the consultation by asking individuals which medications they were not taking regularly.
Overall, the FLOW study confirms semaglutide’s position as a new therapeutic pillar for DKD. This treatment will help address the residual renal risk for patients with DKD despite optimal use of GDMT. However, education and support will be required in primary care to prevent worsening therapeutic inertia.
Kevin Fernando, general practitioner partner, North Berwick Health Centre, North Berwick, UK, has disclosed the following relevant financial relationships: Received speaker fees from: Amarin; Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Dexcom; Daiichi Sankyo; Lilly; Menarini; Novartis; Novo Nordisk; Roche Diagnostics; Embecta; Roche Diabetes Care. Received honoraria for participation in advisory boards from: Amarin; Amgen; AstraZen
A version of this article first appeared on Medscape.com.
Further data from the FLOW study were presented during the 2024 congress of the European Association for the Study of Diabetes (EASD) in Madrid. The FLOW study was originally presented in May at the European Renal Association’s 2024 congress in Stockholm. It was the first dedicated kidney outcomes trial to examine a GLP-1 receptor agonist.
The FLOW study demonstrated significant kidney, cardiovascular, and mortality benefits with semaglutide 1 mg once weekly in patients with type 2 diabetes and chronic kidney disease (CKD). This study has elevated semaglutide to a new pillar of care for the management of diabetic kidney disease (DKD) alongside RAAS inhibitors, SGLT2 inhibitors, and finerenone.
At first, whether the benefits of semaglutide were independent of baseline SGLT2 inhibitor use was uncertain. The data presented at the EASD congress, however, appeared to confirm the additive benefits of semaglutide, when combined with SGLT2 inhibitor use, in patients with DKD. The authors did acknowledge that study power was limited, given the low use of SGLT2 inhibitors at trial recruitment (no licensed SGLT2 inhibitor was available for CKD at that point), so small, clinically relevant interactions may not have been detected.
So, what are the implications of the FLOW study for primary care?
DKD is a common clinical challenge in primary care; a national diabetes audit in the United Kingdom suggested that over 40% of patients with type 2 diabetes had kidney disease. Moreover, DKD is the most common cause of kidney failure in adults starting renal replacement therapy in the United Kingdom.
Residual renal risk in patients with DKD persists despite optimal use of guideline-directed medical therapy (GDMT) with RAAS inhibitors, SGLT2 inhibitors, and finerenone, as demonstrated in the many landmark kidney outcomes trials over the past 25 years.
So, a new pillar of GDMT is welcome, but I am worried that this widened choice of therapies may worsen therapeutic inertia; baseline use of the newer DKD therapies (specifically SGLT2 inhibitors and finerenone) remains low.
In addition, during the EASD FLOW session, Katherine Tuttle, MD, executive director for research at Providence Inland Northwest Health Services in Spokane, Washington, presented data from the US CURE-CKD registry study showing that baseline ACE inhibitor/ARB use of about 70% dropped to 50% after just 90 days. Baseline use of SGLT2 inhibitors was only about 6% and dropped to 5% after 90 days.
I suspect that much of this reduction in prescribing of ACE inhibitors/ARBs will have been in response to an acute dip in estimated glomerular filtration rate (eGFR) or hyperkalemia, which has been a perennial challenge with RAAS inhibitor use in primary care. Ongoing education in primary care is required to manage hyperkalemia and reductions in eGFR after RAAS inhibitor initiation to prevent premature cessation of these foundational therapies.
On a positive note, there was no acute dip in eGFR after prescribing semaglutide in DKD. This observation will be reassuring for primary care and hopefully prevent unnecessary cessation of therapy.
Also reassuring was the lack of difference in diabetic retinopathy adverse events between the semaglutide and placebo groups. These events raised concerns about semaglutide following the SUSTAIN-6 CVOT study and have affected attitudes in primary care. But the rapidity and magnitude of improvement in glycemic control with semaglutide was believed to be the underlying issue, rather than semaglutide itself. A similar phenomenon has been observed with insulin. The ongoing FOCUS study is exploring the long-term effects of semaglutide on diabetic retinopathy in patients with type 2 diabetes. This study will hopefully provide a definite answer to this issue.
Another useful message from the FLOW study for primary care is the utility of semaglutide for glucose-lowering in the context of CKD. A1c was 0.81% lower in the semaglutide group compared with the placebo group in participants with eGFRs as low as 25 mL/min/1.73 m2. It is well established that SGLT2 inhibitors have negligible glucose-lowering effects once eGFR drops below 45 mL/min/1.73 m2. Indeed, my usual practice in CKD, if additional glucose-lowering is required once renal protection has been established with an SGLT2 inhibitor, was to add a GLP-1 receptor agonist. It is reassuring to have my clinical practice ratified by the FLOW study.
Semaglutide also helpfully provides an alternative therapeutic option for patients who do not tolerate SGLT2 inhibitors because of, for example, recurrent mycotic genital infections or polyuria, or for those in whom SGLT2 inhibitors are contraindicated, such as patients who have experienced an unprovoked episode of diabetic ketoacidosis. Many of these patients still require cardiovascular and kidney protection, so the FLOW study gives me a viable evidence-based alternative.
As a class, semaglutide and GLP-1 receptor agonists are, of course, not without side effects. Gastrointestinal side effects are the most common, and this finding was echoed in the FLOW study. Gastrointestinal disorders led to permanent treatment discontinuation in 4.5% of the semaglutide group compared with 1.1% of the placebo group. The overall safety profile of semaglutide was favorable, however.
Gastrointestinal side effects can be particularly concerning in the context of CKD because of the possibility of clinical dehydration and acute kidney injury with persistent vomiting or diarrhea. Patient education is particularly important when using GLP-1 receptor agonists in this group of individuals. Reassuringly, there was no imbalance in dehydration and acute kidney injury between trial arms in the FLOW study.
Notably, past studies have suggested that patients with CKD are more likely to experience gastrointestinal side effects with GLP-1 receptor agonists; in these patients, the usual mantra of GLP-1 receptor agonist prescribing is particularly important: Start low, go slow.
Finally, medication adherence is a challenge with multiple pillars of GDMT: These evidence-based disease-modifying therapies work only if our patients take them regularly. My senior partner had a lovely turn of phrase when reviewing patients with multiple long-term conditions; he would always start the consultation by asking individuals which medications they were not taking regularly.
Overall, the FLOW study confirms semaglutide’s position as a new therapeutic pillar for DKD. This treatment will help address the residual renal risk for patients with DKD despite optimal use of GDMT. However, education and support will be required in primary care to prevent worsening therapeutic inertia.
Kevin Fernando, general practitioner partner, North Berwick Health Centre, North Berwick, UK, has disclosed the following relevant financial relationships: Received speaker fees from: Amarin; Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Dexcom; Daiichi Sankyo; Lilly; Menarini; Novartis; Novo Nordisk; Roche Diagnostics; Embecta; Roche Diabetes Care. Received honoraria for participation in advisory boards from: Amarin; Amgen; AstraZen
A version of this article first appeared on Medscape.com.
FROM EASD 2024
Can Hormones Guide Sex-Specific Treatments for Alcohol Use Disorder?
MILAN — Specific combinations of hormonal and biochemical factors were associated with different clinical characteristics and treatment outcomes of alcohol use disorder (AUD) between men and women.
“These hormones and proteins are known to have an influence on behavior, and indeed we see an association between different levels of these compounds and different behavioral aspects of [AUD], although we can’t for sure say that one directly causes another,” said lead researcher Victor M. Karpyak, MD, PhD, professor of psychiatry at the Mayo Clinic, in a release.
The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress.
Sex Hormone Signatures
Previous research has highlighted differences in symptoms including cravings, withdrawal, consumption patterns, depression, and anxiety between men and women with AUD, said Dr. Karpyak. Differences in hormones and biochemicals have also been observed between individuals with and without AUD.
However, specific biochemical and hormonal “signatures” associated with male and female responses to treatment have thus far not been explored, he told this news organization.
The study included 400 treatment-seeking individuals (132 women and 268 men; mean age, 41.8 years; 93% White) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for AUD and were enrolled in a clinical trial of acamprosate.
Baseline assessment included psychiatric comorbidities and substance use with the Psychiatric Research Interview for Substance and Mental Disorders, alcohol consumption pattern over the past 90 days by Timeline Follow-Back calendar, recent craving on the Penn Alcohol Craving Scale (PACS), situations at the risk of drinking on the Inventory of Drug-Taking Situation, recent depression severity on the Patient Health Questionnaire 9 (PHQ-9), and recent anxiety severity on the Generalized Anxiety Disorder 7 scale.
Plasma sex-related hormone and protein measurements were taken at baseline — after detoxification but before treatment. These included total testosterone, estradiol, estrone, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone–binding globulin (SHBG), and albumin.
“The important thing is that these measurements were taken during sobriety,” said Dr. Karpyak. Study participants were already in residential treatment programs, and the average time since their last drink was approximately 3 weeks. Relapse was defined as any alcohol consumption during the first 3 months.
What Works for Men May Not Work for Women
Results showed that men with symptoms of depression and a higher craving for alcohol, as shown on baseline PHQ-9 and PACS scores, had lower baseline levels of testosterone, estrone, estradiol, and SHBG than those without these symptoms (P = .0102 and P = .0014, respectively).
In addition, a combination of higher progesterone and lower albumin was associated with a lower risk for relapse during the first 3 months (odds ratio [OR], 0.518; P = .0079).
In women, a combination of lower estrone and estradiol and higher FSH and LH levels was associated with higher maximum number of drinks per day (P = .035).
In addition, women who were more likely to relapse during the first 3 months of treatment had higher baseline levels of testosterone, SHBG, and albumin than those at lower relapse risk (OR, 4.536; P = .0057).
Dr. Karpyak noted that these “hormone signatures” were associative and not predictive.
What this means, he said, “is that if you are treating a man and a woman for alcoholism, you are dealing with different biochemical and psychological starting points. This implies that what works for a man may not work for a woman, and vice versa.”
Toward Gender Equity
The findings may eventually lead to a way to predict treatment responses in patients with AUD, Dr. Karpyak added, but cautioned that despite statistical significance, these are preliminary findings.
Before these results can be integrated into clinical practice, they need to be replicated. Dr. Karpyak emphasized the need for follow-up research that builds on these findings, using them as preliminary data to determine whether prediction holds real significance.
“Given that many of these differences are related to sex hormones, we particularly want to see how the dramatic hormonal change women experience during the menstrual cycle and at menopause may affect the biochemistry of alcoholism and guide treatment efforts,” he said.
In a statement, Erika Comasco, PhD, associate professor in molecular psychiatry, Uppsala University, Sweden, said the research “is an important step forward to gender equity in medicine.”
“The findings provide an important first insight into the relationship between sex hormones and alcohol use disorder treatment,” she explained. “While sex differences in the way the disorder manifests itself are known, these results suggest that sex hormones may modulate treatment response, potentially supporting sex-specific pharmacological intervention.”
Dr. Comasco shares Dr. Karpyak’s view that hormonal fluctuations linked to the menstrual cycle may influence alcohol misuse and believes more research is needed to explore their impact on treatment and relapse outcomes in female patients.
This study was funded by the National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health) and the Samuel C. Johnson Genomics of Addiction Program at Mayo Clinic. Dr. Karpyak and Dr. Comasco reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
MILAN — Specific combinations of hormonal and biochemical factors were associated with different clinical characteristics and treatment outcomes of alcohol use disorder (AUD) between men and women.
“These hormones and proteins are known to have an influence on behavior, and indeed we see an association between different levels of these compounds and different behavioral aspects of [AUD], although we can’t for sure say that one directly causes another,” said lead researcher Victor M. Karpyak, MD, PhD, professor of psychiatry at the Mayo Clinic, in a release.
The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress.
Sex Hormone Signatures
Previous research has highlighted differences in symptoms including cravings, withdrawal, consumption patterns, depression, and anxiety between men and women with AUD, said Dr. Karpyak. Differences in hormones and biochemicals have also been observed between individuals with and without AUD.
However, specific biochemical and hormonal “signatures” associated with male and female responses to treatment have thus far not been explored, he told this news organization.
The study included 400 treatment-seeking individuals (132 women and 268 men; mean age, 41.8 years; 93% White) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for AUD and were enrolled in a clinical trial of acamprosate.
Baseline assessment included psychiatric comorbidities and substance use with the Psychiatric Research Interview for Substance and Mental Disorders, alcohol consumption pattern over the past 90 days by Timeline Follow-Back calendar, recent craving on the Penn Alcohol Craving Scale (PACS), situations at the risk of drinking on the Inventory of Drug-Taking Situation, recent depression severity on the Patient Health Questionnaire 9 (PHQ-9), and recent anxiety severity on the Generalized Anxiety Disorder 7 scale.
