Miriam E. Tucker

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

New consensus recommendations address diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), with advice that may also be helpful for patients with lingering symptoms following acute COVID-19 infection.

VioletaStoimenova/Getty Images

The document was published online Aug. 25, 2021, in the Mayo Clinic Proceedings by the 23-member U.S. ME/CFS Clinician Coalition, headed by Lucinda Bateman, MD, of the Bateman Horne Center of Excellence, Salt Lake City. The document is the culmination of work that began with a summit held at the center in March 2018.

The target audience is both generalist and specialist health care providers. While ME/CFS is estimated to affect up to 2.5 million Americans, more than 90% are either undiagnosed or misdiagnosed with other conditions such as depression. And those who are diagnosed often receive inappropriate, outdated treatments such as psychotherapy and exercise prescriptions.

“Despite myalgic encephalomyelitis/chronic fatigue syndrome affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful,” Dr. Bateman and colleagues wrote.

The urgency of appropriate recognition and management of ME/CFS has increased as growing numbers of people are exhibiting signs and symptoms of ME/CFS following acute COVID-19 infection. This isn’t surprising because the illness has long been linked to other infections, including Epstein-Barr virus, the authors noted.

The document covers the epidemiology, impact, and prognosis of ME/CFS, as well as etiology and pathophysiology. “Scientific studies demonstrate multiple dysfunctional organ systems, including neuro, immune, and metabolic, in ME/CFS. These findings are not explained merely by deconditioning,” document coauthor Lily Chu, MD, an independent consultant in Burlingame, Calif., said in an interview.

The document reviews the 2015 U.S. Institute of Medicine (now Academy of Medicine) diagnostic criteria that are now also recommended by the Centers for Disease Control and Prevention. They are based on four main symptoms: substantial reduction or impairment in the ability to engage in preillness levels of occupational, educational, social or personal activities for longer than 6 months; postexertional malaise, a worsening of all current symptoms, that patients often describe as a “crash”; unrefreshing sleep; and cognitive impairment and/or orthostatic intolerance.

“The new diagnostic criteria focusing on the key symptom of postexertional malaise rather than chronic fatigue, which is common in many conditions, may make the diagnostic process quicker and more accurate. Diagnosis now is both an inclusionary and not just exclusionary process, so it’s not necessary to eliminate all causes of fatigue. Diagnose patients who fit the criteria and be alert for it in people with persistent symptoms post COVID,” Dr. Chu said.

The document provides advice for taking a clinical history to obtain the information necessary for making the diagnosis, including use of laboratory testing to rule out other conditions. Physical exams, while they may not reveal specific abnormalities, may help in identifying comorbidities and ruling out alternative diagnoses.

A long list of nonpharmacologic and pharmacologic treatment and management approaches is offered for each of the individual core and common ME/CFS symptoms, including postexertional malaise, orthostatic intolerance, sleep issues, cognitive dysfunction and fatigue, immune dysfunction, pain, and gastrointestinal issues.

The document recommends against using the “outdated standard of care” cognitive-behavioral therapy and graded exercise therapy as primary treatments for the illness. Instead, the authors recommend teaching patients “pacing,” an individualized approach to energy conservation aimed at minimizing the frequency, duration, and severity of postexertional malaise.

Clinicians are also advised to assess patients’ daily living needs and provide support, including acquiring handicap placards, work or school accommodations, and disability benefits.

“There are things clinicians can do now to help patients even without a disease-modifying treatment. These are actions they are already familiar with and carry out for people with other chronic diseases, which often have limited treatment options as well. Don’t underestimate the importance and value of supportive care for patients.” Dr. Chu said.

The recommendations are based primarily on clinical expertise because there are very few randomized trials, and much of the evidence from other types of trials has been flawed, document coauthor Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said in an interview.

“The sad reality is there aren’t very many large randomized clinical trials with this illness and so what a group of very experienced clinicians did was to gather their collective experience and report it as that. It’s largely uncontrolled experience, but from people who have seen a lot of patients, for what it’s worth to the medical community.”

Dr. Komaroff also advised that clinicians watch out for ME/CFS in patients with long COVID. “If we find that those called long COVID meet ME/CFS criteria, the reason for knowing that is that there are already some treatments that according to experienced clinicians are helpful for ME/CFS, and it would be perfectly appropriate to try some of them in long COVID, particularly the ones that have minimal adverse reactions.”

The guidelines project was supported by the Open Medicine Foundation. Dr. Komaroff reported receiving personal fees from Serimmune outside the submitted work. Dr. Chu has no disclosures.

New consensus recommendations address diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), with advice that may also be helpful for patients with lingering symptoms following acute COVID-19 infection.

VioletaStoimenova/Getty Images

The document was published online Aug. 25, 2021, in the Mayo Clinic Proceedings by the 23-member U.S. ME/CFS Clinician Coalition, headed by Lucinda Bateman, MD, of the Bateman Horne Center of Excellence, Salt Lake City. The document is the culmination of work that began with a summit held at the center in March 2018.

The target audience is both generalist and specialist health care providers. While ME/CFS is estimated to affect up to 2.5 million Americans, more than 90% are either undiagnosed or misdiagnosed with other conditions such as depression. And those who are diagnosed often receive inappropriate, outdated treatments such as psychotherapy and exercise prescriptions.

“Despite myalgic encephalomyelitis/chronic fatigue syndrome affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful,” Dr. Bateman and colleagues wrote.

The urgency of appropriate recognition and management of ME/CFS has increased as growing numbers of people are exhibiting signs and symptoms of ME/CFS following acute COVID-19 infection. This isn’t surprising because the illness has long been linked to other infections, including Epstein-Barr virus, the authors noted.

The document covers the epidemiology, impact, and prognosis of ME/CFS, as well as etiology and pathophysiology. “Scientific studies demonstrate multiple dysfunctional organ systems, including neuro, immune, and metabolic, in ME/CFS. These findings are not explained merely by deconditioning,” document coauthor Lily Chu, MD, an independent consultant in Burlingame, Calif., said in an interview.

The document reviews the 2015 U.S. Institute of Medicine (now Academy of Medicine) diagnostic criteria that are now also recommended by the Centers for Disease Control and Prevention. They are based on four main symptoms: substantial reduction or impairment in the ability to engage in preillness levels of occupational, educational, social or personal activities for longer than 6 months; postexertional malaise, a worsening of all current symptoms, that patients often describe as a “crash”; unrefreshing sleep; and cognitive impairment and/or orthostatic intolerance.

“The new diagnostic criteria focusing on the key symptom of postexertional malaise rather than chronic fatigue, which is common in many conditions, may make the diagnostic process quicker and more accurate. Diagnosis now is both an inclusionary and not just exclusionary process, so it’s not necessary to eliminate all causes of fatigue. Diagnose patients who fit the criteria and be alert for it in people with persistent symptoms post COVID,” Dr. Chu said.

The document provides advice for taking a clinical history to obtain the information necessary for making the diagnosis, including use of laboratory testing to rule out other conditions. Physical exams, while they may not reveal specific abnormalities, may help in identifying comorbidities and ruling out alternative diagnoses.

A long list of nonpharmacologic and pharmacologic treatment and management approaches is offered for each of the individual core and common ME/CFS symptoms, including postexertional malaise, orthostatic intolerance, sleep issues, cognitive dysfunction and fatigue, immune dysfunction, pain, and gastrointestinal issues.

The document recommends against using the “outdated standard of care” cognitive-behavioral therapy and graded exercise therapy as primary treatments for the illness. Instead, the authors recommend teaching patients “pacing,” an individualized approach to energy conservation aimed at minimizing the frequency, duration, and severity of postexertional malaise.

Clinicians are also advised to assess patients’ daily living needs and provide support, including acquiring handicap placards, work or school accommodations, and disability benefits.

“There are things clinicians can do now to help patients even without a disease-modifying treatment. These are actions they are already familiar with and carry out for people with other chronic diseases, which often have limited treatment options as well. Don’t underestimate the importance and value of supportive care for patients.” Dr. Chu said.

The recommendations are based primarily on clinical expertise because there are very few randomized trials, and much of the evidence from other types of trials has been flawed, document coauthor Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said in an interview.

“The sad reality is there aren’t very many large randomized clinical trials with this illness and so what a group of very experienced clinicians did was to gather their collective experience and report it as that. It’s largely uncontrolled experience, but from people who have seen a lot of patients, for what it’s worth to the medical community.”

Dr. Komaroff also advised that clinicians watch out for ME/CFS in patients with long COVID. “If we find that those called long COVID meet ME/CFS criteria, the reason for knowing that is that there are already some treatments that according to experienced clinicians are helpful for ME/CFS, and it would be perfectly appropriate to try some of them in long COVID, particularly the ones that have minimal adverse reactions.”

The guidelines project was supported by the Open Medicine Foundation. Dr. Komaroff reported receiving personal fees from Serimmune outside the submitted work. Dr. Chu has no disclosures.

New consensus recommendations address diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), with advice that may also be helpful for patients with lingering symptoms following acute COVID-19 infection.

VioletaStoimenova/Getty Images

The document was published online Aug. 25, 2021, in the Mayo Clinic Proceedings by the 23-member U.S. ME/CFS Clinician Coalition, headed by Lucinda Bateman, MD, of the Bateman Horne Center of Excellence, Salt Lake City. The document is the culmination of work that began with a summit held at the center in March 2018.

The target audience is both generalist and specialist health care providers. While ME/CFS is estimated to affect up to 2.5 million Americans, more than 90% are either undiagnosed or misdiagnosed with other conditions such as depression. And those who are diagnosed often receive inappropriate, outdated treatments such as psychotherapy and exercise prescriptions.

“Despite myalgic encephalomyelitis/chronic fatigue syndrome affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful,” Dr. Bateman and colleagues wrote.

The urgency of appropriate recognition and management of ME/CFS has increased as growing numbers of people are exhibiting signs and symptoms of ME/CFS following acute COVID-19 infection. This isn’t surprising because the illness has long been linked to other infections, including Epstein-Barr virus, the authors noted.

The document covers the epidemiology, impact, and prognosis of ME/CFS, as well as etiology and pathophysiology. “Scientific studies demonstrate multiple dysfunctional organ systems, including neuro, immune, and metabolic, in ME/CFS. These findings are not explained merely by deconditioning,” document coauthor Lily Chu, MD, an independent consultant in Burlingame, Calif., said in an interview.

The document reviews the 2015 U.S. Institute of Medicine (now Academy of Medicine) diagnostic criteria that are now also recommended by the Centers for Disease Control and Prevention. They are based on four main symptoms: substantial reduction or impairment in the ability to engage in preillness levels of occupational, educational, social or personal activities for longer than 6 months; postexertional malaise, a worsening of all current symptoms, that patients often describe as a “crash”; unrefreshing sleep; and cognitive impairment and/or orthostatic intolerance.

“The new diagnostic criteria focusing on the key symptom of postexertional malaise rather than chronic fatigue, which is common in many conditions, may make the diagnostic process quicker and more accurate. Diagnosis now is both an inclusionary and not just exclusionary process, so it’s not necessary to eliminate all causes of fatigue. Diagnose patients who fit the criteria and be alert for it in people with persistent symptoms post COVID,” Dr. Chu said.