Plasma sex-related hormone and protein measurements were taken at baseline — after detoxification but before treatment. These included total testosterone, estradiol, estrone, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone–binding globulin (SHBG), and albumin.
“The important thing is that these measurements were taken during sobriety,” said Dr. Karpyak. Study participants were already in residential treatment programs, and the average time since their last drink was approximately 3 weeks. Relapse was defined as any alcohol consumption during the first 3 months.
What Works for Men May Not Work for Women
Results showed that men with symptoms of depression and a higher craving for alcohol, as shown on baseline PHQ-9 and PACS scores, had lower baseline levels of testosterone, estrone, estradiol, and SHBG than those without these symptoms (P = .0102 and P = .0014, respectively).
In addition, a combination of higher progesterone and lower albumin was associated with a lower risk for relapse during the first 3 months (odds ratio [OR], 0.518; P = .0079).
In women, a combination of lower estrone and estradiol and higher FSH and LH levels was associated with higher maximum number of drinks per day (P = .035).
In addition, women who were more likely to relapse during the first 3 months of treatment had higher baseline levels of testosterone, SHBG, and albumin than those at lower relapse risk (OR, 4.536; P = .0057).
Dr. Karpyak noted that these “hormone signatures” were associative and not predictive.
What this means, he said, “is that if you are treating a man and a woman for alcoholism, you are dealing with different biochemical and psychological starting points. This implies that what works for a man may not work for a woman, and vice versa.”
Toward Gender Equity
The findings may eventually lead to a way to predict treatment responses in patients with AUD, Dr. Karpyak added, but cautioned that despite statistical significance, these are preliminary findings.
Before these results can be integrated into clinical practice, they need to be replicated. Dr. Karpyak emphasized the need for follow-up research that builds on these findings, using them as preliminary data to determine whether prediction holds real significance.
“Given that many of these differences are related to sex hormones, we particularly want to see how the dramatic hormonal change women experience during the menstrual cycle and at menopause may affect the biochemistry of alcoholism and guide treatment efforts,” he said.
In a statement, Erika Comasco, PhD, associate professor in molecular psychiatry, Uppsala University, Sweden, said the research “is an important step forward to gender equity in medicine.”
“The findings provide an important first insight into the relationship between sex hormones and alcohol use disorder treatment,” she explained. “While sex differences in the way the disorder manifests itself are known, these results suggest that sex hormones may modulate treatment response, potentially supporting sex-specific pharmacological intervention.”
Dr. Comasco shares Dr. Karpyak’s view that hormonal fluctuations linked to the menstrual cycle may influence alcohol misuse and believes more research is needed to explore their impact on treatment and relapse outcomes in female patients.
This study was funded by the National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health) and the Samuel C. Johnson Genomics of Addiction Program at Mayo Clinic. Dr. Karpyak and Dr. Comasco reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
MILAN — Specific combinations of hormonal and biochemical factors were associated with different clinical characteristics and treatment outcomes of alcohol use disorder (AUD) between men and women.
“These hormones and proteins are known to have an influence on behavior, and indeed we see an association between different levels of these compounds and different behavioral aspects of [AUD], although we can’t for sure say that one directly causes another,” said lead researcher Victor M. Karpyak, MD, PhD, professor of psychiatry at the Mayo Clinic, in a release.
The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress.
Sex Hormone Signatures
Previous research has highlighted differences in symptoms including cravings, withdrawal, consumption patterns, depression, and anxiety between men and women with AUD, said Dr. Karpyak. Differences in hormones and biochemicals have also been observed between individuals with and without AUD.
However, specific biochemical and hormonal “signatures” associated with male and female responses to treatment have thus far not been explored, he told this news organization.
The study included 400 treatment-seeking individuals (132 women and 268 men; mean age, 41.8 years; 93% White) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for AUD and were enrolled in a clinical trial of acamprosate.
Baseline assessment included psychiatric comorbidities and substance use with the Psychiatric Research Interview for Substance and Mental Disorders, alcohol consumption pattern over the past 90 days by Timeline Follow-Back calendar, recent craving on the Penn Alcohol Craving Scale (PACS), situations at the risk of drinking on the Inventory of Drug-Taking Situation, recent depression severity on the Patient Health Questionnaire 9 (PHQ-9), and recent anxiety severity on the Generalized Anxiety Disorder 7 scale.
Plasma sex-related hormone and protein measurements were taken at baseline — after detoxification but before treatment. These included total testosterone, estradiol, estrone, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone–binding globulin (SHBG), and albumin.
“The important thing is that these measurements were taken during sobriety,” said Dr. Karpyak. Study participants were already in residential treatment programs, and the average time since their last drink was approximately 3 weeks. Relapse was defined as any alcohol consumption during the first 3 months.
What Works for Men May Not Work for Women
Results showed that men with symptoms of depression and a higher craving for alcohol, as shown on baseline PHQ-9 and PACS scores, had lower baseline levels of testosterone, estrone, estradiol, and SHBG than those without these symptoms (P = .0102 and P = .0014, respectively).
In addition, a combination of higher progesterone and lower albumin was associated with a lower risk for relapse during the first 3 months (odds ratio [OR], 0.518; P = .0079).
In women, a combination of lower estrone and estradiol and higher FSH and LH levels was associated with higher maximum number of drinks per day (P = .035).
In addition, women who were more likely to relapse during the first 3 months of treatment had higher baseline levels of testosterone, SHBG, and albumin than those at lower relapse risk (OR, 4.536; P = .0057).
Dr. Karpyak noted that these “hormone signatures” were associative and not predictive.
What this means, he said, “is that if you are treating a man and a woman for alcoholism, you are dealing with different biochemical and psychological starting points. This implies that what works for a man may not work for a woman, and vice versa.”
Toward Gender Equity
The findings may eventually lead to a way to predict treatment responses in patients with AUD, Dr. Karpyak added, but cautioned that despite statistical significance, these are preliminary findings.
Before these results can be integrated into clinical practice, they need to be replicated. Dr. Karpyak emphasized the need for follow-up research that builds on these findings, using them as preliminary data to determine whether prediction holds real significance.
“Given that many of these differences are related to sex hormones, we particularly want to see how the dramatic hormonal change women experience during the menstrual cycle and at menopause may affect the biochemistry of alcoholism and guide treatment efforts,” he said.
In a statement, Erika Comasco, PhD, associate professor in molecular psychiatry, Uppsala University, Sweden, said the research “is an important step forward to gender equity in medicine.”
“The findings provide an important first insight into the relationship between sex hormones and alcohol use disorder treatment,” she explained. “While sex differences in the way the disorder manifests itself are known, these results suggest that sex hormones may modulate treatment response, potentially supporting sex-specific pharmacological intervention.”
Dr. Comasco shares Dr. Karpyak’s view that hormonal fluctuations linked to the menstrual cycle may influence alcohol misuse and believes more research is needed to explore their impact on treatment and relapse outcomes in female patients.
This study was funded by the National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health) and the Samuel C. Johnson Genomics of Addiction Program at Mayo Clinic. Dr. Karpyak and Dr. Comasco reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM ECNP 2024
Head and Neck Cancer: Should Patients Get PEG Access Prior to Therapy? VA pilot study could help clinicians make better-informed decisions to head off malnutrition
Research conducted at the US Department of Veterans Affairs (VA) could offer crucial insight into the hotly debated question of whether patients with head and neck cancer should have access to percutaneous endoscopic gastrostomy (PEG) before they develop malnutrition.
While no definitive conclusions can be drawn until a complete study is performed, early findings of a pilot trial are intriguing, said advanced practice oncology dietitian Katherine Petersen, MS, RDN, CSO, of the Phoenix VA Health Care System, who spoke in an interview with Federal Practitioner and at the annual meeting of the Association of VA Hematology/Oncology.
So far, the 12 patients with head and neck cancer who agreed to the placement of prophylactic feeding tubes prior to chemoradiation have had worse outcomes in some areas compared to the 9 patients who had tubes inserted when clinically indicated and the 12 who didn't need feeding tubes.
Petersen cautioned that the study is small and underpowered at this point. Still, she noted, "We're seeing a hint of exactly the opposite of what I expected. Those who get a tube prophylactically are doing worse than those who are getting it reactively or not at all, If that's the case, that's a really important outcome."
As Petersen explained, the placement of PEG feeding tubes is a hot topic in head and neck cancer care. Malnutrition affects about 80% of these patients and can contribute to mortality, raising the question of whether they should have access to feeding tubes placed prior to treatment in case enteral nutrition is needed.
In some patients with head and neck cancer, malnutrition may arise when tumors block food intake or prevent patients from swallowing. "But in my clinical experience, most often it's from the adverse effects of radiation and chemotherapy. Radiation creates burns inside their throat that make it hard to swallow. Or they have taste changes or really dry mouth," Petersen said.
"On top of these problems, chemotherapy can cause nausea and vomiting," she said. Placing feeding tube access may seem like a smart strategy to head off malnutrition as soon as it occurs. But, as Petersen noted, feeding tube use can lead to dependency as patients lose their ability to swallow. "There's a theory that if we give people feeding tubes, they'll go with the easier route of using a feeding tube and not keep swallowing. Then those swallowing muscles would weaken, and patients would end up permanently on a feeding tube."
In 2020, a retrospective VA study linked feeding tube dependence to lower overall survival in head and neck cancer patients. There are also risks to feeding tube placement, such as infection, pain, leakage, and inflammation.
But what if feeding tube valves are inserted prophylactically so they can be used for nutrition if needed? "We just haven't had any prospective studies to get to the heart of the matter and answer the question," she said. "It's hard to recruit. How do you convince somebody to randomly be assigned to have a hole poked in their stomach?"
For the new pilot study, researchers in Phoenix decided not to randomize patients. Instead, they asked them whether they'd accept the placement of feeding tube valves on a prophylactic basis.
Thirty-six veterans enrolled in 3 years, 33% of those were eligible. Twelve have died, 1 withdrew, and 2 were lost to follow-up.
Those in the prophylactic group had worse physical function and muscle strength over time, while those who received feeding tubes when needed had more adverse events.
Why might some outcomes be worse for patients who chose the prophylactic approach? "The answer is unclear," Petersen said. "Although one possibility is that those patients had higher-risk tumors and were more clued into their own risk."
"The goal now is to get funding for an expanded, multicenter study within the VA," Petersen said. The big question that she hopes to answer is: Does a prophylactic approach work? "Does it make a difference for patients in terms of how quickly they go back to living a full, meaningful life and be able to do all the things that they normally would do?"
A complete study would likely last 7 years, but helpful results may come earlier. "We are starting to see significant differences in terms of our main outcomes of physical function," Petersen said. "We only need 1 to 2 years of data for each patient to get to the heart of that."
The study is not funded, and Petersen reported no disclosures.
Research conducted at the US Department of Veterans Affairs (VA) could offer crucial insight into the hotly debated question of whether patients with head and neck cancer should have access to percutaneous endoscopic gastrostomy (PEG) before they develop malnutrition.
While no definitive conclusions can be drawn until a complete study is performed, early findings of a pilot trial are intriguing, said advanced practice oncology dietitian Katherine Petersen, MS, RDN, CSO, of the Phoenix VA Health Care System, who spoke in an interview with Federal Practitioner and at the annual meeting of the Association of VA Hematology/Oncology.
So far, the 12 patients with head and neck cancer who agreed to the placement of prophylactic feeding tubes prior to chemoradiation have had worse outcomes in some areas compared to the 9 patients who had tubes inserted when clinically indicated and the 12 who didn't need feeding tubes.
Petersen cautioned that the study is small and underpowered at this point. Still, she noted, "We're seeing a hint of exactly the opposite of what I expected. Those who get a tube prophylactically are doing worse than those who are getting it reactively or not at all, If that's the case, that's a really important outcome."
As Petersen explained, the placement of PEG feeding tubes is a hot topic in head and neck cancer care. Malnutrition affects about 80% of these patients and can contribute to mortality, raising the question of whether they should have access to feeding tubes placed prior to treatment in case enteral nutrition is needed.
In some patients with head and neck cancer, malnutrition may arise when tumors block food intake or prevent patients from swallowing. "But in my clinical experience, most often it's from the adverse effects of radiation and chemotherapy. Radiation creates burns inside their throat that make it hard to swallow. Or they have taste changes or really dry mouth," Petersen said.