The document provides advice for taking a clinical history to obtain the information necessary for making the diagnosis, including use of laboratory testing to rule out other conditions. Physical exams, while they may not reveal specific abnormalities, may help in identifying comorbidities and ruling out alternative diagnoses.

A long list of nonpharmacologic and pharmacologic treatment and management approaches is offered for each of the individual core and common ME/CFS symptoms, including postexertional malaise, orthostatic intolerance, sleep issues, cognitive dysfunction and fatigue, immune dysfunction, pain, and gastrointestinal issues.

The document recommends against using the “outdated standard of care” cognitive-behavioral therapy and graded exercise therapy as primary treatments for the illness. Instead, the authors recommend teaching patients “pacing,” an individualized approach to energy conservation aimed at minimizing the frequency, duration, and severity of postexertional malaise.

Clinicians are also advised to assess patients’ daily living needs and provide support, including acquiring handicap placards, work or school accommodations, and disability benefits.

“There are things clinicians can do now to help patients even without a disease-modifying treatment. These are actions they are already familiar with and carry out for people with other chronic diseases, which often have limited treatment options as well. Don’t underestimate the importance and value of supportive care for patients.” Dr. Chu said.

The recommendations are based primarily on clinical expertise because there are very few randomized trials, and much of the evidence from other types of trials has been flawed, document coauthor Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said in an interview.

“The sad reality is there aren’t very many large randomized clinical trials with this illness and so what a group of very experienced clinicians did was to gather their collective experience and report it as that. It’s largely uncontrolled experience, but from people who have seen a lot of patients, for what it’s worth to the medical community.”

Dr. Komaroff also advised that clinicians watch out for ME/CFS in patients with long COVID. “If we find that those called long COVID meet ME/CFS criteria, the reason for knowing that is that there are already some treatments that according to experienced clinicians are helpful for ME/CFS, and it would be perfectly appropriate to try some of them in long COVID, particularly the ones that have minimal adverse reactions.”

The guidelines project was supported by the Open Medicine Foundation. Dr. Komaroff reported receiving personal fees from Serimmune outside the submitted work. Dr. Chu has no disclosures.

The Food and Drug Administration has expanded the label for Eli Lilly’s ultra–rapid-acting insulin lispro-aabc injection 100 units/mL (Lyumjev) for use in insulin pumps.

Olivier Le Moal/Getty Images

Lyumjev (insulin lispro-aabc injection 100 and 200 units/mL) was initially approved in June 2020 to improve glycemic control in adults with type 1 or type 2 diabetes. That formulation is administered by injection from a pen or syringe. Now, the 100 units/mL formulation can also be delivered via continuous subcutaneous insulin infusion with an insulin pump.

Lyumjev will compete with Novo Nordisk’s fast-acting insulin aspart injection 100 units/mL (Fiasp). Fiasp had a head start: it was approved for use in adults in the United States in September 2017. It was approved for use in insulin pumps in October 2019 and for use in children with diabetes in January 2020.

The new approval for Lyumjev was based on data from a phase 3 trial, PRONTO-Pump-2. That trial, which included 432 participants with type 1 diabetes, confirmed the drug’s safety and efficacy when used in pumps.

The study met the primary endpoint of noninferiority in reduction of hemoglobin A1c from baseline to week 16, compared with insulin lispro (Humalog 100 units/mL). It was superior in both 1-hour and 2-hour postprandial glucose reduction when delivered 0-2 minutes before meals, according to a Lilly statement.

Patients who cannot afford the drug can go to www.insulinaffordability.com for assistance. Those with commercial insurance can also visit www.Lyumjev.com to access the Lyumjev Savings Card.

Lyumjev is available in several global markets, including Japan and the European Union, where it is also approved for use in insulin pumps.

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

The Food and Drug Administration has expanded the label for Eli Lilly’s ultra–rapid-acting insulin lispro-aabc injection 100 units/mL (Lyumjev) for use in insulin pumps.

Olivier Le Moal/Getty Images

Lyumjev (insulin lispro-aabc injection 100 and 200 units/mL) was initially approved in June 2020 to improve glycemic control in adults with type 1 or type 2 diabetes. That formulation is administered by injection from a pen or syringe. Now, the 100 units/mL formulation can also be delivered via continuous subcutaneous insulin infusion with an insulin pump.

Lyumjev will compete with Novo Nordisk’s fast-acting insulin aspart injection 100 units/mL (Fiasp). Fiasp had a head start: it was approved for use in adults in the United States in September 2017. It was approved for use in insulin pumps in October 2019 and for use in children with diabetes in January 2020.

The new approval for Lyumjev was based on data from a phase 3 trial, PRONTO-Pump-2. That trial, which included 432 participants with type 1 diabetes, confirmed the drug’s safety and efficacy when used in pumps.

The study met the primary endpoint of noninferiority in reduction of hemoglobin A1c from baseline to week 16, compared with insulin lispro (Humalog 100 units/mL). It was superior in both 1-hour and 2-hour postprandial glucose reduction when delivered 0-2 minutes before meals, according to a Lilly statement.

Patients who cannot afford the drug can go to www.insulinaffordability.com for assistance. Those with commercial insurance can also visit www.Lyumjev.com to access the Lyumjev Savings Card.

Lyumjev is available in several global markets, including Japan and the European Union, where it is also approved for use in insulin pumps.

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

The Food and Drug Administration has expanded the label for Eli Lilly’s ultra–rapid-acting insulin lispro-aabc injection 100 units/mL (Lyumjev) for use in insulin pumps.

Olivier Le Moal/Getty Images

Lyumjev (insulin lispro-aabc injection 100 and 200 units/mL) was initially approved in June 2020 to improve glycemic control in adults with type 1 or type 2 diabetes. That formulation is administered by injection from a pen or syringe. Now, the 100 units/mL formulation can also be delivered via continuous subcutaneous insulin infusion with an insulin pump.

Lyumjev will compete with Novo Nordisk’s fast-acting insulin aspart injection 100 units/mL (Fiasp). Fiasp had a head start: it was approved for use in adults in the United States in September 2017. It was approved for use in insulin pumps in October 2019 and for use in children with diabetes in January 2020.

The new approval for Lyumjev was based on data from a phase 3 trial, PRONTO-Pump-2. That trial, which included 432 participants with type 1 diabetes, confirmed the drug’s safety and efficacy when used in pumps.

The study met the primary endpoint of noninferiority in reduction of hemoglobin A1c from baseline to week 16, compared with insulin lispro (Humalog 100 units/mL). It was superior in both 1-hour and 2-hour postprandial glucose reduction when delivered 0-2 minutes before meals, according to a Lilly statement.

Patients who cannot afford the drug can go to www.insulinaffordability.com for assistance. Those with commercial insurance can also visit www.Lyumjev.com to access the Lyumjev Savings Card.

Lyumjev is available in several global markets, including Japan and the European Union, where it is also approved for use in insulin pumps.

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

Nearly half of adults prescribed metformin after a new diagnosis of type 2 diabetes have stopped taking it by 1 year, new data show.

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The findings, from a retrospective analysis of administrative data from Alberta, Canada, during 2012-2017, also show that the fall-off in metformin adherence was most dramatic during the first 30 days, and in most cases, there was no concomitant substitution of another glucose-lowering drug.

While the majority with newly diagnosed type 2 diabetes were prescribed metformin as first-line therapy, patients started on other agents incurred far higher medication and health care costs.

The data were recently published online in Diabetic Medicine by David J. T. Campbell, MD, PhD, of the University of Calgary (Alta.), and colleagues.

“We realized that even if someone is prescribed metformin that doesn’t mean they’re staying on metformin even for a year ... the drop-off rate is really quite abrupt,” Dr. Campbell said in an interview. Most who discontinued had A1c levels above 7.5%, so it wasn’t that they no longer needed glucose-lowering medication, he noted.
 

People don’t understand chronic use; meds don’t make you feel better

One reason for the discontinuations, he said, is that patients might not realize they need to keep taking the medication.

“When a physician is seeing a person with newly diagnosed diabetes, I think it’s important to remember that they might not know the implications of having a chronic condition. A lot of times we’re quick to prescribe metformin and forget about it. ... Physicians might write a script for 3 months and three refills and not see the patient again for a year ... We may need to keep a closer eye on these folks and have more regular follow-up, and make sure they’re getting early diabetes education.”

Side effects are an issue, but not for most. “Any clinician who prescribes metformin knows there are side effects, such as upset stomach, diarrhea, and nausea. But certainly, it’s not half [who experience these]. ... A lot of people just aren’t accepting of having to take it lifelong, especially since they probably don’t feel any better on it,” Dr. Campbell said.  

James Flory, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center, New York, said in an interview that about 25% of patients taking metformin experience gastrointestinal side effects.

Moreover, he noted that the drop-off in adherence is also seen with antihypertensive and lipid-lowering drugs that have fewer side effects than those of metformin. He pointed to a “striking example” of this, a 2011 randomized trial published in the New England Journal of Medicine, and as reported by this news organization, showing overall rates of adherence to these medications was around 50%, even among people who had already had a myocardial infarction.   

“People really don’t want to be on these medications. ... They have an aversion to being medicalized and taking pills. If they’re not being pretty consistently prompted and reminded and urged to take them, I think people will find rationalizations, reasons for stopping. ... I think people want to handle things through lifestyle and not be on a drug,” noted Dr. Flory, who has published on the subject of metformin adherence.

“These drugs don’t make people feel better. None of them do. At best they don’t make you feel worse. You have to really believe in the chronic condition and believe that it’s hurting you and that you can’t handle it without the drugs to motivate you to keep taking them,” Dr. Flory explained.

Communication with the patient is key, he added.

“I don’t have empirical data to support this, but I feel it’s helpful to acknowledge the downsides to patients. I tell them to let me know [if they’re having side effects] and we’ll work on it. Don’t just stop taking the drug and never circle back.” At the same time, he added, “I think it’s important to emphasize metformin’s safety and effectiveness.”

For patients experiencing gastrointestinal side effects, options including switching to extended-release metformin or lowering the dose.

Also, while patients are typically advised to take metformin with food, some experience diarrhea when they do that and prefer to take it at bedtime than with dinner. “If that’s what works for people, that’s what they should do,” Dr. Flory advised.

“It doesn’t take a lot of time to emphasize to patients the safety and this level of flexibility and control they should be able to exercise over how much they take and when. These things should really help.”  
 

Metformin usually prescribed, but not always taken

Dr. Campbell and colleagues analyzed 17,932 individuals with incident type 2 diabetes diagnosed between April 1, 2012, and March 31, 2017. Overall, 89% received metformin monotherapy as their initial diabetes prescription, 7.6% started metformin in combination with another glucose-lowering drug, and 3.3% were prescribed a nonmetformin diabetes medication. (Those prescribed insulin as their first diabetes medication were excluded.) 

The most commonly coprescribed drugs with metformin were sulfonylureas (in 47%) and DPP-4 inhibitors (28%). Of those initiated with only nonmetformin medications, sulfonylureas were also the most common (53%) and dipeptidyl peptidase-4 (DPP-4) inhibitors second (21%).

The metformin prescribing rate of 89% reflects current guidelines, Dr. Campbell noted.