"On top of these problems, chemotherapy can cause nausea and vomiting," she said. Placing feeding tube access may seem like a smart strategy to head off malnutrition as soon as it occurs. But, as Petersen noted, feeding tube use can lead to dependency as patients lose their ability to swallow. "There's a theory that if we give people feeding tubes, they'll go with the easier route of using a feeding tube and not keep swallowing. Then those swallowing muscles would weaken, and patients would end up permanently on a feeding tube."
In 2020, a retrospective VA study linked feeding tube dependence to lower overall survival in head and neck cancer patients. There are also risks to feeding tube placement, such as infection, pain, leakage, and inflammation.
But what if feeding tube valves are inserted prophylactically so they can be used for nutrition if needed? "We just haven't had any prospective studies to get to the heart of the matter and answer the question," she said. "It's hard to recruit. How do you convince somebody to randomly be assigned to have a hole poked in their stomach?"
For the new pilot study, researchers in Phoenix decided not to randomize patients. Instead, they asked them whether they'd accept the placement of feeding tube valves on a prophylactic basis.
Thirty-six veterans enrolled in 3 years, 33% of those were eligible. Twelve have died, 1 withdrew, and 2 were lost to follow-up.
Those in the prophylactic group had worse physical function and muscle strength over time, while those who received feeding tubes when needed had more adverse events.
Why might some outcomes be worse for patients who chose the prophylactic approach? "The answer is unclear," Petersen said. "Although one possibility is that those patients had higher-risk tumors and were more clued into their own risk."
"The goal now is to get funding for an expanded, multicenter study within the VA," Petersen said. The big question that she hopes to answer is: Does a prophylactic approach work? "Does it make a difference for patients in terms of how quickly they go back to living a full, meaningful life and be able to do all the things that they normally would do?"
A complete study would likely last 7 years, but helpful results may come earlier. "We are starting to see significant differences in terms of our main outcomes of physical function," Petersen said. "We only need 1 to 2 years of data for each patient to get to the heart of that."
The study is not funded, and Petersen reported no disclosures.
Research conducted at the US Department of Veterans Affairs (VA) could offer crucial insight into the hotly debated question of whether patients with head and neck cancer should have access to percutaneous endoscopic gastrostomy (PEG) before they develop malnutrition.
While no definitive conclusions can be drawn until a complete study is performed, early findings of a pilot trial are intriguing, said advanced practice oncology dietitian Katherine Petersen, MS, RDN, CSO, of the Phoenix VA Health Care System, who spoke in an interview with Federal Practitioner and at the annual meeting of the Association of VA Hematology/Oncology.
So far, the 12 patients with head and neck cancer who agreed to the placement of prophylactic feeding tubes prior to chemoradiation have had worse outcomes in some areas compared to the 9 patients who had tubes inserted when clinically indicated and the 12 who didn't need feeding tubes.
Petersen cautioned that the study is small and underpowered at this point. Still, she noted, "We're seeing a hint of exactly the opposite of what I expected. Those who get a tube prophylactically are doing worse than those who are getting it reactively or not at all, If that's the case, that's a really important outcome."
As Petersen explained, the placement of PEG feeding tubes is a hot topic in head and neck cancer care. Malnutrition affects about 80% of these patients and can contribute to mortality, raising the question of whether they should have access to feeding tubes placed prior to treatment in case enteral nutrition is needed.
In some patients with head and neck cancer, malnutrition may arise when tumors block food intake or prevent patients from swallowing. "But in my clinical experience, most often it's from the adverse effects of radiation and chemotherapy. Radiation creates burns inside their throat that make it hard to swallow. Or they have taste changes or really dry mouth," Petersen said.
"On top of these problems, chemotherapy can cause nausea and vomiting," she said. Placing feeding tube access may seem like a smart strategy to head off malnutrition as soon as it occurs. But, as Petersen noted, feeding tube use can lead to dependency as patients lose their ability to swallow. "There's a theory that if we give people feeding tubes, they'll go with the easier route of using a feeding tube and not keep swallowing. Then those swallowing muscles would weaken, and patients would end up permanently on a feeding tube."
In 2020, a retrospective VA study linked feeding tube dependence to lower overall survival in head and neck cancer patients. There are also risks to feeding tube placement, such as infection, pain, leakage, and inflammation.
But what if feeding tube valves are inserted prophylactically so they can be used for nutrition if needed? "We just haven't had any prospective studies to get to the heart of the matter and answer the question," she said. "It's hard to recruit. How do you convince somebody to randomly be assigned to have a hole poked in their stomach?"
For the new pilot study, researchers in Phoenix decided not to randomize patients. Instead, they asked them whether they'd accept the placement of feeding tube valves on a prophylactic basis.
Thirty-six veterans enrolled in 3 years, 33% of those were eligible. Twelve have died, 1 withdrew, and 2 were lost to follow-up.
Those in the prophylactic group had worse physical function and muscle strength over time, while those who received feeding tubes when needed had more adverse events.
Why might some outcomes be worse for patients who chose the prophylactic approach? "The answer is unclear," Petersen said. "Although one possibility is that those patients had higher-risk tumors and were more clued into their own risk."
"The goal now is to get funding for an expanded, multicenter study within the VA," Petersen said. The big question that she hopes to answer is: Does a prophylactic approach work? "Does it make a difference for patients in terms of how quickly they go back to living a full, meaningful life and be able to do all the things that they normally would do?"
A complete study would likely last 7 years, but helpful results may come earlier. "We are starting to see significant differences in terms of our main outcomes of physical function," Petersen said. "We only need 1 to 2 years of data for each patient to get to the heart of that."
The study is not funded, and Petersen reported no disclosures.
Air Travel Alters Insulin Pump Delivery on Takeoff, Landing
MADRID —
This phenomenon is due to air bubble formation and reabsorption in the insulin caused by ambient pressure changes in the airplane’s cabin. It has nothing to do with the pump itself and happens with all insulin pumps, including those in hybrid closed-loop systems, Bruce King, MD, said at the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.
The extent to which this affects people with diabetes who use insulin pumps depends on their dose and insulin sensitivity among other factors, but all who fly should be aware of the possibility and take precautions, particularly with children, Dr. King, a pediatric endocrinologist at John Hunter Children’s Hospital, Newcastle, Australia, told this news organization.
“Basically, the pumps are very safe in flight, but they deliver a little bit of extra insulin when you go up and stop delivery when you come back down again. There are a couple of simple steps that people can take to make sure that they don’t have problems during the flight,” he said.
Specifically, he advised that for pumps with tubing, wearers can disconnect just prior to takeoff and reconnect when the plane reaches cruising altitude, about 20 minutes into the flight. The insulin will still come out, but it won’t be delivered to the person, Dr. King said.
On descent, they can disconnect after landing and prime the line to remove the insulin deficit.
With the Omnipod, which can’t be disconnected, the only solution is to eat a small snack on takeoff. And on landing, eat another small snack such as a banana, and give a bolus for it to overcome the blockage of insulin delivery.
In any case, Dr. King said, “One of the most important things is informing people with diabetes about this effect so they’re aware of it and can act appropriately when they fly.”
Asked to comment, Nicholas B. Argento, MD, a practicing endocrinologist in Columbia, Maryland, and author of the American Diabetes Association’s book, “Putting Your Patients on the Pump,” called the issue a “minor effect,” adding, “While I think it would be reasonable to make those changes ... it seems like a lot of effort for a difference of 0.6 units extra on ascent and 0.5 units less on descent.”
He noted there is a risk that the individual might forget to reattach the pump after 20 minutes, leading to hyperglycemia and even diabetic ketoacidosis. Instead, “one could put the pump on suspend for 1 hour on ascent. That would not stop the extra insulin but would net less insulin during that time period.”
And after descent, “you have to walk a lot in most cases, so I don’t think they need to take this into consideration. So many other factors change in air travel that I don’t think this is a significant enough effect to make the effort.”
A Known Phenomenon, the Manufacturers Are Aware
This phenomenon has been described previously, including by Dr. King in a 2011 Diabetes Care paper. The new research is among a series of experiments funded by the European Union Aviation Safety Agency in collaboration with the pump manufacturers Medtronic (MiniMed), Tandem (t:slim), and Insulet (Omnipod), primarily aimed at establishing safety parameters for airline pilots with insulin-treated diabetes.
Both the Omnipod DASH and Omnipod 5 User Guides include warnings about unintended insulin delivery during flight, and both advise users to check their blood glucose levels frequently while flying.
In a statement, Jordan Pinsker, MD, Chief Medical Officer at Tandem Diabetes Care, told this news organization, “While it has long been known that routine air travel pressure changes can cause minor fluctuations in insulin pump delivery, the impact of these variations have been found to be generally minor as it relates to glycemic control.”
Dr. Pinsker added that the Tandem Mobi user manual includes a warning related to significant pressure changes in specific air travel situations and offers guidance to disconnect. However, “the t:slim X2 pump’s microdelivery technology limits how much extra insulin can get delivered from air pressure changes due to a mechanism between the tubing and the contents of the bag inside the cartridge.”
Medtronic’s user guide says that the 780G system has not been tested at altitudes higher than 10,150 feet.
Hypobaric Chamber Used to Simulate Flight
The study was conducted in vitro, in a hypobaric chamber designed to mimic atmospheric changes during commercial flight. A total of 10 Medtronic MiniMed 780G, 10 Tandem t:slim X2, and six Insulet Omnipod DASH pumps were tested.
The hypobaric chamber was depressurized to 550 mm Hg over a 20-minute ascent, maintained at a 30-minute cruise, followed by a 20-minute descent to ground (750 mm Hg). During the simulated flights, insulin infusion was set at 0.6 units per hour, a rate typical for both adults and children, to allow accurate measurements with multiple flights.
Insulin delivery rates and bubble formation were recorded by attaching infusion sets to open-ended 100 µL capillary tubes against 1-mm grid paper.
Full cartridges — Medtronic: 3 mL, t:slim: 3 mL, and Omnipod: 2 mL — all over-delivered 0.60 units of insulin over a 20-minute ascent compared with delivery at ground level. And during descent, the cartridges under-delivered 0.51 units of insulin.
But if There’s Rapid Decompression…
In a separate protocol, insulin infusion sets without pumps were tested in a simulation of rapid decompression. Insulin delivery during both ascent and descent showed statistically significant differences compared with delivery at ground level (both P < .001). In this scenario, fluid delivery was equivalent to 5.6 units of excess insulin.
Dr. King pointed out that while these are rare events, about 40-50 occur annually. One was the widely publicized Alaska Airlines flight in January 2024 when the door fell off in midair.
Dr. Argento said, “The catastrophic decompression is of note, and I would want patients to be aware of this, but it is asking a lot for someone thinking they are going to die to remember to disconnect as it starts.”
The researchers are investigating this phenomenon further in people, including airline pilots.
Dr. King’s research group has been involved in research with Medtronic, Tandem, and Insulet. Dr. Argento has consulted or been on advisory boards for Eli Lilly Diabetes, Dexcom, Diabeloop, Convatec, and Senseonics and served on the speakers’ bureaus for Boehringer Ingelheim, Dexcom, Eli Lilly Diabetes, MannKind, Novo Nordisk, Xeris, and Zealand Pharma.
A version of this article appeared on Medscape.com.
MADRID —
This phenomenon is due to air bubble formation and reabsorption in the insulin caused by ambient pressure changes in the airplane’s cabin. It has nothing to do with the pump itself and happens with all insulin pumps, including those in hybrid closed-loop systems, Bruce King, MD, said at the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.
The extent to which this affects people with diabetes who use insulin pumps depends on their dose and insulin sensitivity among other factors, but all who fly should be aware of the possibility and take precautions, particularly with children, Dr. King, a pediatric endocrinologist at John Hunter Children’s Hospital, Newcastle, Australia, told this news organization.
“Basically, the pumps are very safe in flight, but they deliver a little bit of extra insulin when you go up and stop delivery when you come back down again. There are a couple of simple steps that people can take to make sure that they don’t have problems during the flight,” he said.
Specifically, he advised that for pumps with tubing, wearers can disconnect just prior to takeoff and reconnect when the plane reaches cruising altitude, about 20 minutes into the flight. The insulin will still come out, but it won’t be delivered to the person, Dr. King said.
On descent, they can disconnect after landing and prime the line to remove the insulin deficit.
With the Omnipod, which can’t be disconnected, the only solution is to eat a small snack on takeoff. And on landing, eat another small snack such as a banana, and give a bolus for it to overcome the blockage of insulin delivery.
In any case, Dr. King said, “One of the most important things is informing people with diabetes about this effect so they’re aware of it and can act appropriately when they fly.”