“In hypertension, clinicians weren’t really following the guidelines ... they were prescribing more expensive drugs than the guidelines say. ... We showed that in diabetes, contrary to hypertension, clinicians really are generally following the clinical practice guidelines. ... The vast majority who are started on metformin are started on monotherapy. That was reassuring to us. We’re not paying for a bunch of expensive drugs when metformin would do just as well,” he said.

However, the proportion who had been dispensed metformin to cover the prescribed number of days dropped by about 10% after 30 days, by a further 10% after 90 days, and yet again after 100 days, resulting in just 54% remaining on the drug by 1 year.

Factors associated with higher adherence included older age, presence of comorbidities, and highest versus lowest neighborhood income quintile.

Those who had been prescribed nonmetformin monotherapy had about twice the total health care costs of those initially prescribed metformin monotherapy. Higher health care costs were seen among patients who were younger, had lower incomes, had higher baseline A1c, had more comorbidities, and were men.

How will the newer type 2 diabetes drugs change prescribing?

Dr. Campbell noted that “a lot has changed since 2017. ... At least in Canada, the sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists were supposed to be reserved as second-line agents in patients with cardiovascular disease, but more and more they’re being thought of as first-line agents in high-risk patients.”

“I suspect as those guidelines are transmitted to primary care colleagues who are doing the bulk of the prescribing we’ll see more and more uptake of these agents.”

Indeed, Dr. Flory said, “The metformin data at this point are very dated and the body of trials showing health benefits for it is actually very weak compared to the big trials that have been done for the newer agents, to the point where you can imagine a consensus gradually forming where people start to recommend something other than metformin for nearly everybody with type 2 diabetes. The cost implications are just huge, and I think the safety implications as well.”

According to Dr. Flory, the SGLT2 inhibitors “are fundamentally not as safe as metformin. I think they’re very safe drugs – large good studies have established that – but if you’re going to give drugs to a large number of people who are pretty healthy at baseline the safety standards have to be pretty high.”

Just the elevated risk of euglycemic diabetic ketoacidosis alone is reason for pause, Dr. Flory said. “Even though it’s manageable ... metformin just doesn’t have a safety problem like that. I’m very comfortable prescribing SGLT2 inhibitors, but If I’m going to give a drug to a million people and have nothing go wrong with any of them, that would be metformin, not an SGLT2 [inhibitor].”

Dr. Campbell and colleagues will be conducting a follow-up of prescribing data through 2019, which will of course include the newer agents. They’ll also investigate reasons for drug discontinuation and outcomes of those who discontinue versus continue metformin.

Dr. Campbell has reported no relevant financial relationships. Dr. Flory consults for a legal firm on litigation related to insulin analog pricing issues, not for or pertaining to a specific company.

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

Nearly half of adults prescribed metformin after a new diagnosis of type 2 diabetes have stopped taking it by 1 year, new data show.

SDI Productions/E+

The findings, from a retrospective analysis of administrative data from Alberta, Canada, during 2012-2017, also show that the fall-off in metformin adherence was most dramatic during the first 30 days, and in most cases, there was no concomitant substitution of another glucose-lowering drug.

While the majority with newly diagnosed type 2 diabetes were prescribed metformin as first-line therapy, patients started on other agents incurred far higher medication and health care costs.

The data were recently published online in Diabetic Medicine by David J. T. Campbell, MD, PhD, of the University of Calgary (Alta.), and colleagues.

“We realized that even if someone is prescribed metformin that doesn’t mean they’re staying on metformin even for a year ... the drop-off rate is really quite abrupt,” Dr. Campbell said in an interview. Most who discontinued had A1c levels above 7.5%, so it wasn’t that they no longer needed glucose-lowering medication, he noted.
 

People don’t understand chronic use; meds don’t make you feel better

One reason for the discontinuations, he said, is that patients might not realize they need to keep taking the medication.

“When a physician is seeing a person with newly diagnosed diabetes, I think it’s important to remember that they might not know the implications of having a chronic condition. A lot of times we’re quick to prescribe metformin and forget about it. ... Physicians might write a script for 3 months and three refills and not see the patient again for a year ... We may need to keep a closer eye on these folks and have more regular follow-up, and make sure they’re getting early diabetes education.”

Side effects are an issue, but not for most. “Any clinician who prescribes metformin knows there are side effects, such as upset stomach, diarrhea, and nausea. But certainly, it’s not half [who experience these]. ... A lot of people just aren’t accepting of having to take it lifelong, especially since they probably don’t feel any better on it,” Dr. Campbell said.  

James Flory, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center, New York, said in an interview that about 25% of patients taking metformin experience gastrointestinal side effects.

Moreover, he noted that the drop-off in adherence is also seen with antihypertensive and lipid-lowering drugs that have fewer side effects than those of metformin. He pointed to a “striking example” of this, a 2011 randomized trial published in the New England Journal of Medicine, and as reported by this news organization, showing overall rates of adherence to these medications was around 50%, even among people who had already had a myocardial infarction.   

“People really don’t want to be on these medications. ... They have an aversion to being medicalized and taking pills. If they’re not being pretty consistently prompted and reminded and urged to take them, I think people will find rationalizations, reasons for stopping. ... I think people want to handle things through lifestyle and not be on a drug,” noted Dr. Flory, who has published on the subject of metformin adherence.

“These drugs don’t make people feel better. None of them do. At best they don’t make you feel worse. You have to really believe in the chronic condition and believe that it’s hurting you and that you can’t handle it without the drugs to motivate you to keep taking them,” Dr. Flory explained.

Communication with the patient is key, he added.

“I don’t have empirical data to support this, but I feel it’s helpful to acknowledge the downsides to patients. I tell them to let me know [if they’re having side effects] and we’ll work on it. Don’t just stop taking the drug and never circle back.” At the same time, he added, “I think it’s important to emphasize metformin’s safety and effectiveness.”

For patients experiencing gastrointestinal side effects, options including switching to extended-release metformin or lowering the dose.

Also, while patients are typically advised to take metformin with food, some experience diarrhea when they do that and prefer to take it at bedtime than with dinner. “If that’s what works for people, that’s what they should do,” Dr. Flory advised.

“It doesn’t take a lot of time to emphasize to patients the safety and this level of flexibility and control they should be able to exercise over how much they take and when. These things should really help.”  
 

Metformin usually prescribed, but not always taken

Dr. Campbell and colleagues analyzed 17,932 individuals with incident type 2 diabetes diagnosed between April 1, 2012, and March 31, 2017. Overall, 89% received metformin monotherapy as their initial diabetes prescription, 7.6% started metformin in combination with another glucose-lowering drug, and 3.3% were prescribed a nonmetformin diabetes medication. (Those prescribed insulin as their first diabetes medication were excluded.) 

The most commonly coprescribed drugs with metformin were sulfonylureas (in 47%) and DPP-4 inhibitors (28%). Of those initiated with only nonmetformin medications, sulfonylureas were also the most common (53%) and dipeptidyl peptidase-4 (DPP-4) inhibitors second (21%).

The metformin prescribing rate of 89% reflects current guidelines, Dr. Campbell noted.

“In hypertension, clinicians weren’t really following the guidelines ... they were prescribing more expensive drugs than the guidelines say. ... We showed that in diabetes, contrary to hypertension, clinicians really are generally following the clinical practice guidelines. ... The vast majority who are started on metformin are started on monotherapy. That was reassuring to us. We’re not paying for a bunch of expensive drugs when metformin would do just as well,” he said.

However, the proportion who had been dispensed metformin to cover the prescribed number of days dropped by about 10% after 30 days, by a further 10% after 90 days, and yet again after 100 days, resulting in just 54% remaining on the drug by 1 year.

Factors associated with higher adherence included older age, presence of comorbidities, and highest versus lowest neighborhood income quintile.

Those who had been prescribed nonmetformin monotherapy had about twice the total health care costs of those initially prescribed metformin monotherapy. Higher health care costs were seen among patients who were younger, had lower incomes, had higher baseline A1c, had more comorbidities, and were men.

How will the newer type 2 diabetes drugs change prescribing?

Dr. Campbell noted that “a lot has changed since 2017. ... At least in Canada, the sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists were supposed to be reserved as second-line agents in patients with cardiovascular disease, but more and more they’re being thought of as first-line agents in high-risk patients.”

“I suspect as those guidelines are transmitted to primary care colleagues who are doing the bulk of the prescribing we’ll see more and more uptake of these agents.”

Indeed, Dr. Flory said, “The metformin data at this point are very dated and the body of trials showing health benefits for it is actually very weak compared to the big trials that have been done for the newer agents, to the point where you can imagine a consensus gradually forming where people start to recommend something other than metformin for nearly everybody with type 2 diabetes. The cost implications are just huge, and I think the safety implications as well.”

According to Dr. Flory, the SGLT2 inhibitors “are fundamentally not as safe as metformin. I think they’re very safe drugs – large good studies have established that – but if you’re going to give drugs to a large number of people who are pretty healthy at baseline the safety standards have to be pretty high.”

Just the elevated risk of euglycemic diabetic ketoacidosis alone is reason for pause, Dr. Flory said. “Even though it’s manageable ... metformin just doesn’t have a safety problem like that. I’m very comfortable prescribing SGLT2 inhibitors, but If I’m going to give a drug to a million people and have nothing go wrong with any of them, that would be metformin, not an SGLT2 [inhibitor].”

Dr. Campbell and colleagues will be conducting a follow-up of prescribing data through 2019, which will of course include the newer agents. They’ll also investigate reasons for drug discontinuation and outcomes of those who discontinue versus continue metformin.

Dr. Campbell has reported no relevant financial relationships. Dr. Flory consults for a legal firm on litigation related to insulin analog pricing issues, not for or pertaining to a specific company.

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

Nearly half of adults prescribed metformin after a new diagnosis of type 2 diabetes have stopped taking it by 1 year, new data show.

SDI Productions/E+

The findings, from a retrospective analysis of administrative data from Alberta, Canada, during 2012-2017, also show that the fall-off in metformin adherence was most dramatic during the first 30 days, and in most cases, there was no concomitant substitution of another glucose-lowering drug.

While the majority with newly diagnosed type 2 diabetes were prescribed metformin as first-line therapy, patients started on other agents incurred far higher medication and health care costs.

The data were recently published online in Diabetic Medicine by David J. T. Campbell, MD, PhD, of the University of Calgary (Alta.), and colleagues.

“We realized that even if someone is prescribed metformin that doesn’t mean they’re staying on metformin even for a year ... the drop-off rate is really quite abrupt,” Dr. Campbell said in an interview. Most who discontinued had A1c levels above 7.5%, so it wasn’t that they no longer needed glucose-lowering medication, he noted.
 

People don’t understand chronic use; meds don’t make you feel better

One reason for the discontinuations, he said, is that patients might not realize they need to keep taking the medication.

“When a physician is seeing a person with newly diagnosed diabetes, I think it’s important to remember that they might not know the implications of having a chronic condition. A lot of times we’re quick to prescribe metformin and forget about it. ... Physicians might write a script for 3 months and three refills and not see the patient again for a year ... We may need to keep a closer eye on these folks and have more regular follow-up, and make sure they’re getting early diabetes education.”

Side effects are an issue, but not for most. “Any clinician who prescribes metformin knows there are side effects, such as upset stomach, diarrhea, and nausea. But certainly, it’s not half [who experience these]. ... A lot of people just aren’t accepting of having to take it lifelong, especially since they probably don’t feel any better on it,” Dr. Campbell said.  