Asked to comment, Nicholas B. Argento, MD, a practicing endocrinologist in Columbia, Maryland, and author of the American Diabetes Association’s book, “Putting Your Patients on the Pump,” called the issue a “minor effect,” adding, “While I think it would be reasonable to make those changes ... it seems like a lot of effort for a difference of 0.6 units extra on ascent and 0.5 units less on descent.”
He noted there is a risk that the individual might forget to reattach the pump after 20 minutes, leading to hyperglycemia and even diabetic ketoacidosis. Instead, “one could put the pump on suspend for 1 hour on ascent. That would not stop the extra insulin but would net less insulin during that time period.”
And after descent, “you have to walk a lot in most cases, so I don’t think they need to take this into consideration. So many other factors change in air travel that I don’t think this is a significant enough effect to make the effort.”
A Known Phenomenon, the Manufacturers Are Aware
This phenomenon has been described previously, including by Dr. King in a 2011 Diabetes Care paper. The new research is among a series of experiments funded by the European Union Aviation Safety Agency in collaboration with the pump manufacturers Medtronic (MiniMed), Tandem (t:slim), and Insulet (Omnipod), primarily aimed at establishing safety parameters for airline pilots with insulin-treated diabetes.
Both the Omnipod DASH and Omnipod 5 User Guides include warnings about unintended insulin delivery during flight, and both advise users to check their blood glucose levels frequently while flying.
In a statement, Jordan Pinsker, MD, Chief Medical Officer at Tandem Diabetes Care, told this news organization, “While it has long been known that routine air travel pressure changes can cause minor fluctuations in insulin pump delivery, the impact of these variations have been found to be generally minor as it relates to glycemic control.”
Dr. Pinsker added that the Tandem Mobi user manual includes a warning related to significant pressure changes in specific air travel situations and offers guidance to disconnect. However, “the t:slim X2 pump’s microdelivery technology limits how much extra insulin can get delivered from air pressure changes due to a mechanism between the tubing and the contents of the bag inside the cartridge.”
Medtronic’s user guide says that the 780G system has not been tested at altitudes higher than 10,150 feet.
Hypobaric Chamber Used to Simulate Flight
The study was conducted in vitro, in a hypobaric chamber designed to mimic atmospheric changes during commercial flight. A total of 10 Medtronic MiniMed 780G, 10 Tandem t:slim X2, and six Insulet Omnipod DASH pumps were tested.
The hypobaric chamber was depressurized to 550 mm Hg over a 20-minute ascent, maintained at a 30-minute cruise, followed by a 20-minute descent to ground (750 mm Hg). During the simulated flights, insulin infusion was set at 0.6 units per hour, a rate typical for both adults and children, to allow accurate measurements with multiple flights.
Insulin delivery rates and bubble formation were recorded by attaching infusion sets to open-ended 100 µL capillary tubes against 1-mm grid paper.
Full cartridges — Medtronic: 3 mL, t:slim: 3 mL, and Omnipod: 2 mL — all over-delivered 0.60 units of insulin over a 20-minute ascent compared with delivery at ground level. And during descent, the cartridges under-delivered 0.51 units of insulin.
But if There’s Rapid Decompression…
In a separate protocol, insulin infusion sets without pumps were tested in a simulation of rapid decompression. Insulin delivery during both ascent and descent showed statistically significant differences compared with delivery at ground level (both P < .001). In this scenario, fluid delivery was equivalent to 5.6 units of excess insulin.
Dr. King pointed out that while these are rare events, about 40-50 occur annually. One was the widely publicized Alaska Airlines flight in January 2024 when the door fell off in midair.
Dr. Argento said, “The catastrophic decompression is of note, and I would want patients to be aware of this, but it is asking a lot for someone thinking they are going to die to remember to disconnect as it starts.”
The researchers are investigating this phenomenon further in people, including airline pilots.
Dr. King’s research group has been involved in research with Medtronic, Tandem, and Insulet. Dr. Argento has consulted or been on advisory boards for Eli Lilly Diabetes, Dexcom, Diabeloop, Convatec, and Senseonics and served on the speakers’ bureaus for Boehringer Ingelheim, Dexcom, Eli Lilly Diabetes, MannKind, Novo Nordisk, Xeris, and Zealand Pharma.
A version of this article appeared on Medscape.com.
MADRID —
This phenomenon is due to air bubble formation and reabsorption in the insulin caused by ambient pressure changes in the airplane’s cabin. It has nothing to do with the pump itself and happens with all insulin pumps, including those in hybrid closed-loop systems, Bruce King, MD, said at the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.
The extent to which this affects people with diabetes who use insulin pumps depends on their dose and insulin sensitivity among other factors, but all who fly should be aware of the possibility and take precautions, particularly with children, Dr. King, a pediatric endocrinologist at John Hunter Children’s Hospital, Newcastle, Australia, told this news organization.
“Basically, the pumps are very safe in flight, but they deliver a little bit of extra insulin when you go up and stop delivery when you come back down again. There are a couple of simple steps that people can take to make sure that they don’t have problems during the flight,” he said.
Specifically, he advised that for pumps with tubing, wearers can disconnect just prior to takeoff and reconnect when the plane reaches cruising altitude, about 20 minutes into the flight. The insulin will still come out, but it won’t be delivered to the person, Dr. King said.
On descent, they can disconnect after landing and prime the line to remove the insulin deficit.
With the Omnipod, which can’t be disconnected, the only solution is to eat a small snack on takeoff. And on landing, eat another small snack such as a banana, and give a bolus for it to overcome the blockage of insulin delivery.
In any case, Dr. King said, “One of the most important things is informing people with diabetes about this effect so they’re aware of it and can act appropriately when they fly.”
Asked to comment, Nicholas B. Argento, MD, a practicing endocrinologist in Columbia, Maryland, and author of the American Diabetes Association’s book, “Putting Your Patients on the Pump,” called the issue a “minor effect,” adding, “While I think it would be reasonable to make those changes ... it seems like a lot of effort for a difference of 0.6 units extra on ascent and 0.5 units less on descent.”
He noted there is a risk that the individual might forget to reattach the pump after 20 minutes, leading to hyperglycemia and even diabetic ketoacidosis. Instead, “one could put the pump on suspend for 1 hour on ascent. That would not stop the extra insulin but would net less insulin during that time period.”
And after descent, “you have to walk a lot in most cases, so I don’t think they need to take this into consideration. So many other factors change in air travel that I don’t think this is a significant enough effect to make the effort.”
A Known Phenomenon, the Manufacturers Are Aware
This phenomenon has been described previously, including by Dr. King in a 2011 Diabetes Care paper. The new research is among a series of experiments funded by the European Union Aviation Safety Agency in collaboration with the pump manufacturers Medtronic (MiniMed), Tandem (t:slim), and Insulet (Omnipod), primarily aimed at establishing safety parameters for airline pilots with insulin-treated diabetes.
Both the Omnipod DASH and Omnipod 5 User Guides include warnings about unintended insulin delivery during flight, and both advise users to check their blood glucose levels frequently while flying.
In a statement, Jordan Pinsker, MD, Chief Medical Officer at Tandem Diabetes Care, told this news organization, “While it has long been known that routine air travel pressure changes can cause minor fluctuations in insulin pump delivery, the impact of these variations have been found to be generally minor as it relates to glycemic control.”
Dr. Pinsker added that the Tandem Mobi user manual includes a warning related to significant pressure changes in specific air travel situations and offers guidance to disconnect. However, “the t:slim X2 pump’s microdelivery technology limits how much extra insulin can get delivered from air pressure changes due to a mechanism between the tubing and the contents of the bag inside the cartridge.”
Medtronic’s user guide says that the 780G system has not been tested at altitudes higher than 10,150 feet.
Hypobaric Chamber Used to Simulate Flight
The study was conducted in vitro, in a hypobaric chamber designed to mimic atmospheric changes during commercial flight. A total of 10 Medtronic MiniMed 780G, 10 Tandem t:slim X2, and six Insulet Omnipod DASH pumps were tested.
The hypobaric chamber was depressurized to 550 mm Hg over a 20-minute ascent, maintained at a 30-minute cruise, followed by a 20-minute descent to ground (750 mm Hg). During the simulated flights, insulin infusion was set at 0.6 units per hour, a rate typical for both adults and children, to allow accurate measurements with multiple flights.
Insulin delivery rates and bubble formation were recorded by attaching infusion sets to open-ended 100 µL capillary tubes against 1-mm grid paper.
Full cartridges — Medtronic: 3 mL, t:slim: 3 mL, and Omnipod: 2 mL — all over-delivered 0.60 units of insulin over a 20-minute ascent compared with delivery at ground level. And during descent, the cartridges under-delivered 0.51 units of insulin.
But if There’s Rapid Decompression…
In a separate protocol, insulin infusion sets without pumps were tested in a simulation of rapid decompression. Insulin delivery during both ascent and descent showed statistically significant differences compared with delivery at ground level (both P < .001). In this scenario, fluid delivery was equivalent to 5.6 units of excess insulin.
Dr. King pointed out that while these are rare events, about 40-50 occur annually. One was the widely publicized Alaska Airlines flight in January 2024 when the door fell off in midair.
Dr. Argento said, “The catastrophic decompression is of note, and I would want patients to be aware of this, but it is asking a lot for someone thinking they are going to die to remember to disconnect as it starts.”
The researchers are investigating this phenomenon further in people, including airline pilots.
Dr. King’s research group has been involved in research with Medtronic, Tandem, and Insulet. Dr. Argento has consulted or been on advisory boards for Eli Lilly Diabetes, Dexcom, Diabeloop, Convatec, and Senseonics and served on the speakers’ bureaus for Boehringer Ingelheim, Dexcom, Eli Lilly Diabetes, MannKind, Novo Nordisk, Xeris, and Zealand Pharma.
A version of this article appeared on Medscape.com.
FROM EASD 2024
‘Call to Action’: Greater CVD Focus Urged for Type 1 Diabetes
MADRID — Emerging data points to the urgent need for cardiovascular risk reduction in all adults with type 1 diabetes (T1D), including those who are young and those diagnosed in adulthood.
At the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting, two entire oral abstract sessions were devoted to research examining cardiovascular risk specifically in people with T1D. There is increasing evidence that as with type 2 diabetes (T2D), clinical visits need to focus on other cardiovascular risk factors and glucose.
Findings included the evidence of severe coronary artery disease (CAD) in asymptomatic adults with T1D, increased risks for mortality and cardiac events in people diagnosed with T1D in adulthood, and a greater cardiovascular risk for those with overweight/obesity and among those with more cumulative exposure to both hyperglycemia and dyslipidemia.
One speaker, Dr. Rebecka Johanna Bergdal, of the Folkhälsan Research Center and the University of Helsinki, Finland, issued a “call to action,” saying, “We call on healthcare professionals to continue supporting and encouraging individuals with T1D towards better management of diabetes, including both glucose and lipid management.”
Session Moderator Krzysztof Strojek, MD, PhD, head of the Department of Internal Medicine, Diabetology and Cardiometabolic Diseases at the Medical University of Silesia, Katowice, Poland, told this news organization that all the data point in the same direction for T1D management, to “look not only at A1c and blood glucose control but also lipids, hypertension, smoking status, all these risk factors recognized in type 2 ... are also important in T1D.”
The ‘Alarming’ Finding of CAD in Asymptomatic Patients
Michal Dubsky, MD, PhD, of the Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic, presented findings from 62 asymptomatic patients with T1D for > 10 years (mean, 36 years), with a mean A1c of 7.5% (58 mmol/mol), and no prior history of cardiovascular disease (CVD). They had slightly elevated CVD biomarkers, including a mean low-density lipoprotein (LDL) cholesterol level of 2.33 mmol/L, lipoprotein (a) level of 15 nmol/L, and N-terminal pro-B-type natriuretic peptide level of 125.3 ng/L.
All underwent a noninvasive carotid ultrasound and coronary artery calcium (CAC) scoring. Of those, 12 patients had a CAC score > 400 and/or presence of two or more carotid plaques identified as high-risk.
Those 12 patients underwent coronary angiography and had a total of 29 vessels examined by optical coherence tomography (OCT), “an invasive intravascular method for assessing coronary atherosclerosis that is far more sensitive than standard coronary angiography, especially for the detection of high-risk vulnerable plaques without a hemodynamically significant stenosis,” Dr. Dubsky explained.
Coronary angiography showed obstructive CAD in 5 of the 12 patients. Their mean calcium score was 950 and mean number of carotid plaques was 2.8. Features associated with plaque vulnerability included microphage accumulation in 24 vessels, lipid-rich plaques in 23, spotty calcium in 19, and neovascularizations in 13.