James Flory, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center, New York, said in an interview that about 25% of patients taking metformin experience gastrointestinal side effects.

Moreover, he noted that the drop-off in adherence is also seen with antihypertensive and lipid-lowering drugs that have fewer side effects than those of metformin. He pointed to a “striking example” of this, a 2011 randomized trial published in the New England Journal of Medicine, and as reported by this news organization, showing overall rates of adherence to these medications was around 50%, even among people who had already had a myocardial infarction.   

“People really don’t want to be on these medications. ... They have an aversion to being medicalized and taking pills. If they’re not being pretty consistently prompted and reminded and urged to take them, I think people will find rationalizations, reasons for stopping. ... I think people want to handle things through lifestyle and not be on a drug,” noted Dr. Flory, who has published on the subject of metformin adherence.

“These drugs don’t make people feel better. None of them do. At best they don’t make you feel worse. You have to really believe in the chronic condition and believe that it’s hurting you and that you can’t handle it without the drugs to motivate you to keep taking them,” Dr. Flory explained.

Communication with the patient is key, he added.

“I don’t have empirical data to support this, but I feel it’s helpful to acknowledge the downsides to patients. I tell them to let me know [if they’re having side effects] and we’ll work on it. Don’t just stop taking the drug and never circle back.” At the same time, he added, “I think it’s important to emphasize metformin’s safety and effectiveness.”

For patients experiencing gastrointestinal side effects, options including switching to extended-release metformin or lowering the dose.

Also, while patients are typically advised to take metformin with food, some experience diarrhea when they do that and prefer to take it at bedtime than with dinner. “If that’s what works for people, that’s what they should do,” Dr. Flory advised.

“It doesn’t take a lot of time to emphasize to patients the safety and this level of flexibility and control they should be able to exercise over how much they take and when. These things should really help.”  
 

Metformin usually prescribed, but not always taken

Dr. Campbell and colleagues analyzed 17,932 individuals with incident type 2 diabetes diagnosed between April 1, 2012, and March 31, 2017. Overall, 89% received metformin monotherapy as their initial diabetes prescription, 7.6% started metformin in combination with another glucose-lowering drug, and 3.3% were prescribed a nonmetformin diabetes medication. (Those prescribed insulin as their first diabetes medication were excluded.) 

The most commonly coprescribed drugs with metformin were sulfonylureas (in 47%) and DPP-4 inhibitors (28%). Of those initiated with only nonmetformin medications, sulfonylureas were also the most common (53%) and dipeptidyl peptidase-4 (DPP-4) inhibitors second (21%).

The metformin prescribing rate of 89% reflects current guidelines, Dr. Campbell noted.

“In hypertension, clinicians weren’t really following the guidelines ... they were prescribing more expensive drugs than the guidelines say. ... We showed that in diabetes, contrary to hypertension, clinicians really are generally following the clinical practice guidelines. ... The vast majority who are started on metformin are started on monotherapy. That was reassuring to us. We’re not paying for a bunch of expensive drugs when metformin would do just as well,” he said.

However, the proportion who had been dispensed metformin to cover the prescribed number of days dropped by about 10% after 30 days, by a further 10% after 90 days, and yet again after 100 days, resulting in just 54% remaining on the drug by 1 year.

Factors associated with higher adherence included older age, presence of comorbidities, and highest versus lowest neighborhood income quintile.

Those who had been prescribed nonmetformin monotherapy had about twice the total health care costs of those initially prescribed metformin monotherapy. Higher health care costs were seen among patients who were younger, had lower incomes, had higher baseline A1c, had more comorbidities, and were men.

How will the newer type 2 diabetes drugs change prescribing?

Dr. Campbell noted that “a lot has changed since 2017. ... At least in Canada, the sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists were supposed to be reserved as second-line agents in patients with cardiovascular disease, but more and more they’re being thought of as first-line agents in high-risk patients.”

“I suspect as those guidelines are transmitted to primary care colleagues who are doing the bulk of the prescribing we’ll see more and more uptake of these agents.”

Indeed, Dr. Flory said, “The metformin data at this point are very dated and the body of trials showing health benefits for it is actually very weak compared to the big trials that have been done for the newer agents, to the point where you can imagine a consensus gradually forming where people start to recommend something other than metformin for nearly everybody with type 2 diabetes. The cost implications are just huge, and I think the safety implications as well.”

According to Dr. Flory, the SGLT2 inhibitors “are fundamentally not as safe as metformin. I think they’re very safe drugs – large good studies have established that – but if you’re going to give drugs to a large number of people who are pretty healthy at baseline the safety standards have to be pretty high.”

Just the elevated risk of euglycemic diabetic ketoacidosis alone is reason for pause, Dr. Flory said. “Even though it’s manageable ... metformin just doesn’t have a safety problem like that. I’m very comfortable prescribing SGLT2 inhibitors, but If I’m going to give a drug to a million people and have nothing go wrong with any of them, that would be metformin, not an SGLT2 [inhibitor].”

Dr. Campbell and colleagues will be conducting a follow-up of prescribing data through 2019, which will of course include the newer agents. They’ll also investigate reasons for drug discontinuation and outcomes of those who discontinue versus continue metformin.

Dr. Campbell has reported no relevant financial relationships. Dr. Flory consults for a legal firm on litigation related to insulin analog pricing issues, not for or pertaining to a specific company.

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

The Food and Drug Administration has cleared the FreeStyle Libre 2 iOS application for use with compatible iPhones.

The new app works with the FreeStyle Libre 2 with optional glucose alarms, which was approved in the United States in June 2020 for people with diabetes aged 4 years and older.

Until now, it was only a reader device with no app compatibility. The older FreeStyle Libre 14-day, available in the United States since July 2018, has both a reader and an app, but not optional alarms.

The new app, which will soon be available for download from the App Store, enables users to view glucose readings on their iPhones and allows for caregivers or other individuals to remotely monitor the patient’s glucose levels and receive real-time alarms via the LibreLinkUp app.

Worn for 14 days before replacement is needed, the FreeStyle Libre 2 is the longest-lasting integrated continuous glucose monitoring (iCGM) sensor currently on the market. The first iCGM, the Dexcom G6, is worn for 10 days.

The Libre 2 is available at pharmacies, typically at a lower cost than other CGM systems based on a list price comparison. The actual cost for patients varies depending on insurance coverage.

Abbott has secured partial or full reimbursement for the FreeStyle Libre system in 38 countries, including Canada, France, Germany, Japan, the United Kingdom, and the United States.

The FreeStyle Libre 3 is approved for use in the European Union.

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

The Food and Drug Administration has cleared the FreeStyle Libre 2 iOS application for use with compatible iPhones.

The new app works with the FreeStyle Libre 2 with optional glucose alarms, which was approved in the United States in June 2020 for people with diabetes aged 4 years and older.

Until now, it was only a reader device with no app compatibility. The older FreeStyle Libre 14-day, available in the United States since July 2018, has both a reader and an app, but not optional alarms.

The new app, which will soon be available for download from the App Store, enables users to view glucose readings on their iPhones and allows for caregivers or other individuals to remotely monitor the patient’s glucose levels and receive real-time alarms via the LibreLinkUp app.

Worn for 14 days before replacement is needed, the FreeStyle Libre 2 is the longest-lasting integrated continuous glucose monitoring (iCGM) sensor currently on the market. The first iCGM, the Dexcom G6, is worn for 10 days.

The Libre 2 is available at pharmacies, typically at a lower cost than other CGM systems based on a list price comparison. The actual cost for patients varies depending on insurance coverage.

Abbott has secured partial or full reimbursement for the FreeStyle Libre system in 38 countries, including Canada, France, Germany, Japan, the United Kingdom, and the United States.

The FreeStyle Libre 3 is approved for use in the European Union.

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

The Food and Drug Administration has cleared the FreeStyle Libre 2 iOS application for use with compatible iPhones.

The new app works with the FreeStyle Libre 2 with optional glucose alarms, which was approved in the United States in June 2020 for people with diabetes aged 4 years and older.

Until now, it was only a reader device with no app compatibility. The older FreeStyle Libre 14-day, available in the United States since July 2018, has both a reader and an app, but not optional alarms.

The new app, which will soon be available for download from the App Store, enables users to view glucose readings on their iPhones and allows for caregivers or other individuals to remotely monitor the patient’s glucose levels and receive real-time alarms via the LibreLinkUp app.

Worn for 14 days before replacement is needed, the FreeStyle Libre 2 is the longest-lasting integrated continuous glucose monitoring (iCGM) sensor currently on the market. The first iCGM, the Dexcom G6, is worn for 10 days.

The Libre 2 is available at pharmacies, typically at a lower cost than other CGM systems based on a list price comparison. The actual cost for patients varies depending on insurance coverage.

Abbott has secured partial or full reimbursement for the FreeStyle Libre system in 38 countries, including Canada, France, Germany, Japan, the United Kingdom, and the United States.

The FreeStyle Libre 3 is approved for use in the European Union.

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

Newly published data show alarmingly high rates and severity of early diabetes-specific complications in individuals who develop type 2 diabetes at a young age. This suggests intervention should be early and aggressive among these youngsters, said the researchers.

AzmanJaka/E+/Getty Images

The results for the 500 young adult participants in the Treatment Options for Type 2 Diabetes in Adolescents and Youth 2 (TODAY 2) study were published online July 29 in the New England Journal of Medicine by the TODAY study group.

At follow-up – after originally participating in the TODAY trial when they were young teenagers – they had a mean age of 26.4 years.

At this time, more than two thirds had hypertension and half had dyslipidemia.

Overall, 60% had at least one diabetic microvascular complication (retinal disease, neuropathy, or diabetic kidney disease), and more than a quarter had two or more such complications.

“These data illustrate the serious personal and public health consequences of youth-onset type 2 diabetes in the transition to adulthood,” the researchers noted.
 

Don’t tread lightly just because they are young

“The fact that these youth are accumulating complications at a rapid rate and are broadly affected early in adulthood certainly suggests that aggressive therapy is needed, both for glycemic control and treatment of risk factors like hypertension and dyslipidemia,” study coauthor Philip S. Zeitler, MD, PhD, said in an interview.

“In the absence of studies specifically addressing this, we need to take a more aggressive approach than people might be inclined to, given that the age at diagnosis is young, around 14 years,” he added.

“Contrary to the inclination to be ‘gentle’ in treating them because they are kids, these data suggest that we can’t let these initial years go by without strong intervention, and we need to be prepared for polypharmacy.”

Unfortunately, as Dr. Zeitler and coauthors explained, youth-onset type 2 diabetes is characterized by a suboptimal response to currently approved diabetes medications.

New pediatric indications in the United States for drugs used to treat type 2 diabetes in adults, including the recent Food and Drug Administration approval of extended-release exenatide for children as young as 10 years of age, “helps, but only marginally,” said Dr. Zeitler, of the Clinical & Translational Research Center, Children’s Hospital Colorado, Aurora.

“In some cases, it will help get them covered by carriers, which is always good. But this is still a very limited set of medications. It doesn’t include more recently approved more potent glucagon-like peptide-1 (GLP-1) agonists, like semaglutide, and doesn’t include the sodium-glucose cotransporter 2 (SGLT2) inhibitors. Pediatricians are used to using medications off label and that is necessary here while we await further approvals,” he said.  