Thin-cap fibroatheroma, a strong predictor of plaque rupture, was present in 7 of the 12 patients (58.3%), and four had features of very high-risk plaques, defined as thin-cap fibroatheroma with a minimal lumen area < 3.5 mm2, a lipid arch > 180 degrees, and macrophages.
“Our study showed that asymptomatic T1D patients with high CAC score and carotid plaques had very severe OCT findings. We observed a significant proportion of high-risk lesions potentially associated with plaque rupture and risk of CV death. Therefore, we believe these patients should be treated as very high-risk with target LDL below 1.4 mmol/L (55 mg/dL), even though they are completely asymptomatic,” Dr. Dubsky concluded.
He added that because OCT is invasive and costly, the CAC score can be used to guide the decision for statin use, with any score above 100 considered elevated risk.
Study coauthor Martin Haluzik, MD, professor of internal medicine in the Charles University, Prague, Czech Republic, told this news organization, “I think it’s very alarming because some of these are basically very healthy-looking young people, so you don’t really expect them to have significant cardiovascular complications already or significant plaques. I think it shows that we should be more proactive in looking into the risk of cardiovascular complications and in looking into the early cardiovascular changes.”
Later Diagnosis Doesn’t Always Protect: Risk Seen in Adult-Onset T1D
Yuxia Wei, a PhD student at the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, presented an analysis of data from Sweden’s national health databases comparing cardiovascular outcomes between 10,184 people diagnosed with T1D at ages 18-29 years, 30-39 years, and ≥ 40 years; another 375,523 people diagnosed with T2D at those ages; and 509,172 population controls matched for age, sex, and county.
Those diagnosed after age 40 years had higher A1c levels and were less likely to be using insulin pumps than those diagnosed at younger adult ages.
Compared with population controls, at a median of about 7 years of follow-up, people with T1D had significantly higher all-cause mortality at all diagnosis age groups, with a hazard ratio of 1.71. This rose to 2.78 for those diagnosed at age 30-39 years.
Compared with those with T2D, the mortality risks weren’t significantly different at any age, but the risks for non-cardiovascular death, including from cancer and infection, were significantly higher among those diagnosed after age 40 years (1.31 overall). Those diagnosed with T1D at any adult age had lower risks for major cardiovascular events than those diagnosed with T2D. Hazard ratios ranged from 0.27 for those diagnosed at age 18-29 years to 0.78 for those diagnosed after the age of 40 years.
Smoking and A1c above target were the greatest contributors to mortality. Those two factors, along with body mass index (BMI), were the strongest contributors to major adverse cardiovascular events (MACE).
“Adult-onset T1D carries excess risk of death and cardiovascular disease, without obvious attenuation over age at diagnosis…Smoking, A1c, and BMI are the key factors to be managed to improve prognosis in adult-onset T1D,” Ms. Wei concluded.
BMI: Often Overlooked in T1D, but a Major CVD Risk Factor
Two studies examined the link between overweight/obesity and cardiovascular risk in T1D. One, by Laurence Salle, MCU PH, of the Endocrinology, Diabetes and Metabolic Diseases Department at CHU Limoges, France, was a prospective, longitudinal cohort study of 2367 people with T1D at 68 centers in France who didn’t have a cardiovascular history at baseline.
Of those, 51% had normal BMI (18.5-24.9), 31% had overweight (25-29.9), and 18% had obesity (≥ 30). Cardiovascular risk factors, including LDL cholesterol, triglycerides, and hypertension increased with an increasing BMI. The 10-year CVD risk was significantly higher for those with overweight (9.61%) and obesity (9.93%) than for those with normal weight (7.24%), in both men and women.
However, BMI was found to be an independent predictor of 10-year high cardiovascular risk in men but not women, while waist:height ratio independently predicted risk in both men and women, Dr. Salle reported.
The second BMI study, from Enrique Soto-Pedre, MBBS, of the Division of Population Health and Genomics at the University of Dundee, Scotland, presented data on a retrospective follow-up from 1995 to 2019 of 1973 people with T1D aged > 18 years at diagnosis (42% women; mean age, 34.2 years; 18.9% had obesity.
After 10 years of follow-up, those with overweight and obesity had significantly higher odds of developing arterial hypertension, even among those taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, with statistically significant adjusted hazard ratios of 1.73 and 3.37 for the obese and overweight groups, respectively.
MACE were significantly more common among those with obesity, with an adjusted hazard ratio of 2.95, as was acute myocardial infarction, 3.33.
“These results emphasize the importance of incorporating weight management into the overall management of individuals with T1D. No one has doubts about weight management in T2D, but in type 1, it’s not so clear. One of the main [concerns] would be safety [in terms of hypoglycemia],” Dr. Soto-Pedre concluded.
Call for Action: Cumulative Glucose and Lipid Exposures Increase Risk
Dr. Bergdal presented data on the effects of cumulative glycemia and lipids on the risk for CAD in 3495 adults with T1D who had been diagnosed prior to the age of 40 years. The history of CAD or stroke was exclusion criteria. There were a total of 534 CAD events within a median follow-up of 19.4 years.
Cumulative glycemia, LDL cholesterol, triglycerides, and non–high-density lipoprotein cholesterol exposures were all significantly associated with CAD risk (P < .001 for all). With an adjustment for confounders, the highest tertile of glycemia was associated with a twofold increased risk for CAD. Both hyperglycemia and dyslipidemia were independently associated with CAD risk, Dr. Bergdal reported.
“It’s important to minimize the time spent above A1c 7%, and lipid management in T1D must not be forgotten,” she said, prior to issuing her call for action.
Dr. Haluzik reported receiving honoraria for talks and/or consultancy and/or research funding from Eli Lilly, Novo Nordisk, Sanofi, AstraZeneca, Mundipharma, Bristol Myers Squibb, Amgen, Boehringer Ingelheim, Janssen, Ypsomed, and Johnson & Johnson. The presenters had no disclosures.
A version of this article first appeared on Medscape.com.
MADRID — Emerging data points to the urgent need for cardiovascular risk reduction in all adults with type 1 diabetes (T1D), including those who are young and those diagnosed in adulthood.
At the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting, two entire oral abstract sessions were devoted to research examining cardiovascular risk specifically in people with T1D. There is increasing evidence that as with type 2 diabetes (T2D), clinical visits need to focus on other cardiovascular risk factors and glucose.
Findings included the evidence of severe coronary artery disease (CAD) in asymptomatic adults with T1D, increased risks for mortality and cardiac events in people diagnosed with T1D in adulthood, and a greater cardiovascular risk for those with overweight/obesity and among those with more cumulative exposure to both hyperglycemia and dyslipidemia.
One speaker, Dr. Rebecka Johanna Bergdal, of the Folkhälsan Research Center and the University of Helsinki, Finland, issued a “call to action,” saying, “We call on healthcare professionals to continue supporting and encouraging individuals with T1D towards better management of diabetes, including both glucose and lipid management.”
Session Moderator Krzysztof Strojek, MD, PhD, head of the Department of Internal Medicine, Diabetology and Cardiometabolic Diseases at the Medical University of Silesia, Katowice, Poland, told this news organization that all the data point in the same direction for T1D management, to “look not only at A1c and blood glucose control but also lipids, hypertension, smoking status, all these risk factors recognized in type 2 ... are also important in T1D.”
The ‘Alarming’ Finding of CAD in Asymptomatic Patients
Michal Dubsky, MD, PhD, of the Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic, presented findings from 62 asymptomatic patients with T1D for > 10 years (mean, 36 years), with a mean A1c of 7.5% (58 mmol/mol), and no prior history of cardiovascular disease (CVD). They had slightly elevated CVD biomarkers, including a mean low-density lipoprotein (LDL) cholesterol level of 2.33 mmol/L, lipoprotein (a) level of 15 nmol/L, and N-terminal pro-B-type natriuretic peptide level of 125.3 ng/L.
All underwent a noninvasive carotid ultrasound and coronary artery calcium (CAC) scoring. Of those, 12 patients had a CAC score > 400 and/or presence of two or more carotid plaques identified as high-risk.
Those 12 patients underwent coronary angiography and had a total of 29 vessels examined by optical coherence tomography (OCT), “an invasive intravascular method for assessing coronary atherosclerosis that is far more sensitive than standard coronary angiography, especially for the detection of high-risk vulnerable plaques without a hemodynamically significant stenosis,” Dr. Dubsky explained.
Coronary angiography showed obstructive CAD in 5 of the 12 patients. Their mean calcium score was 950 and mean number of carotid plaques was 2.8. Features associated with plaque vulnerability included microphage accumulation in 24 vessels, lipid-rich plaques in 23, spotty calcium in 19, and neovascularizations in 13.
Thin-cap fibroatheroma, a strong predictor of plaque rupture, was present in 7 of the 12 patients (58.3%), and four had features of very high-risk plaques, defined as thin-cap fibroatheroma with a minimal lumen area < 3.5 mm2, a lipid arch > 180 degrees, and macrophages.
“Our study showed that asymptomatic T1D patients with high CAC score and carotid plaques had very severe OCT findings. We observed a significant proportion of high-risk lesions potentially associated with plaque rupture and risk of CV death. Therefore, we believe these patients should be treated as very high-risk with target LDL below 1.4 mmol/L (55 mg/dL), even though they are completely asymptomatic,” Dr. Dubsky concluded.
He added that because OCT is invasive and costly, the CAC score can be used to guide the decision for statin use, with any score above 100 considered elevated risk.
Study coauthor Martin Haluzik, MD, professor of internal medicine in the Charles University, Prague, Czech Republic, told this news organization, “I think it’s very alarming because some of these are basically very healthy-looking young people, so you don’t really expect them to have significant cardiovascular complications already or significant plaques. I think it shows that we should be more proactive in looking into the risk of cardiovascular complications and in looking into the early cardiovascular changes.”
Later Diagnosis Doesn’t Always Protect: Risk Seen in Adult-Onset T1D
Yuxia Wei, a PhD student at the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, presented an analysis of data from Sweden’s national health databases comparing cardiovascular outcomes between 10,184 people diagnosed with T1D at ages 18-29 years, 30-39 years, and ≥ 40 years; another 375,523 people diagnosed with T2D at those ages; and 509,172 population controls matched for age, sex, and county.
Those diagnosed after age 40 years had higher A1c levels and were less likely to be using insulin pumps than those diagnosed at younger adult ages.
Compared with population controls, at a median of about 7 years of follow-up, people with T1D had significantly higher all-cause mortality at all diagnosis age groups, with a hazard ratio of 1.71. This rose to 2.78 for those diagnosed at age 30-39 years.
Compared with those with T2D, the mortality risks weren’t significantly different at any age, but the risks for non-cardiovascular death, including from cancer and infection, were significantly higher among those diagnosed after age 40 years (1.31 overall). Those diagnosed with T1D at any adult age had lower risks for major cardiovascular events than those diagnosed with T2D. Hazard ratios ranged from 0.27 for those diagnosed at age 18-29 years to 0.78 for those diagnosed after the age of 40 years.
Smoking and A1c above target were the greatest contributors to mortality. Those two factors, along with body mass index (BMI), were the strongest contributors to major adverse cardiovascular events (MACE).
“Adult-onset T1D carries excess risk of death and cardiovascular disease, without obvious attenuation over age at diagnosis…Smoking, A1c, and BMI are the key factors to be managed to improve prognosis in adult-onset T1D,” Ms. Wei concluded.
BMI: Often Overlooked in T1D, but a Major CVD Risk Factor
Two studies examined the link between overweight/obesity and cardiovascular risk in T1D. One, by Laurence Salle, MCU PH, of the Endocrinology, Diabetes and Metabolic Diseases Department at CHU Limoges, France, was a prospective, longitudinal cohort study of 2367 people with T1D at 68 centers in France who didn’t have a cardiovascular history at baseline.
Of those, 51% had normal BMI (18.5-24.9), 31% had overweight (25-29.9), and 18% had obesity (≥ 30). Cardiovascular risk factors, including LDL cholesterol, triglycerides, and hypertension increased with an increasing BMI. The 10-year CVD risk was significantly higher for those with overweight (9.61%) and obesity (9.93%) than for those with normal weight (7.24%), in both men and women.
However, BMI was found to be an independent predictor of 10-year high cardiovascular risk in men but not women, while waist:height ratio independently predicted risk in both men and women, Dr. Salle reported.
The second BMI study, from Enrique Soto-Pedre, MBBS, of the Division of Population Health and Genomics at the University of Dundee, Scotland, presented data on a retrospective follow-up from 1995 to 2019 of 1973 people with T1D aged > 18 years at diagnosis (42% women; mean age, 34.2 years; 18.9% had obesity.