And he noted that most individuals with youth-onset type 2 diabetes in the United States are covered by public insurance or are uninsured, depending on which state they live in. While the two major Medicaid programs in Colorado allow full access to adult formularies, that’s not the case everywhere. Moreover, patients often face further access barriers in states without expanded Medicaid.
 

Follow-up shows all metrics worsening over time

In TODAY 2, patients participated in an observational follow-up in their usual care settings in 2011-2020. At the start, they were receiving metformin with or without insulin for diabetes, but whether this continued and whether they were treated for other risk factors was down to individual circumstances.

Participants’ median A1c increased over time, and the percentage with A1c < 6% (< 48 mmol/mol) declined from 75% at the time of TODAY entry to just 19% at the 15-year end of follow-up.

The proportion with an A1c ≤ 10% (≤ 86 mmol/mol) rose from 0% at baseline to 34% at 15 years.

At that time, nearly 50% were taking both metformin and insulin, while more than a quarter were taking no medications.

The prevalence of hypertension increased from 19.2% at baseline to 67.5% at 15 years, while dyslipidemia rose from 20.8% to 51.6%.

Kidney disease prevalence increased from 8.0% at baseline to 54.8% at 15 years. Nerve disease rose from 1.0% to 32.4%. Retinal disease jumped from 13.7% with milder nonproliferative retinopathy in 2010-2011 to 51.0% with any eye disease in 2017-2018, including 8.8% with moderate to severe retinal changes and 3.5% with macular edema.  

Overall, at the time of the last visit, 39.9% had no diabetes complications, 31.8% had one, 21.3% had two, and 7.1% had three complications.
 

Serious cardiovascular events in mid-20s

There were 17 adjudicated serious cardiovascular events, including four myocardial infarctions, six heart failure events, three diagnoses of coronary artery disease, and four strokes.

Six participants died, one each from myocardial infarction, kidney failure, and drug overdose, and three from sepsis.

Dr. Zeitler called the macrovascular events “shocking,” noting that although the numbers are small, for people in their mid-20s “they should be zero ... While we don’t yet know if the rates are the same or faster than in adults, even if they are the same, these kids are only in their late 20s, as opposed to adults experiencing these problems in their 50s, 60s, and 70s.  

“The fact that these complications are occurring when these individuals should be in the prime of their life for both family and work has huge implications,” he stressed.
 

Findings have multiple causes

The reasons for the findings are both biologic and socioeconomic, Dr. Zeitler said.

“We know already that many kids with type 2 have rapid [deterioration of] beta-cell [function], which is probably very biologic. It stands to reason that an individual who can get diabetes as an adolescent probably has more fragile beta cells in some way,” he noted.

“But we also know that many other things contribute: stress, social determinants, access to quality care and medications, access to healthy foods and physical activity, availability of family supervision given the realities of families’ economic status and jobs, etc.”

It’s also known that youth with type 2 diabetes have much more severe insulin resistance than that of adults with the condition, and that “once the kids left ... the [TODAY] study, risk factor treatment in the community was less than ideal, and a lot of kids who met criteria for treatment of their blood pressure or lipids were not being treated. This is likely at least partly sociologic and partly the general pediatric hesitancy to use medications.”

He said the TODAY team will soon have some new data to show that “glycemia during the early years makes a difference, again supporting intensive intervention early on.”

The TODAY study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler had no further disclosures.

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

Newly published data show alarmingly high rates and severity of early diabetes-specific complications in individuals who develop type 2 diabetes at a young age. This suggests intervention should be early and aggressive among these youngsters, said the researchers.

AzmanJaka/E+/Getty Images

The results for the 500 young adult participants in the Treatment Options for Type 2 Diabetes in Adolescents and Youth 2 (TODAY 2) study were published online July 29 in the New England Journal of Medicine by the TODAY study group.

At follow-up – after originally participating in the TODAY trial when they were young teenagers – they had a mean age of 26.4 years.

At this time, more than two thirds had hypertension and half had dyslipidemia.

Overall, 60% had at least one diabetic microvascular complication (retinal disease, neuropathy, or diabetic kidney disease), and more than a quarter had two or more such complications.

“These data illustrate the serious personal and public health consequences of youth-onset type 2 diabetes in the transition to adulthood,” the researchers noted.
 

Don’t tread lightly just because they are young

“The fact that these youth are accumulating complications at a rapid rate and are broadly affected early in adulthood certainly suggests that aggressive therapy is needed, both for glycemic control and treatment of risk factors like hypertension and dyslipidemia,” study coauthor Philip S. Zeitler, MD, PhD, said in an interview.

“In the absence of studies specifically addressing this, we need to take a more aggressive approach than people might be inclined to, given that the age at diagnosis is young, around 14 years,” he added.

“Contrary to the inclination to be ‘gentle’ in treating them because they are kids, these data suggest that we can’t let these initial years go by without strong intervention, and we need to be prepared for polypharmacy.”

Unfortunately, as Dr. Zeitler and coauthors explained, youth-onset type 2 diabetes is characterized by a suboptimal response to currently approved diabetes medications.

New pediatric indications in the United States for drugs used to treat type 2 diabetes in adults, including the recent Food and Drug Administration approval of extended-release exenatide for children as young as 10 years of age, “helps, but only marginally,” said Dr. Zeitler, of the Clinical & Translational Research Center, Children’s Hospital Colorado, Aurora.

“In some cases, it will help get them covered by carriers, which is always good. But this is still a very limited set of medications. It doesn’t include more recently approved more potent glucagon-like peptide-1 (GLP-1) agonists, like semaglutide, and doesn’t include the sodium-glucose cotransporter 2 (SGLT2) inhibitors. Pediatricians are used to using medications off label and that is necessary here while we await further approvals,” he said.  

And he noted that most individuals with youth-onset type 2 diabetes in the United States are covered by public insurance or are uninsured, depending on which state they live in. While the two major Medicaid programs in Colorado allow full access to adult formularies, that’s not the case everywhere. Moreover, patients often face further access barriers in states without expanded Medicaid.
 

Follow-up shows all metrics worsening over time

In TODAY 2, patients participated in an observational follow-up in their usual care settings in 2011-2020. At the start, they were receiving metformin with or without insulin for diabetes, but whether this continued and whether they were treated for other risk factors was down to individual circumstances.

Participants’ median A1c increased over time, and the percentage with A1c < 6% (< 48 mmol/mol) declined from 75% at the time of TODAY entry to just 19% at the 15-year end of follow-up.

The proportion with an A1c ≤ 10% (≤ 86 mmol/mol) rose from 0% at baseline to 34% at 15 years.

At that time, nearly 50% were taking both metformin and insulin, while more than a quarter were taking no medications.

The prevalence of hypertension increased from 19.2% at baseline to 67.5% at 15 years, while dyslipidemia rose from 20.8% to 51.6%.

Kidney disease prevalence increased from 8.0% at baseline to 54.8% at 15 years. Nerve disease rose from 1.0% to 32.4%. Retinal disease jumped from 13.7% with milder nonproliferative retinopathy in 2010-2011 to 51.0% with any eye disease in 2017-2018, including 8.8% with moderate to severe retinal changes and 3.5% with macular edema.  

Overall, at the time of the last visit, 39.9% had no diabetes complications, 31.8% had one, 21.3% had two, and 7.1% had three complications.
 

Serious cardiovascular events in mid-20s

There were 17 adjudicated serious cardiovascular events, including four myocardial infarctions, six heart failure events, three diagnoses of coronary artery disease, and four strokes.

Six participants died, one each from myocardial infarction, kidney failure, and drug overdose, and three from sepsis.

Dr. Zeitler called the macrovascular events “shocking,” noting that although the numbers are small, for people in their mid-20s “they should be zero ... While we don’t yet know if the rates are the same or faster than in adults, even if they are the same, these kids are only in their late 20s, as opposed to adults experiencing these problems in their 50s, 60s, and 70s.  

“The fact that these complications are occurring when these individuals should be in the prime of their life for both family and work has huge implications,” he stressed.
 

Findings have multiple causes

The reasons for the findings are both biologic and socioeconomic, Dr. Zeitler said.

“We know already that many kids with type 2 have rapid [deterioration of] beta-cell [function], which is probably very biologic. It stands to reason that an individual who can get diabetes as an adolescent probably has more fragile beta cells in some way,” he noted.

“But we also know that many other things contribute: stress, social determinants, access to quality care and medications, access to healthy foods and physical activity, availability of family supervision given the realities of families’ economic status and jobs, etc.”

It’s also known that youth with type 2 diabetes have much more severe insulin resistance than that of adults with the condition, and that “once the kids left ... the [TODAY] study, risk factor treatment in the community was less than ideal, and a lot of kids who met criteria for treatment of their blood pressure or lipids were not being treated. This is likely at least partly sociologic and partly the general pediatric hesitancy to use medications.”

He said the TODAY team will soon have some new data to show that “glycemia during the early years makes a difference, again supporting intensive intervention early on.”

The TODAY study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler had no further disclosures.

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

Newly published data show alarmingly high rates and severity of early diabetes-specific complications in individuals who develop type 2 diabetes at a young age. This suggests intervention should be early and aggressive among these youngsters, said the researchers.

AzmanJaka/E+/Getty Images

The results for the 500 young adult participants in the Treatment Options for Type 2 Diabetes in Adolescents and Youth 2 (TODAY 2) study were published online July 29 in the New England Journal of Medicine by the TODAY study group.

At follow-up – after originally participating in the TODAY trial when they were young teenagers – they had a mean age of 26.4 years.

At this time, more than two thirds had hypertension and half had dyslipidemia.

Overall, 60% had at least one diabetic microvascular complication (retinal disease, neuropathy, or diabetic kidney disease), and more than a quarter had two or more such complications.

“These data illustrate the serious personal and public health consequences of youth-onset type 2 diabetes in the transition to adulthood,” the researchers noted.
 

Don’t tread lightly just because they are young

“The fact that these youth are accumulating complications at a rapid rate and are broadly affected early in adulthood certainly suggests that aggressive therapy is needed, both for glycemic control and treatment of risk factors like hypertension and dyslipidemia,” study coauthor Philip S. Zeitler, MD, PhD, said in an interview.

“In the absence of studies specifically addressing this, we need to take a more aggressive approach than people might be inclined to, given that the age at diagnosis is young, around 14 years,” he added.

“Contrary to the inclination to be ‘gentle’ in treating them because they are kids, these data suggest that we can’t let these initial years go by without strong intervention, and we need to be prepared for polypharmacy.”

Unfortunately, as Dr. Zeitler and coauthors explained, youth-onset type 2 diabetes is characterized by a suboptimal response to currently approved diabetes medications.

New pediatric indications in the United States for drugs used to treat type 2 diabetes in adults, including the recent Food and Drug Administration approval of extended-release exenatide for children as young as 10 years of age, “helps, but only marginally,” said Dr. Zeitler, of the Clinical & Translational Research Center, Children’s Hospital Colorado, Aurora.

“In some cases, it will help get them covered by carriers, which is always good. But this is still a very limited set of medications. It doesn’t include more recently approved more potent glucagon-like peptide-1 (GLP-1) agonists, like semaglutide, and doesn’t include the sodium-glucose cotransporter 2 (SGLT2) inhibitors. Pediatricians are used to using medications off label and that is necessary here while we await further approvals,” he said.  

And he noted that most individuals with youth-onset type 2 diabetes in the United States are covered by public insurance or are uninsured, depending on which state they live in. While the two major Medicaid programs in Colorado allow full access to adult formularies, that’s not the case everywhere. Moreover, patients often face further access barriers in states without expanded Medicaid.
 

Follow-up shows all metrics worsening over time

In TODAY 2, patients participated in an observational follow-up in their usual care settings in 2011-2020. At the start, they were receiving metformin with or without insulin for diabetes, but whether this continued and whether they were treated for other risk factors was down to individual circumstances.

Participants’ median A1c increased over time, and the percentage with A1c < 6% (< 48 mmol/mol) declined from 75% at the time of TODAY entry to just 19% at the 15-year end of follow-up.

The proportion with an A1c ≤ 10% (≤ 86 mmol/mol) rose from 0% at baseline to 34% at 15 years.

At that time, nearly 50% were taking both metformin and insulin, while more than a quarter were taking no medications.

The prevalence of hypertension increased from 19.2% at baseline to 67.5% at 15 years, while dyslipidemia rose from 20.8% to 51.6%.

Kidney disease prevalence increased from 8.0% at baseline to 54.8% at 15 years. Nerve disease rose from 1.0% to 32.4%. Retinal disease jumped from 13.7% with milder nonproliferative retinopathy in 2010-2011 to 51.0% with any eye disease in 2017-2018, including 8.8% with moderate to severe retinal changes and 3.5% with macular edema.  

Overall, at the time of the last visit, 39.9% had no diabetes complications, 31.8% had one, 21.3% had two, and 7.1% had three complications.
 

Serious cardiovascular events in mid-20s

There were 17 adjudicated serious cardiovascular events, including four myocardial infarctions, six heart failure events, three diagnoses of coronary artery disease, and four strokes.

Six participants died, one each from myocardial infarction, kidney failure, and drug overdose, and three from sepsis.

Dr. Zeitler called the macrovascular events “shocking,” noting that although the numbers are small, for people in their mid-20s “they should be zero ... While we don’t yet know if the rates are the same or faster than in adults, even if they are the same, these kids are only in their late 20s, as opposed to adults experiencing these problems in their 50s, 60s, and 70s.  

“The fact that these complications are occurring when these individuals should be in the prime of their life for both family and work has huge implications,” he stressed.
 

Findings have multiple causes

The reasons for the findings are both biologic and socioeconomic, Dr. Zeitler said.

“We know already that many kids with type 2 have rapid [deterioration of] beta-cell [function], which is probably very biologic. It stands to reason that an individual who can get diabetes as an adolescent probably has more fragile beta cells in some way,” he noted.

“But we also know that many other things contribute: stress, social determinants, access to quality care and medications, access to healthy foods and physical activity, availability of family supervision given the realities of families’ economic status and jobs, etc.”

It’s also known that youth with type 2 diabetes have much more severe insulin resistance than that of adults with the condition, and that “once the kids left ... the [TODAY] study, risk factor treatment in the community was less than ideal, and a lot of kids who met criteria for treatment of their blood pressure or lipids were not being treated. This is likely at least partly sociologic and partly the general pediatric hesitancy to use medications.”

He said the TODAY team will soon have some new data to show that “glycemia during the early years makes a difference, again supporting intensive intervention early on.”

The TODAY study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler had no further disclosures.

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

The Food and Drug Administration has approved the first interchangeable insulin, Semglee (Mylan Pharmaceuticals), which can be substituted for glargine (Lantus, Sanofi) at the pharmacy without the need for a separate prescription.

The approval will allow Semglee to function like a generic drug in the market and may reduce insulin costs.

It is indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes and in adults with type 2 diabetes.

Originally approved in June 2020 as a biosimilar to glargine, Semglee is now an “interchangeable biosimilar,” meaning that it has no clinically meaningful difference from the reference product and also may be substituted for that product – in this case, glargine (Lantus) – without prescriber intervention, just as generic drugs typically are, subject to state pharmacy laws.

For approval as an interchangeable biosimilar, manufacturers are required to provide additional data reflecting how the interchangeable biosimilar may be used in the marketplace with patients.

“Biosimilar and interchangeable biosimilar products have the potential to reduce health care costs, similar to how generic drugs have reduced costs. Biosimilars marketed in the U.S. typically have launched with initial list prices 15% to 35% lower than comparative list prices of the reference products,” the FDA said in a statement.

Semglee comes in 10-mL and 3-mL prefilled pens, and is administered subcutaneously once daily, with individualized doses. The most common side effects are hypoglycemia, edema, lipodystrophy, weight gain, and allergic reactions.

The FDA released new materials for health care providers regarding biosimilar and interchangeable biosimilar products, including a fact sheet about interchangeable biosimilar products.

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

The Food and Drug Administration has approved the first interchangeable insulin, Semglee (Mylan Pharmaceuticals), which can be substituted for glargine (Lantus, Sanofi) at the pharmacy without the need for a separate prescription.

The approval will allow Semglee to function like a generic drug in the market and may reduce insulin costs.

It is indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes and in adults with type 2 diabetes.

Originally approved in June 2020 as a biosimilar to glargine, Semglee is now an “interchangeable biosimilar,” meaning that it has no clinically meaningful difference from the reference product and also may be substituted for that product – in this case, glargine (Lantus) – without prescriber intervention, just as generic drugs typically are, subject to state pharmacy laws.

For approval as an interchangeable biosimilar, manufacturers are required to provide additional data reflecting how the interchangeable biosimilar may be used in the marketplace with patients.

“Biosimilar and interchangeable biosimilar products have the potential to reduce health care costs, similar to how generic drugs have reduced costs. Biosimilars marketed in the U.S. typically have launched with initial list prices 15% to 35% lower than comparative list prices of the reference products,” the FDA said in a statement.

Semglee comes in 10-mL and 3-mL prefilled pens, and is administered subcutaneously once daily, with individualized doses. The most common side effects are hypoglycemia, edema, lipodystrophy, weight gain, and allergic reactions.

The FDA released new materials for health care providers regarding biosimilar and interchangeable biosimilar products, including a fact sheet about interchangeable biosimilar products.

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

The Food and Drug Administration has approved the first interchangeable insulin, Semglee (Mylan Pharmaceuticals), which can be substituted for glargine (Lantus, Sanofi) at the pharmacy without the need for a separate prescription.

The approval will allow Semglee to function like a generic drug in the market and may reduce insulin costs.

It is indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes and in adults with type 2 diabetes.

Originally approved in June 2020 as a biosimilar to glargine, Semglee is now an “interchangeable biosimilar,” meaning that it has no clinically meaningful difference from the reference product and also may be substituted for that product – in this case, glargine (Lantus) – without prescriber intervention, just as generic drugs typically are, subject to state pharmacy laws.

For approval as an interchangeable biosimilar, manufacturers are required to provide additional data reflecting how the interchangeable biosimilar may be used in the marketplace with patients.

“Biosimilar and interchangeable biosimilar products have the potential to reduce health care costs, similar to how generic drugs have reduced costs. Biosimilars marketed in the U.S. typically have launched with initial list prices 15% to 35% lower than comparative list prices of the reference products,” the FDA said in a statement.

Semglee comes in 10-mL and 3-mL prefilled pens, and is administered subcutaneously once daily, with individualized doses. The most common side effects are hypoglycemia, edema, lipodystrophy, weight gain, and allergic reactions.

The FDA released new materials for health care providers regarding biosimilar and interchangeable biosimilar products, including a fact sheet about interchangeable biosimilar products.

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

The Food and Drug Administration has approved exenatide extended release (Bydureon/Bydureon BCise, AstraZeneca) for use in children with type 2 diabetes down to 10 years of age, the agency announced July 22.

Olivier Le Moal/Getty Images

Previously approved in adults, the injectable is now the second glucagonlike peptide-1 receptor agonist approved for use in pediatric type 2 diabetes, after liraglutide (Victoza, Novo Nordisk) in 2019, and the first with once-weekly administration.

The two extended-release Bydureon products – which differ in delivery device and mixing procedure – are now indicated for use in addition to diet and exercise to improve glycemic control in pediatric patients 10 years of age or older with type 2 diabetes.

Exenatide extended release is not recommended as first-line treatment following diet and exercise.

The approval was based on a 24-week, double-blind, placebo-controlled study in 82 children with type 2 diabetes aged 10 and older. They were randomized to 2 mg once-weekly exenatide extended release or placebo. At week 24, hemoglobin A1c in those randomized to the drug had dropped by 0.25 percentage points, compared with a 0.45 percentage point increase in the placebo group.

Side effects were similar to those seen in adults, including injection site reactions, headaches, and gastrointestinal discomfort.

Currently, metformin is the only oral medication approved for treating pediatric type 2 diabetes, while the injectables also include insulin in addition to the two GLP-1 receptor agonists. During a symposium held in June 2021 at the annual scientific sessions of the American Diabetes Association, speakers expressed alarm about the rise in youth developing type 2 diabetes, noting that the condition typically progresses more rapidly and is less likely to respond well to metformin, compared with adults.

But, the panelists were also optimistic about extended-release exenatide as well as several other therapies for pediatric patients with type 2 diabetes in ongoing phase 3 trials, including the sodium-glucose cotransporter 2 inhibitors dapagliflozin and empagliflozin, and the dipeptidyl peptidase–4 inhibitors alogliptin and linagliptin. Results are expected in the next 1-2 years.

The Food and Drug Administration has approved exenatide extended release (Bydureon/Bydureon BCise, AstraZeneca) for use in children with type 2 diabetes down to 10 years of age, the agency announced July 22.

Olivier Le Moal/Getty Images

Previously approved in adults, the injectable is now the second glucagonlike peptide-1 receptor agonist approved for use in pediatric type 2 diabetes, after liraglutide (Victoza, Novo Nordisk) in 2019, and the first with once-weekly administration.

The two extended-release Bydureon products – which differ in delivery device and mixing procedure – are now indicated for use in addition to diet and exercise to improve glycemic control in pediatric patients 10 years of age or older with type 2 diabetes.

Exenatide extended release is not recommended as first-line treatment following diet and exercise.

The approval was based on a 24-week, double-blind, placebo-controlled study in 82 children with type 2 diabetes aged 10 and older. They were randomized to 2 mg once-weekly exenatide extended release or placebo. At week 24, hemoglobin A1c in those randomized to the drug had dropped by 0.25 percentage points, compared with a 0.45 percentage point increase in the placebo group.

Side effects were similar to those seen in adults, including injection site reactions, headaches, and gastrointestinal discomfort.

Currently, metformin is the only oral medication approved for treating pediatric type 2 diabetes, while the injectables also include insulin in addition to the two GLP-1 receptor agonists. During a symposium held in June 2021 at the annual scientific sessions of the American Diabetes Association, speakers expressed alarm about the rise in youth developing type 2 diabetes, noting that the condition typically progresses more rapidly and is less likely to respond well to metformin, compared with adults.

But, the panelists were also optimistic about extended-release exenatide as well as several other therapies for pediatric patients with type 2 diabetes in ongoing phase 3 trials, including the sodium-glucose cotransporter 2 inhibitors dapagliflozin and empagliflozin, and the dipeptidyl peptidase–4 inhibitors alogliptin and linagliptin. Results are expected in the next 1-2 years.