After 10 years of follow-up, those with overweight and obesity had significantly higher odds of developing arterial hypertension, even among those taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, with statistically significant adjusted hazard ratios of 1.73 and 3.37 for the obese and overweight groups, respectively.
MACE were significantly more common among those with obesity, with an adjusted hazard ratio of 2.95, as was acute myocardial infarction, 3.33.
“These results emphasize the importance of incorporating weight management into the overall management of individuals with T1D. No one has doubts about weight management in T2D, but in type 1, it’s not so clear. One of the main [concerns] would be safety [in terms of hypoglycemia],” Dr. Soto-Pedre concluded.
Call for Action: Cumulative Glucose and Lipid Exposures Increase Risk
Dr. Bergdal presented data on the effects of cumulative glycemia and lipids on the risk for CAD in 3495 adults with T1D who had been diagnosed prior to the age of 40 years. The history of CAD or stroke was exclusion criteria. There were a total of 534 CAD events within a median follow-up of 19.4 years.
Cumulative glycemia, LDL cholesterol, triglycerides, and non–high-density lipoprotein cholesterol exposures were all significantly associated with CAD risk (P < .001 for all). With an adjustment for confounders, the highest tertile of glycemia was associated with a twofold increased risk for CAD. Both hyperglycemia and dyslipidemia were independently associated with CAD risk, Dr. Bergdal reported.
“It’s important to minimize the time spent above A1c 7%, and lipid management in T1D must not be forgotten,” she said, prior to issuing her call for action.
Dr. Haluzik reported receiving honoraria for talks and/or consultancy and/or research funding from Eli Lilly, Novo Nordisk, Sanofi, AstraZeneca, Mundipharma, Bristol Myers Squibb, Amgen, Boehringer Ingelheim, Janssen, Ypsomed, and Johnson & Johnson. The presenters had no disclosures.
A version of this article first appeared on Medscape.com.
MADRID — Emerging data points to the urgent need for cardiovascular risk reduction in all adults with type 1 diabetes (T1D), including those who are young and those diagnosed in adulthood.
At the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting, two entire oral abstract sessions were devoted to research examining cardiovascular risk specifically in people with T1D. There is increasing evidence that as with type 2 diabetes (T2D), clinical visits need to focus on other cardiovascular risk factors and glucose.
Findings included the evidence of severe coronary artery disease (CAD) in asymptomatic adults with T1D, increased risks for mortality and cardiac events in people diagnosed with T1D in adulthood, and a greater cardiovascular risk for those with overweight/obesity and among those with more cumulative exposure to both hyperglycemia and dyslipidemia.
One speaker, Dr. Rebecka Johanna Bergdal, of the Folkhälsan Research Center and the University of Helsinki, Finland, issued a “call to action,” saying, “We call on healthcare professionals to continue supporting and encouraging individuals with T1D towards better management of diabetes, including both glucose and lipid management.”
Session Moderator Krzysztof Strojek, MD, PhD, head of the Department of Internal Medicine, Diabetology and Cardiometabolic Diseases at the Medical University of Silesia, Katowice, Poland, told this news organization that all the data point in the same direction for T1D management, to “look not only at A1c and blood glucose control but also lipids, hypertension, smoking status, all these risk factors recognized in type 2 ... are also important in T1D.”
The ‘Alarming’ Finding of CAD in Asymptomatic Patients
Michal Dubsky, MD, PhD, of the Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic, presented findings from 62 asymptomatic patients with T1D for > 10 years (mean, 36 years), with a mean A1c of 7.5% (58 mmol/mol), and no prior history of cardiovascular disease (CVD). They had slightly elevated CVD biomarkers, including a mean low-density lipoprotein (LDL) cholesterol level of 2.33 mmol/L, lipoprotein (a) level of 15 nmol/L, and N-terminal pro-B-type natriuretic peptide level of 125.3 ng/L.
All underwent a noninvasive carotid ultrasound and coronary artery calcium (CAC) scoring. Of those, 12 patients had a CAC score > 400 and/or presence of two or more carotid plaques identified as high-risk.
Those 12 patients underwent coronary angiography and had a total of 29 vessels examined by optical coherence tomography (OCT), “an invasive intravascular method for assessing coronary atherosclerosis that is far more sensitive than standard coronary angiography, especially for the detection of high-risk vulnerable plaques without a hemodynamically significant stenosis,” Dr. Dubsky explained.
Coronary angiography showed obstructive CAD in 5 of the 12 patients. Their mean calcium score was 950 and mean number of carotid plaques was 2.8. Features associated with plaque vulnerability included microphage accumulation in 24 vessels, lipid-rich plaques in 23, spotty calcium in 19, and neovascularizations in 13.
Thin-cap fibroatheroma, a strong predictor of plaque rupture, was present in 7 of the 12 patients (58.3%), and four had features of very high-risk plaques, defined as thin-cap fibroatheroma with a minimal lumen area < 3.5 mm2, a lipid arch > 180 degrees, and macrophages.
“Our study showed that asymptomatic T1D patients with high CAC score and carotid plaques had very severe OCT findings. We observed a significant proportion of high-risk lesions potentially associated with plaque rupture and risk of CV death. Therefore, we believe these patients should be treated as very high-risk with target LDL below 1.4 mmol/L (55 mg/dL), even though they are completely asymptomatic,” Dr. Dubsky concluded.
He added that because OCT is invasive and costly, the CAC score can be used to guide the decision for statin use, with any score above 100 considered elevated risk.
Study coauthor Martin Haluzik, MD, professor of internal medicine in the Charles University, Prague, Czech Republic, told this news organization, “I think it’s very alarming because some of these are basically very healthy-looking young people, so you don’t really expect them to have significant cardiovascular complications already or significant plaques. I think it shows that we should be more proactive in looking into the risk of cardiovascular complications and in looking into the early cardiovascular changes.”
Later Diagnosis Doesn’t Always Protect: Risk Seen in Adult-Onset T1D
Yuxia Wei, a PhD student at the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, presented an analysis of data from Sweden’s national health databases comparing cardiovascular outcomes between 10,184 people diagnosed with T1D at ages 18-29 years, 30-39 years, and ≥ 40 years; another 375,523 people diagnosed with T2D at those ages; and 509,172 population controls matched for age, sex, and county.
Those diagnosed after age 40 years had higher A1c levels and were less likely to be using insulin pumps than those diagnosed at younger adult ages.
Compared with population controls, at a median of about 7 years of follow-up, people with T1D had significantly higher all-cause mortality at all diagnosis age groups, with a hazard ratio of 1.71. This rose to 2.78 for those diagnosed at age 30-39 years.
Compared with those with T2D, the mortality risks weren’t significantly different at any age, but the risks for non-cardiovascular death, including from cancer and infection, were significantly higher among those diagnosed after age 40 years (1.31 overall). Those diagnosed with T1D at any adult age had lower risks for major cardiovascular events than those diagnosed with T2D. Hazard ratios ranged from 0.27 for those diagnosed at age 18-29 years to 0.78 for those diagnosed after the age of 40 years.
Smoking and A1c above target were the greatest contributors to mortality. Those two factors, along with body mass index (BMI), were the strongest contributors to major adverse cardiovascular events (MACE).
“Adult-onset T1D carries excess risk of death and cardiovascular disease, without obvious attenuation over age at diagnosis…Smoking, A1c, and BMI are the key factors to be managed to improve prognosis in adult-onset T1D,” Ms. Wei concluded.
BMI: Often Overlooked in T1D, but a Major CVD Risk Factor
Two studies examined the link between overweight/obesity and cardiovascular risk in T1D. One, by Laurence Salle, MCU PH, of the Endocrinology, Diabetes and Metabolic Diseases Department at CHU Limoges, France, was a prospective, longitudinal cohort study of 2367 people with T1D at 68 centers in France who didn’t have a cardiovascular history at baseline.
Of those, 51% had normal BMI (18.5-24.9), 31% had overweight (25-29.9), and 18% had obesity (≥ 30). Cardiovascular risk factors, including LDL cholesterol, triglycerides, and hypertension increased with an increasing BMI. The 10-year CVD risk was significantly higher for those with overweight (9.61%) and obesity (9.93%) than for those with normal weight (7.24%), in both men and women.
However, BMI was found to be an independent predictor of 10-year high cardiovascular risk in men but not women, while waist:height ratio independently predicted risk in both men and women, Dr. Salle reported.
The second BMI study, from Enrique Soto-Pedre, MBBS, of the Division of Population Health and Genomics at the University of Dundee, Scotland, presented data on a retrospective follow-up from 1995 to 2019 of 1973 people with T1D aged > 18 years at diagnosis (42% women; mean age, 34.2 years; 18.9% had obesity.
After 10 years of follow-up, those with overweight and obesity had significantly higher odds of developing arterial hypertension, even among those taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, with statistically significant adjusted hazard ratios of 1.73 and 3.37 for the obese and overweight groups, respectively.
MACE were significantly more common among those with obesity, with an adjusted hazard ratio of 2.95, as was acute myocardial infarction, 3.33.
“These results emphasize the importance of incorporating weight management into the overall management of individuals with T1D. No one has doubts about weight management in T2D, but in type 1, it’s not so clear. One of the main [concerns] would be safety [in terms of hypoglycemia],” Dr. Soto-Pedre concluded.
Call for Action: Cumulative Glucose and Lipid Exposures Increase Risk
Dr. Bergdal presented data on the effects of cumulative glycemia and lipids on the risk for CAD in 3495 adults with T1D who had been diagnosed prior to the age of 40 years. The history of CAD or stroke was exclusion criteria. There were a total of 534 CAD events within a median follow-up of 19.4 years.
Cumulative glycemia, LDL cholesterol, triglycerides, and non–high-density lipoprotein cholesterol exposures were all significantly associated with CAD risk (P < .001 for all). With an adjustment for confounders, the highest tertile of glycemia was associated with a twofold increased risk for CAD. Both hyperglycemia and dyslipidemia were independently associated with CAD risk, Dr. Bergdal reported.
“It’s important to minimize the time spent above A1c 7%, and lipid management in T1D must not be forgotten,” she said, prior to issuing her call for action.
Dr. Haluzik reported receiving honoraria for talks and/or consultancy and/or research funding from Eli Lilly, Novo Nordisk, Sanofi, AstraZeneca, Mundipharma, Bristol Myers Squibb, Amgen, Boehringer Ingelheim, Janssen, Ypsomed, and Johnson & Johnson. The presenters had no disclosures.
A version of this article first appeared on Medscape.com.
FROM EASD 2024
Childhood-Onset Atopic Dermatitis Adds Burden in Adulthood
AMSTERDAM — There is a mountain of evidence that atopic dermatitis (AD) exerts a large negative impact on quality of life, but a unique study with
These data, drawn from the ambitious Scars of Life (SOL) project, “suggest that childhood AD persisting into adulthood is its own phenotype,” reported Jonathan I. Silverberg, MD, PhD, director of clinical research, Department of Dermatology, George Washington University, Washington, DC.
One reasonable message from these data is that the failure to achieve adequate control of AD in children, whether by a late start of systemic agents or other reasons, results in a greater lifetime burden of disease when the burden beyond physical symptoms is measured, according to Dr. Silverberg.
More Than 30,000 From Five Continents Participated
In the SOL project, which was designed to analyze how the age of AD onset affects the severity of symptoms and quality of life, completed questionnaires were collected from 30,801 individuals in 27 countries on five continents. The questions, which elicited data to measure the burden of AD, were developed in association with several professional and patient associations with an interest in AD, including the National Eczema Association.
The SOL project has produced an enormous amount of data in four distinct groups, but Dr. Silverberg, speaking in a late-breaking news session at the annual congress of the European Academy of Dermatology and Venereology, focused on a comparison between the 2875 participants who had AD in childhood that has persisted into adulthood and the 7383 adults with adult-onset AD. Data from the other two subsets in SOL — AD in childhood but not in adulthood and no AD in either phase of life — are expected to fuel an extended series of publications.
In the two groups, baseline characteristics were similar with about 60% reporting moderate to severe symptoms and a median age of about 37 years. The proportion of women was 61% in both groups.
Using the PUSH-D questionnaire, which Dr. Silverberg described as a validated tool for gauging a sense of stigmatization, the greater burden of AD was remarkably consistent for those with childhood-onset AD vs adult-onset AD. With higher scores representing a greater sense of stigmatization, the differences in the overall score (23.0 vs 18.1; P < .0001) were highly significant as was every other domain evaluated.