The Food and Drug Administration has approved exenatide extended release (Bydureon/Bydureon BCise, AstraZeneca) for use in children with type 2 diabetes down to 10 years of age, the agency announced July 22.

Olivier Le Moal/Getty Images

Previously approved in adults, the injectable is now the second glucagonlike peptide-1 receptor agonist approved for use in pediatric type 2 diabetes, after liraglutide (Victoza, Novo Nordisk) in 2019, and the first with once-weekly administration.

The two extended-release Bydureon products – which differ in delivery device and mixing procedure – are now indicated for use in addition to diet and exercise to improve glycemic control in pediatric patients 10 years of age or older with type 2 diabetes.

Exenatide extended release is not recommended as first-line treatment following diet and exercise.

The approval was based on a 24-week, double-blind, placebo-controlled study in 82 children with type 2 diabetes aged 10 and older. They were randomized to 2 mg once-weekly exenatide extended release or placebo. At week 24, hemoglobin A1c in those randomized to the drug had dropped by 0.25 percentage points, compared with a 0.45 percentage point increase in the placebo group.

Side effects were similar to those seen in adults, including injection site reactions, headaches, and gastrointestinal discomfort.

Currently, metformin is the only oral medication approved for treating pediatric type 2 diabetes, while the injectables also include insulin in addition to the two GLP-1 receptor agonists. During a symposium held in June 2021 at the annual scientific sessions of the American Diabetes Association, speakers expressed alarm about the rise in youth developing type 2 diabetes, noting that the condition typically progresses more rapidly and is less likely to respond well to metformin, compared with adults.

But, the panelists were also optimistic about extended-release exenatide as well as several other therapies for pediatric patients with type 2 diabetes in ongoing phase 3 trials, including the sodium-glucose cotransporter 2 inhibitors dapagliflozin and empagliflozin, and the dipeptidyl peptidase–4 inhibitors alogliptin and linagliptin. Results are expected in the next 1-2 years.

The Food and Drug Administration has approved the first high-frequency spinal cord stimulation (SCS) therapy for treating painful diabetic neuropathy (PDN).

Olivier Le Moal/Getty Images

The approval is specific for the treatment of chronic pain associated with PDN using the Nevro’s Senza System with 10 kHz stimulation. It is intended for patients whose pain is refractory to, or who can’t tolerate, conventional medical treatment. According to the company, there are currently about 2.3 million individuals with refractory PDN in the United States.

The 10 kHz device, called HFX, involves minimally invasive epidural implantation of the stimulator device, which delivers mild electrical impulses to the nerves to interrupt pain signal to the brain. Such spinal cord stimulation “is a straightforward, well-established treatment for chronic pain that’s been used for over 30 years,” according to the company, although this is the first approval of the modality specifically for PDN.

Asked to comment, Rodica Pop-Busui MD, PhD, the Larry D. Soderquist Professor in Diabetes at the University of Michigan, Ann Arbor, said that “the approval of the Nevro 10kHz high-frequency spinal cord stimulation to treat pain associated with diabetic neuropathy has the potential for benefit for many patients with diabetes and painful diabetic peripheral neuropathy.”

She noted that, “although there are several other pharmacological agents that currently carry the FDA approval for PDN, this is a condition that is notoriously difficult to treat, particularly when taking into account the actual number needed to treat with a specific agent to achieve a clinically meaningful pain reduction, as well as the spectrum of side effects and drug-drug interactions in a patient population that require many other additional agents to manage diabetes and comorbidities on a daily basis. Thus, this new therapeutic approach besides effective pain reduction has the additional benefit of bypassing drug interactions.” Dr. Pop-Busui was the lead author on the American Diabetes Association’s 2017 position statement on diabetic neuropathy.

She also cautioned, on the other hand, that “it is not very clear yet how easy it will be for all eligible patients to have access to this technology, what will be the actual costs, the insurance coverage, or the acceptance by patients across various sociodemographic backgrounds from the at-large clinical care. However, given the challenges we encounter to treat diabetic neuropathy and particularly the pain associated with it, it is quite encouraging to see that the tools available to help our patients are now broader.”

Both 6-and 12-month results show benefit

The FDA approval was based on 6-month data from a prospective, multicenter, open-label randomized clinical trial published in JAMA Neurology.

Use of the 10-kHz SCS device was compared with conventional treatment alone in 216 patients with PDN refractory to gabapentinoids and at least one other analgesic class and lower limb pain intensity of 5 cm or more on a 10-cm visual analog scale.

The primary endpoint, percentage of participants reporting 50% pain relief or more without worsening of baseline neurologic deficits at 3 months, was met by 5 of 94 (5%) patients in the conventional group, compared with 75 of 95 (79%) with the 10-kHz SCS plus conventional treatment (P < .001).

Infections requiring device explant occurred in two patients in the 10-kHz SCS group (2%).

At 12 months, those in the original SCS group plus 86% of subjects given the option to cross over from the conventional treatment group showed “clear and sustained” benefits of the 10-kHz SCS with regard to lower-limb pain, pain interference with daily living, sleep quality, and activity, Erika Petersen, MD, director of the section of functional and restorative neurosurgery at the University of Arkansas for Medical Sciences, Little Rock , reported at the 2021 annual scientific sessions of the ADA.

Infection was the most common study-related adverse event, affecting 8 of 154 patients with the SCS implants (5.2%). Three resolved with conservative treatment and five (3.2%) required removal of the device.

The patients will be followed for a total of 24 months.

Commercial launch of HFX in the United States will begin immediately, the company said.

Dr. Pop-Busui has received consultant fees in the last 12 months from Averitas Pharma, Boehringer Ingelheim, Nevro, and Novo Nordisk. Dr. Petersen has financial relationships with Nevro, Medtronic, and several other neuromodulator makers.

The Food and Drug Administration has approved the first high-frequency spinal cord stimulation (SCS) therapy for treating painful diabetic neuropathy (PDN).

Olivier Le Moal/Getty Images

The approval is specific for the treatment of chronic pain associated with PDN using the Nevro’s Senza System with 10 kHz stimulation. It is intended for patients whose pain is refractory to, or who can’t tolerate, conventional medical treatment. According to the company, there are currently about 2.3 million individuals with refractory PDN in the United States.

The 10 kHz device, called HFX, involves minimally invasive epidural implantation of the stimulator device, which delivers mild electrical impulses to the nerves to interrupt pain signal to the brain. Such spinal cord stimulation “is a straightforward, well-established treatment for chronic pain that’s been used for over 30 years,” according to the company, although this is the first approval of the modality specifically for PDN.

Asked to comment, Rodica Pop-Busui MD, PhD, the Larry D. Soderquist Professor in Diabetes at the University of Michigan, Ann Arbor, said that “the approval of the Nevro 10kHz high-frequency spinal cord stimulation to treat pain associated with diabetic neuropathy has the potential for benefit for many patients with diabetes and painful diabetic peripheral neuropathy.”

She noted that, “although there are several other pharmacological agents that currently carry the FDA approval for PDN, this is a condition that is notoriously difficult to treat, particularly when taking into account the actual number needed to treat with a specific agent to achieve a clinically meaningful pain reduction, as well as the spectrum of side effects and drug-drug interactions in a patient population that require many other additional agents to manage diabetes and comorbidities on a daily basis. Thus, this new therapeutic approach besides effective pain reduction has the additional benefit of bypassing drug interactions.” Dr. Pop-Busui was the lead author on the American Diabetes Association’s 2017 position statement on diabetic neuropathy.

She also cautioned, on the other hand, that “it is not very clear yet how easy it will be for all eligible patients to have access to this technology, what will be the actual costs, the insurance coverage, or the acceptance by patients across various sociodemographic backgrounds from the at-large clinical care. However, given the challenges we encounter to treat diabetic neuropathy and particularly the pain associated with it, it is quite encouraging to see that the tools available to help our patients are now broader.”

Both 6-and 12-month results show benefit

The FDA approval was based on 6-month data from a prospective, multicenter, open-label randomized clinical trial published in JAMA Neurology.

Use of the 10-kHz SCS device was compared with conventional treatment alone in 216 patients with PDN refractory to gabapentinoids and at least one other analgesic class and lower limb pain intensity of 5 cm or more on a 10-cm visual analog scale.

The primary endpoint, percentage of participants reporting 50% pain relief or more without worsening of baseline neurologic deficits at 3 months, was met by 5 of 94 (5%) patients in the conventional group, compared with 75 of 95 (79%) with the 10-kHz SCS plus conventional treatment (P < .001).

Infections requiring device explant occurred in two patients in the 10-kHz SCS group (2%).

At 12 months, those in the original SCS group plus 86% of subjects given the option to cross over from the conventional treatment group showed “clear and sustained” benefits of the 10-kHz SCS with regard to lower-limb pain, pain interference with daily living, sleep quality, and activity, Erika Petersen, MD, director of the section of functional and restorative neurosurgery at the University of Arkansas for Medical Sciences, Little Rock , reported at the 2021 annual scientific sessions of the ADA.

Infection was the most common study-related adverse event, affecting 8 of 154 patients with the SCS implants (5.2%). Three resolved with conservative treatment and five (3.2%) required removal of the device.

The patients will be followed for a total of 24 months.

Commercial launch of HFX in the United States will begin immediately, the company said.

Dr. Pop-Busui has received consultant fees in the last 12 months from Averitas Pharma, Boehringer Ingelheim, Nevro, and Novo Nordisk. Dr. Petersen has financial relationships with Nevro, Medtronic, and several other neuromodulator makers.

The Food and Drug Administration has approved the first high-frequency spinal cord stimulation (SCS) therapy for treating painful diabetic neuropathy (PDN).

Olivier Le Moal/Getty Images

The approval is specific for the treatment of chronic pain associated with PDN using the Nevro’s Senza System with 10 kHz stimulation. It is intended for patients whose pain is refractory to, or who can’t tolerate, conventional medical treatment. According to the company, there are currently about 2.3 million individuals with refractory PDN in the United States.

The 10 kHz device, called HFX, involves minimally invasive epidural implantation of the stimulator device, which delivers mild electrical impulses to the nerves to interrupt pain signal to the brain. Such spinal cord stimulation “is a straightforward, well-established treatment for chronic pain that’s been used for over 30 years,” according to the company, although this is the first approval of the modality specifically for PDN.

Asked to comment, Rodica Pop-Busui MD, PhD, the Larry D. Soderquist Professor in Diabetes at the University of Michigan, Ann Arbor, said that “the approval of the Nevro 10kHz high-frequency spinal cord stimulation to treat pain associated with diabetic neuropathy has the potential for benefit for many patients with diabetes and painful diabetic peripheral neuropathy.”

She noted that, “although there are several other pharmacological agents that currently carry the FDA approval for PDN, this is a condition that is notoriously difficult to treat, particularly when taking into account the actual number needed to treat with a specific agent to achieve a clinically meaningful pain reduction, as well as the spectrum of side effects and drug-drug interactions in a patient population that require many other additional agents to manage diabetes and comorbidities on a daily basis. Thus, this new therapeutic approach besides effective pain reduction has the additional benefit of bypassing drug interactions.” Dr. Pop-Busui was the lead author on the American Diabetes Association’s 2017 position statement on diabetic neuropathy.