For all five social behavior domains, such as avoiding contact in public and wariness of approaching people spontaneously, having AD onset in childhood persisting into adulthood produced significantly higher scores than having AD onset in adulthood, with no exceptions (P < .001 for all).
AD From Childhood Consistently Results in Worse Outcomes
Providing examples for some of the other 12 domains, Dr. Silverberg maintained that feelings of shame and psychological discomfort were always greater in adults with AD persistent since childhood vs AD starting in adulthood. The P values for these outcomes, such as experiencing bias at work or reporting a sense that others avoided them, were typically highly significant (P < .001).
Compared with those whose AD started in adulthood, “adults with atopic eczema that started during childhood have significantly more difficulties in their life, including occupational relationships, daily life, personal life, and partner or family relationships,” Dr. Silverberg reported.
He said that the data were controlled for multiple confounders, particularly greater severity of AD. He acknowledged that childhood onset might be considered a surrogate for more severe disease, but the data were controlled for this possibility.
Despite the fact that there are “thousands of studies across all age groups showing the burden of AD,” Dr. Silverberg considers these data to be unique by emphasizing the burden of chronicity rather than the impact of AD in any single moment in time.
For those with chronic AD from childhood, “the effect is not just on physical health but a deep negative influence on psychological and social aspects of life,” Dr. Silverberg said, suggesting that the independent effects of chronicity might be worth studying across other dermatologic diseases.
“Regulatory agencies focus on what you can do in that moment of time, losing the bigger picture of how patients are affected chronically,” he said, adding that this is an area of clinical research that should be further explored.
What the data further suggest “is that the earlier we intervene, the more likely patients will do better long term,” he said.
Data Provide Evidence of Systemic Therapy in Kids
For Gudrun Ratzinger, MD, of the Department of Dermatology and Venerology at the Medical University of Innsbruck in Austria, these are valuable data.
“When I prescribe systemic therapies to children, I often get resistance from the healthcare system and even other colleagues,” said Dr. Ratzinger, who was asked to comment on the results. “We are at a teaching hospital, but I often find that when patients return to their home physician, the systemic therapies are stopped.”
In her own practice, she believes the most effective therapies should be introduced in children and adults when complete control is not achieved on first-line drugs. “These data are very helpful for me in explaining to others the importance of effective treatment of atopic dermatitis in children,” she said.
Dr. Silverberg reported financial relationships with more than 40 pharmaceutical companies, including those that make drugs for AD. Dr. Ratzinger reported financial relationships with AbbVie, Almirall, Boehringer Ingelheim, Eli Lilly, Janssen, Leo Pharma, Novartis, Pelpharma, Pfizer, and UCB.
A version of this article first appeared on Medscape.com.
AMSTERDAM — There is a mountain of evidence that atopic dermatitis (AD) exerts a large negative impact on quality of life, but a unique study with
These data, drawn from the ambitious Scars of Life (SOL) project, “suggest that childhood AD persisting into adulthood is its own phenotype,” reported Jonathan I. Silverberg, MD, PhD, director of clinical research, Department of Dermatology, George Washington University, Washington, DC.
One reasonable message from these data is that the failure to achieve adequate control of AD in children, whether by a late start of systemic agents or other reasons, results in a greater lifetime burden of disease when the burden beyond physical symptoms is measured, according to Dr. Silverberg.
More Than 30,000 From Five Continents Participated
In the SOL project, which was designed to analyze how the age of AD onset affects the severity of symptoms and quality of life, completed questionnaires were collected from 30,801 individuals in 27 countries on five continents. The questions, which elicited data to measure the burden of AD, were developed in association with several professional and patient associations with an interest in AD, including the National Eczema Association.
The SOL project has produced an enormous amount of data in four distinct groups, but Dr. Silverberg, speaking in a late-breaking news session at the annual congress of the European Academy of Dermatology and Venereology, focused on a comparison between the 2875 participants who had AD in childhood that has persisted into adulthood and the 7383 adults with adult-onset AD. Data from the other two subsets in SOL — AD in childhood but not in adulthood and no AD in either phase of life — are expected to fuel an extended series of publications.
In the two groups, baseline characteristics were similar with about 60% reporting moderate to severe symptoms and a median age of about 37 years. The proportion of women was 61% in both groups.
Using the PUSH-D questionnaire, which Dr. Silverberg described as a validated tool for gauging a sense of stigmatization, the greater burden of AD was remarkably consistent for those with childhood-onset AD vs adult-onset AD. With higher scores representing a greater sense of stigmatization, the differences in the overall score (23.0 vs 18.1; P < .0001) were highly significant as was every other domain evaluated.
For all five social behavior domains, such as avoiding contact in public and wariness of approaching people spontaneously, having AD onset in childhood persisting into adulthood produced significantly higher scores than having AD onset in adulthood, with no exceptions (P < .001 for all).
AD From Childhood Consistently Results in Worse Outcomes
Providing examples for some of the other 12 domains, Dr. Silverberg maintained that feelings of shame and psychological discomfort were always greater in adults with AD persistent since childhood vs AD starting in adulthood. The P values for these outcomes, such as experiencing bias at work or reporting a sense that others avoided them, were typically highly significant (P < .001).
Compared with those whose AD started in adulthood, “adults with atopic eczema that started during childhood have significantly more difficulties in their life, including occupational relationships, daily life, personal life, and partner or family relationships,” Dr. Silverberg reported.
He said that the data were controlled for multiple confounders, particularly greater severity of AD. He acknowledged that childhood onset might be considered a surrogate for more severe disease, but the data were controlled for this possibility.
Despite the fact that there are “thousands of studies across all age groups showing the burden of AD,” Dr. Silverberg considers these data to be unique by emphasizing the burden of chronicity rather than the impact of AD in any single moment in time.
For those with chronic AD from childhood, “the effect is not just on physical health but a deep negative influence on psychological and social aspects of life,” Dr. Silverberg said, suggesting that the independent effects of chronicity might be worth studying across other dermatologic diseases.
“Regulatory agencies focus on what you can do in that moment of time, losing the bigger picture of how patients are affected chronically,” he said, adding that this is an area of clinical research that should be further explored.
What the data further suggest “is that the earlier we intervene, the more likely patients will do better long term,” he said.
Data Provide Evidence of Systemic Therapy in Kids
For Gudrun Ratzinger, MD, of the Department of Dermatology and Venerology at the Medical University of Innsbruck in Austria, these are valuable data.
“When I prescribe systemic therapies to children, I often get resistance from the healthcare system and even other colleagues,” said Dr. Ratzinger, who was asked to comment on the results. “We are at a teaching hospital, but I often find that when patients return to their home physician, the systemic therapies are stopped.”
In her own practice, she believes the most effective therapies should be introduced in children and adults when complete control is not achieved on first-line drugs. “These data are very helpful for me in explaining to others the importance of effective treatment of atopic dermatitis in children,” she said.
Dr. Silverberg reported financial relationships with more than 40 pharmaceutical companies, including those that make drugs for AD. Dr. Ratzinger reported financial relationships with AbbVie, Almirall, Boehringer Ingelheim, Eli Lilly, Janssen, Leo Pharma, Novartis, Pelpharma, Pfizer, and UCB.
A version of this article first appeared on Medscape.com.
AMSTERDAM — There is a mountain of evidence that atopic dermatitis (AD) exerts a large negative impact on quality of life, but a unique study with
These data, drawn from the ambitious Scars of Life (SOL) project, “suggest that childhood AD persisting into adulthood is its own phenotype,” reported Jonathan I. Silverberg, MD, PhD, director of clinical research, Department of Dermatology, George Washington University, Washington, DC.
One reasonable message from these data is that the failure to achieve adequate control of AD in children, whether by a late start of systemic agents or other reasons, results in a greater lifetime burden of disease when the burden beyond physical symptoms is measured, according to Dr. Silverberg.
More Than 30,000 From Five Continents Participated
In the SOL project, which was designed to analyze how the age of AD onset affects the severity of symptoms and quality of life, completed questionnaires were collected from 30,801 individuals in 27 countries on five continents. The questions, which elicited data to measure the burden of AD, were developed in association with several professional and patient associations with an interest in AD, including the National Eczema Association.
The SOL project has produced an enormous amount of data in four distinct groups, but Dr. Silverberg, speaking in a late-breaking news session at the annual congress of the European Academy of Dermatology and Venereology, focused on a comparison between the 2875 participants who had AD in childhood that has persisted into adulthood and the 7383 adults with adult-onset AD. Data from the other two subsets in SOL — AD in childhood but not in adulthood and no AD in either phase of life — are expected to fuel an extended series of publications.
In the two groups, baseline characteristics were similar with about 60% reporting moderate to severe symptoms and a median age of about 37 years. The proportion of women was 61% in both groups.
Using the PUSH-D questionnaire, which Dr. Silverberg described as a validated tool for gauging a sense of stigmatization, the greater burden of AD was remarkably consistent for those with childhood-onset AD vs adult-onset AD. With higher scores representing a greater sense of stigmatization, the differences in the overall score (23.0 vs 18.1; P < .0001) were highly significant as was every other domain evaluated.
For all five social behavior domains, such as avoiding contact in public and wariness of approaching people spontaneously, having AD onset in childhood persisting into adulthood produced significantly higher scores than having AD onset in adulthood, with no exceptions (P < .001 for all).
AD From Childhood Consistently Results in Worse Outcomes
Providing examples for some of the other 12 domains, Dr. Silverberg maintained that feelings of shame and psychological discomfort were always greater in adults with AD persistent since childhood vs AD starting in adulthood. The P values for these outcomes, such as experiencing bias at work or reporting a sense that others avoided them, were typically highly significant (P < .001).
Compared with those whose AD started in adulthood, “adults with atopic eczema that started during childhood have significantly more difficulties in their life, including occupational relationships, daily life, personal life, and partner or family relationships,” Dr. Silverberg reported.
He said that the data were controlled for multiple confounders, particularly greater severity of AD. He acknowledged that childhood onset might be considered a surrogate for more severe disease, but the data were controlled for this possibility.
Despite the fact that there are “thousands of studies across all age groups showing the burden of AD,” Dr. Silverberg considers these data to be unique by emphasizing the burden of chronicity rather than the impact of AD in any single moment in time.
For those with chronic AD from childhood, “the effect is not just on physical health but a deep negative influence on psychological and social aspects of life,” Dr. Silverberg said, suggesting that the independent effects of chronicity might be worth studying across other dermatologic diseases.
“Regulatory agencies focus on what you can do in that moment of time, losing the bigger picture of how patients are affected chronically,” he said, adding that this is an area of clinical research that should be further explored.
What the data further suggest “is that the earlier we intervene, the more likely patients will do better long term,” he said.
Data Provide Evidence of Systemic Therapy in Kids
For Gudrun Ratzinger, MD, of the Department of Dermatology and Venerology at the Medical University of Innsbruck in Austria, these are valuable data.
“When I prescribe systemic therapies to children, I often get resistance from the healthcare system and even other colleagues,” said Dr. Ratzinger, who was asked to comment on the results. “We are at a teaching hospital, but I often find that when patients return to their home physician, the systemic therapies are stopped.”
In her own practice, she believes the most effective therapies should be introduced in children and adults when complete control is not achieved on first-line drugs. “These data are very helpful for me in explaining to others the importance of effective treatment of atopic dermatitis in children,” she said.
Dr. Silverberg reported financial relationships with more than 40 pharmaceutical companies, including those that make drugs for AD. Dr. Ratzinger reported financial relationships with AbbVie, Almirall, Boehringer Ingelheim, Eli Lilly, Janssen, Leo Pharma, Novartis, Pelpharma, Pfizer, and UCB.
A version of this article first appeared on Medscape.com.
FROM EADV 2024
Sex and Gender Influence Outcomes in Colorectal Cancer
BARCELONA, SPAIN — , according to experts speaking here at the European Society for Medical Oncology (ESMO) Annual Meeting 2024.
“The concepts of gender and sex are not at all new in oncology, but what is needed is a renewed focus on them and the prospective collection of data in this regard,” said Kathrin Heinrich, MD, of University Hospital LMU Munich, Germany.
Sex and Gender: What’s New?
Speaking at the conference, Dr. Heinrich cited a 2020 study published in The Lancet that stated, “Sex and gender are the foundation of precision medicine, and their differences should guide decision-making processes to promote gender equity.”
Sex differences have clear biological and pathophysiological consequences in oncology. Available data show differences between men and women in terms of gene expression, epigenetics, metabolomics, tumor microenvironment, immune system, and microbiome. These are all critical for understanding tumor biology and identifying new treatments.
Colorectal cancer provides an excellent example of how sex differences can influence treatment outcomes.
From an incidence perspective, the numbers reported by the large epidemiological GLOBOCAN study are quite similar between the two sexes, with men accounting for 56% of patients and women for 44%.
However, there are noticeable differences in tumor characteristics, with women more frequently presenting with right-sided colon tumors and BRAF mutations; both features associated with a worse prognosis.
Sex also affects body composition, influencing the percentage of metabolically active body mass, which can alter the effectiveness and distribution of a drug and the necessary dose to achieve the desired effect.
“Despite this evidence, clinical practice often overlooks differences between the sexes when planning therapies,” Dr. Heinrich said, also recalling how in many cases the side effects of treatments — from chemotherapy to immunotherapy — differ in intensity and type between men and women.
Toward a More Targeted and Inclusive Approach
Sex is a well-defined concept from a biological standpoint and, consequently, the differences between the sexes are easy to identify. Analyzing gender differences is much more complex.
“It is not enough to tick the male or female box on a questionnaire. It is necessary to consider more complex aspects to measure, such as identity, role, and gender relations,” Dr. Heinrich said, also presenting a list of specific questionnaires to assess these components.
In today’s oncology, however, such questionnaires are mainly used to analyze secondary outcomes such as quality of life, while examples from other areas of medicine, particularly cardiology, show how questionnaires on gender can predict some clinical outcomes better than those on sex alone and that studies considering sex and gender are feasible.
Gender identity influences many aspects of health, such as attitudes toward prevention, the seeking of information and medical care, and risk behaviors. “The new approach to discussing sex and gender in oncology is to consider these factors in therapeutic decisions,” Dr. Heinrich said. “I hope that within a few years this will be fully achievable, thanks to the inclusion in our studies of gender scores, ad hoc patient-reported outcomes, and information related, for example, to menopausal status or the number of pregnancies,” she added.
To harness the differences between sex and gender in favor of the patient, however, it is also necessary to change the approach to clinical studies. Currently, data on these aspects are typically collected retrospectively. However, they should be integrated prospectively from the study’s beginning.
“We look at increasingly smaller subgroups of patients, at mutations affecting 1%-2% of our patients, but we do not collect data on sex or menopausal status, which are actually extremely simple to record,” Dr. Heinrich said, calling for more inclusive studies, especially involving the LGBTQI+ community, traditionally excluded from clinical trials and many services.
“Fortunately, we live in an era in which sensitivity towards this community is continuously increasing. We must gather information on this population, which fully belongs to what we scientifically define as the ‘real-world’ approach.”
Dr. Heinrich declared honoraria, consulting and advisory roles, and travel support from several companies, including Amgen, BMS, Merck, MSD, Roche-Janssen, Taiho, Servier, and Streamed Up.
This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
BARCELONA, SPAIN — , according to experts speaking here at the European Society for Medical Oncology (ESMO) Annual Meeting 2024.
“The concepts of gender and sex are not at all new in oncology, but what is needed is a renewed focus on them and the prospective collection of data in this regard,” said Kathrin Heinrich, MD, of University Hospital LMU Munich, Germany.
Sex and Gender: What’s New?
Speaking at the conference, Dr. Heinrich cited a 2020 study published in The Lancet that stated, “Sex and gender are the foundation of precision medicine, and their differences should guide decision-making processes to promote gender equity.”
Sex differences have clear biological and pathophysiological consequences in oncology. Available data show differences between men and women in terms of gene expression, epigenetics, metabolomics, tumor microenvironment, immune system, and microbiome. These are all critical for understanding tumor biology and identifying new treatments.
Colorectal cancer provides an excellent example of how sex differences can influence treatment outcomes.
From an incidence perspective, the numbers reported by the large epidemiological GLOBOCAN study are quite similar between the two sexes, with men accounting for 56% of patients and women for 44%.
However, there are noticeable differences in tumor characteristics, with women more frequently presenting with right-sided colon tumors and BRAF mutations; both features associated with a worse prognosis.
Sex also affects body composition, influencing the percentage of metabolically active body mass, which can alter the effectiveness and distribution of a drug and the necessary dose to achieve the desired effect.
“Despite this evidence, clinical practice often overlooks differences between the sexes when planning therapies,” Dr. Heinrich said, also recalling how in many cases the side effects of treatments — from chemotherapy to immunotherapy — differ in intensity and type between men and women.
Toward a More Targeted and Inclusive Approach
Sex is a well-defined concept from a biological standpoint and, consequently, the differences between the sexes are easy to identify. Analyzing gender differences is much more complex.
“It is not enough to tick the male or female box on a questionnaire. It is necessary to consider more complex aspects to measure, such as identity, role, and gender relations,” Dr. Heinrich said, also presenting a list of specific questionnaires to assess these components.
In today’s oncology, however, such questionnaires are mainly used to analyze secondary outcomes such as quality of life, while examples from other areas of medicine, particularly cardiology, show how questionnaires on gender can predict some clinical outcomes better than those on sex alone and that studies considering sex and gender are feasible.
Gender identity influences many aspects of health, such as attitudes toward prevention, the seeking of information and medical care, and risk behaviors. “The new approach to discussing sex and gender in oncology is to consider these factors in therapeutic decisions,” Dr. Heinrich said. “I hope that within a few years this will be fully achievable, thanks to the inclusion in our studies of gender scores, ad hoc patient-reported outcomes, and information related, for example, to menopausal status or the number of pregnancies,” she added.
To harness the differences between sex and gender in favor of the patient, however, it is also necessary to change the approach to clinical studies. Currently, data on these aspects are typically collected retrospectively. However, they should be integrated prospectively from the study’s beginning.
“We look at increasingly smaller subgroups of patients, at mutations affecting 1%-2% of our patients, but we do not collect data on sex or menopausal status, which are actually extremely simple to record,” Dr. Heinrich said, calling for more inclusive studies, especially involving the LGBTQI+ community, traditionally excluded from clinical trials and many services.
“Fortunately, we live in an era in which sensitivity towards this community is continuously increasing. We must gather information on this population, which fully belongs to what we scientifically define as the ‘real-world’ approach.”
Dr. Heinrich declared honoraria, consulting and advisory roles, and travel support from several companies, including Amgen, BMS, Merck, MSD, Roche-Janssen, Taiho, Servier, and Streamed Up.
This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
BARCELONA, SPAIN — , according to experts speaking here at the European Society for Medical Oncology (ESMO) Annual Meeting 2024.
“The concepts of gender and sex are not at all new in oncology, but what is needed is a renewed focus on them and the prospective collection of data in this regard,” said Kathrin Heinrich, MD, of University Hospital LMU Munich, Germany.
Sex and Gender: What’s New?
Speaking at the conference, Dr. Heinrich cited a 2020 study published in The Lancet that stated, “Sex and gender are the foundation of precision medicine, and their differences should guide decision-making processes to promote gender equity.”
Sex differences have clear biological and pathophysiological consequences in oncology. Available data show differences between men and women in terms of gene expression, epigenetics, metabolomics, tumor microenvironment, immune system, and microbiome. These are all critical for understanding tumor biology and identifying new treatments.
Colorectal cancer provides an excellent example of how sex differences can influence treatment outcomes.
From an incidence perspective, the numbers reported by the large epidemiological GLOBOCAN study are quite similar between the two sexes, with men accounting for 56% of patients and women for 44%.
However, there are noticeable differences in tumor characteristics, with women more frequently presenting with right-sided colon tumors and BRAF mutations; both features associated with a worse prognosis.
Sex also affects body composition, influencing the percentage of metabolically active body mass, which can alter the effectiveness and distribution of a drug and the necessary dose to achieve the desired effect.
“Despite this evidence, clinical practice often overlooks differences between the sexes when planning therapies,” Dr. Heinrich said, also recalling how in many cases the side effects of treatments — from chemotherapy to immunotherapy — differ in intensity and type between men and women.
Toward a More Targeted and Inclusive Approach
Sex is a well-defined concept from a biological standpoint and, consequently, the differences between the sexes are easy to identify. Analyzing gender differences is much more complex.
“It is not enough to tick the male or female box on a questionnaire. It is necessary to consider more complex aspects to measure, such as identity, role, and gender relations,” Dr. Heinrich said, also presenting a list of specific questionnaires to assess these components.
In today’s oncology, however, such questionnaires are mainly used to analyze secondary outcomes such as quality of life, while examples from other areas of medicine, particularly cardiology, show how questionnaires on gender can predict some clinical outcomes better than those on sex alone and that studies considering sex and gender are feasible.
Gender identity influences many aspects of health, such as attitudes toward prevention, the seeking of information and medical care, and risk behaviors. “The new approach to discussing sex and gender in oncology is to consider these factors in therapeutic decisions,” Dr. Heinrich said. “I hope that within a few years this will be fully achievable, thanks to the inclusion in our studies of gender scores, ad hoc patient-reported outcomes, and information related, for example, to menopausal status or the number of pregnancies,” she added.
To harness the differences between sex and gender in favor of the patient, however, it is also necessary to change the approach to clinical studies. Currently, data on these aspects are typically collected retrospectively. However, they should be integrated prospectively from the study’s beginning.
“We look at increasingly smaller subgroups of patients, at mutations affecting 1%-2% of our patients, but we do not collect data on sex or menopausal status, which are actually extremely simple to record,” Dr. Heinrich said, calling for more inclusive studies, especially involving the LGBTQI+ community, traditionally excluded from clinical trials and many services.
“Fortunately, we live in an era in which sensitivity towards this community is continuously increasing. We must gather information on this population, which fully belongs to what we scientifically define as the ‘real-world’ approach.”
Dr. Heinrich declared honoraria, consulting and advisory roles, and travel support from several companies, including Amgen, BMS, Merck, MSD, Roche-Janssen, Taiho, Servier, and Streamed Up.
This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
FROM ESMO CONGRESS 2024
McDonald Criteria Update Aims to Simplify, Speed MS Diagnosis
COPENHAGEN —
Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required.
The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.
Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.
Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.
Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.
Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said.
Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
DIS Alone Sufficient?
The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.
The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.
Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).
The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.
Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
Stricter Criteria
The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).
The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.
Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS.
Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.
During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial.
These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.
Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.
The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.
Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”
“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”
Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme.
A version of this article appeared on Medscape.com.
COPENHAGEN —
Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required.
The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.
Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.
Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.
Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.
Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said.
Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
DIS Alone Sufficient?
The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.
The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.
Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).
The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.
Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
Stricter Criteria
The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).
The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.
Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS.
Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.
During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial.
These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.
Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.
The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.
Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”
“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”
Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme.
A version of this article appeared on Medscape.com.
COPENHAGEN —
Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required.
The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.
Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.
Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.
Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.
Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said.
Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
DIS Alone Sufficient?
The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.
The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.
Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).
The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.
Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
Stricter Criteria
The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).
The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.
Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS.
Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.
During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial.
These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.
Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.
The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.
Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”
“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”
Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme.
A version of this article appeared on Medscape.com.
FROM ECTRIMS 2024
Genetically Driven Depression Tied to Increased MS Disease Activity
COPENHAGEN — , early results of a new study showed.
Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.
This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.
The findings were presented at the 2024 ECTRIMS annual meeting.
Common Comorbidity
Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.
The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.
The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.
The median follow-up in these cohorts ranged from 3 to 5 years.
Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.
The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
Inherited Variants
To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.
Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.
Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.
Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).
“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”
Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
‘An Ideal Marker’
Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”
The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.
Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.
Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.
A limitation of the study was that it included only participants of European ancestry.
Clinical Implications Unclear
Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.
“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”
Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.
“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”
The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.
Dr. Kowalec reported no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
COPENHAGEN — , early results of a new study showed.
Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.
This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.
The findings were presented at the 2024 ECTRIMS annual meeting.
Common Comorbidity
Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.
The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.
The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.
The median follow-up in these cohorts ranged from 3 to 5 years.
Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.
The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
Inherited Variants
To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.
Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.
Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.
Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).
“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”
Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
‘An Ideal Marker’
Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”
The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.
Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.
Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.
A limitation of the study was that it included only participants of European ancestry.
Clinical Implications Unclear
Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.
“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”
Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.
“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”
The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.
Dr. Kowalec reported no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
COPENHAGEN — , early results of a new study showed.
Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.
This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.
The findings were presented at the 2024 ECTRIMS annual meeting.
Common Comorbidity
Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.
The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.
The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.
The median follow-up in these cohorts ranged from 3 to 5 years.
Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.
The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
Inherited Variants
To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.
Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.
Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.
Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).
“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”
Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
‘An Ideal Marker’
Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”
The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.
Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.
Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.
A limitation of the study was that it included only participants of European ancestry.
Clinical Implications Unclear
Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.
“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”
Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.
“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”
The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.
Dr. Kowalec reported no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
FROM ECTRIMS 2024