She also cautioned, on the other hand, that “it is not very clear yet how easy it will be for all eligible patients to have access to this technology, what will be the actual costs, the insurance coverage, or the acceptance by patients across various sociodemographic backgrounds from the at-large clinical care. However, given the challenges we encounter to treat diabetic neuropathy and particularly the pain associated with it, it is quite encouraging to see that the tools available to help our patients are now broader.”

Both 6-and 12-month results show benefit

The FDA approval was based on 6-month data from a prospective, multicenter, open-label randomized clinical trial published in JAMA Neurology.

Use of the 10-kHz SCS device was compared with conventional treatment alone in 216 patients with PDN refractory to gabapentinoids and at least one other analgesic class and lower limb pain intensity of 5 cm or more on a 10-cm visual analog scale.

The primary endpoint, percentage of participants reporting 50% pain relief or more without worsening of baseline neurologic deficits at 3 months, was met by 5 of 94 (5%) patients in the conventional group, compared with 75 of 95 (79%) with the 10-kHz SCS plus conventional treatment (P < .001).

Infections requiring device explant occurred in two patients in the 10-kHz SCS group (2%).

At 12 months, those in the original SCS group plus 86% of subjects given the option to cross over from the conventional treatment group showed “clear and sustained” benefits of the 10-kHz SCS with regard to lower-limb pain, pain interference with daily living, sleep quality, and activity, Erika Petersen, MD, director of the section of functional and restorative neurosurgery at the University of Arkansas for Medical Sciences, Little Rock , reported at the 2021 annual scientific sessions of the ADA.

Infection was the most common study-related adverse event, affecting 8 of 154 patients with the SCS implants (5.2%). Three resolved with conservative treatment and five (3.2%) required removal of the device.

The patients will be followed for a total of 24 months.

Commercial launch of HFX in the United States will begin immediately, the company said.

Dr. Pop-Busui has received consultant fees in the last 12 months from Averitas Pharma, Boehringer Ingelheim, Nevro, and Novo Nordisk. Dr. Petersen has financial relationships with Nevro, Medtronic, and several other neuromodulator makers.

Bicycle riding may help people with diabetes live longer, new research suggests.

NicolasMcComber/E+/Getty Images

Among more than 7,000 adults with diabetes in 10 Western European countries followed for about 15 years, those who cycled regularly were significantly less likely to die of any cause or of cardiovascular causes, even after accounting for differences in factors such as sex, age, educational level, diet, comorbidities, and other physical activities.

“The association between cycling and all-cause and CVD [cardiovascular disease] mortality in this study of person[s] with diabetes was of the same magnitude and direction as observed in the healthy population,” wrote Mathias Ried-Larsen, PhD, of the Centre for Physical Activity Research, Rigshospitalet, Copenhagen, and colleagues. The findings were published online July 19, 2021, in JAMA Internal Medicine.

In an accompanying Editor’s Note, JAMA Internal Medicine editor Rita F. Redberg, MD, and two deputy editors said that the new data add to previous studies showing benefits of cycling, compared with other physical activities. “The analysis from Ried-Larsen and colleagues strengthens the epidemiologic data on cycling and strongly suggests that it may contribute directly to longer and healthier lives,” they wrote.

Dr. Redberg, of the University of California, San Francisco, told this news organization: “I think the number of cyclists grew greatly during pandemic, when there was little auto traffic, and people did not want to take public transportation. Cities that add bike lanes, especially protected bike lanes, see an increase in cyclists. I think Americans can cycle more, would enjoy cycling more, and would live longer [by] cycling, to work and for pleasure.”

Dr. Redberg disclosed that she is “an avid cyclist and am currently on a bike ride in Glacier National Park. ... This group [Climate Ride] raises money for more bike lanes, promotes climate change awareness, has paid for solar panels at Glacier, and more.”

However, Dr. Redberg and colleagues also “recognize that cycling requires fitness, a good sense of balance, and the means to purchase a bicycle. We also understand that regular cycling requires living in an area where it is reasonably safe, and we celebrate the installation of more bike lanes, particularly protected lanes, in many cities around the world.”

But, despite the limitations of an observational study and possible selection bias of people who are able to cycle, “it is important to share this evidence for the potentially large health benefits of cycling, which almost surely generalize to persons without diabetes.”
 

Cycling tied to lower all-cause and CVD mortality

The prospective cohort study included 7,459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition. All were assessed during 1992-1998 and again in 1996-2011, with a mean follow-up of roughly 15 years. During that time, there were 1,673 deaths from all causes, with 811 attributed to CVD.

Compared with no cycling, those who reported any cycling had a 24% lower risk of death from any cause over a 5-year period, after adjustment for confounders and for other physical activity. The greatest risk reduction was seen in those who reported cycling between 150-299 minutes per week, particularly in CVD mortality.

In a subanalysis of 5,423 individuals with 10.7 years of follow-up, there were 975 all-cause deaths and 429 from CVD. Individuals who began or continued cycling during follow-up experienced reductions of about 35% for both all-cause and CVD mortality, compared with those who never cycled.

Dr. Redberg and colleagues added that “there are environmental benefits to increasing the use of cycling for commuting and other transport because cycling helps to decrease the adverse environmental and health effects of automobile exhaust.”

They concluded: “As avid and/or aspiring cyclists ourselves, we are sold on the mental and physical benefits of getting to work and seeing the world on two wheels, self-propelled, and think it is well worth a try.”

The study work was supported by the Health Research Fund of Instituto de Salud Carlos III; the Spanish regional governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra; and the Catalan Institute of Oncology. The Centre for Physical Activity Research is supported by a grant from TrygFonden. Dr. Ried-Larsen reported personal fees from Novo Nordisk. Dr. Redberg reported receiving grants from Arnold Ventures; the Greenwall Foundation; and the National Heart, Lung, and Blood Institute.

Bicycle riding may help people with diabetes live longer, new research suggests.

NicolasMcComber/E+/Getty Images

Among more than 7,000 adults with diabetes in 10 Western European countries followed for about 15 years, those who cycled regularly were significantly less likely to die of any cause or of cardiovascular causes, even after accounting for differences in factors such as sex, age, educational level, diet, comorbidities, and other physical activities.

“The association between cycling and all-cause and CVD [cardiovascular disease] mortality in this study of person[s] with diabetes was of the same magnitude and direction as observed in the healthy population,” wrote Mathias Ried-Larsen, PhD, of the Centre for Physical Activity Research, Rigshospitalet, Copenhagen, and colleagues. The findings were published online July 19, 2021, in JAMA Internal Medicine.

In an accompanying Editor’s Note, JAMA Internal Medicine editor Rita F. Redberg, MD, and two deputy editors said that the new data add to previous studies showing benefits of cycling, compared with other physical activities. “The analysis from Ried-Larsen and colleagues strengthens the epidemiologic data on cycling and strongly suggests that it may contribute directly to longer and healthier lives,” they wrote.

Dr. Redberg, of the University of California, San Francisco, told this news organization: “I think the number of cyclists grew greatly during pandemic, when there was little auto traffic, and people did not want to take public transportation. Cities that add bike lanes, especially protected bike lanes, see an increase in cyclists. I think Americans can cycle more, would enjoy cycling more, and would live longer [by] cycling, to work and for pleasure.”

Dr. Redberg disclosed that she is “an avid cyclist and am currently on a bike ride in Glacier National Park. ... This group [Climate Ride] raises money for more bike lanes, promotes climate change awareness, has paid for solar panels at Glacier, and more.”

However, Dr. Redberg and colleagues also “recognize that cycling requires fitness, a good sense of balance, and the means to purchase a bicycle. We also understand that regular cycling requires living in an area where it is reasonably safe, and we celebrate the installation of more bike lanes, particularly protected lanes, in many cities around the world.”

But, despite the limitations of an observational study and possible selection bias of people who are able to cycle, “it is important to share this evidence for the potentially large health benefits of cycling, which almost surely generalize to persons without diabetes.”
 

Cycling tied to lower all-cause and CVD mortality

The prospective cohort study included 7,459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition. All were assessed during 1992-1998 and again in 1996-2011, with a mean follow-up of roughly 15 years. During that time, there were 1,673 deaths from all causes, with 811 attributed to CVD.

Compared with no cycling, those who reported any cycling had a 24% lower risk of death from any cause over a 5-year period, after adjustment for confounders and for other physical activity. The greatest risk reduction was seen in those who reported cycling between 150-299 minutes per week, particularly in CVD mortality.

In a subanalysis of 5,423 individuals with 10.7 years of follow-up, there were 975 all-cause deaths and 429 from CVD. Individuals who began or continued cycling during follow-up experienced reductions of about 35% for both all-cause and CVD mortality, compared with those who never cycled.

Dr. Redberg and colleagues added that “there are environmental benefits to increasing the use of cycling for commuting and other transport because cycling helps to decrease the adverse environmental and health effects of automobile exhaust.”

They concluded: “As avid and/or aspiring cyclists ourselves, we are sold on the mental and physical benefits of getting to work and seeing the world on two wheels, self-propelled, and think it is well worth a try.”

The study work was supported by the Health Research Fund of Instituto de Salud Carlos III; the Spanish regional governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra; and the Catalan Institute of Oncology. The Centre for Physical Activity Research is supported by a grant from TrygFonden. Dr. Ried-Larsen reported personal fees from Novo Nordisk. Dr. Redberg reported receiving grants from Arnold Ventures; the Greenwall Foundation; and the National Heart, Lung, and Blood Institute.

Bicycle riding may help people with diabetes live longer, new research suggests.

NicolasMcComber/E+/Getty Images

Among more than 7,000 adults with diabetes in 10 Western European countries followed for about 15 years, those who cycled regularly were significantly less likely to die of any cause or of cardiovascular causes, even after accounting for differences in factors such as sex, age, educational level, diet, comorbidities, and other physical activities.

“The association between cycling and all-cause and CVD [cardiovascular disease] mortality in this study of person[s] with diabetes was of the same magnitude and direction as observed in the healthy population,” wrote Mathias Ried-Larsen, PhD, of the Centre for Physical Activity Research, Rigshospitalet, Copenhagen, and colleagues. The findings were published online July 19, 2021, in JAMA Internal Medicine.

In an accompanying Editor’s Note, JAMA Internal Medicine editor Rita F. Redberg, MD, and two deputy editors said that the new data add to previous studies showing benefits of cycling, compared with other physical activities. “The analysis from Ried-Larsen and colleagues strengthens the epidemiologic data on cycling and strongly suggests that it may contribute directly to longer and healthier lives,” they wrote.

Dr. Redberg, of the University of California, San Francisco, told this news organization: “I think the number of cyclists grew greatly during pandemic, when there was little auto traffic, and people did not want to take public transportation. Cities that add bike lanes, especially protected bike lanes, see an increase in cyclists. I think Americans can cycle more, would enjoy cycling more, and would live longer [by] cycling, to work and for pleasure.”

Dr. Redberg disclosed that she is “an avid cyclist and am currently on a bike ride in Glacier National Park. ... This group [Climate Ride] raises money for more bike lanes, promotes climate change awareness, has paid for solar panels at Glacier, and more.”

However, Dr. Redberg and colleagues also “recognize that cycling requires fitness, a good sense of balance, and the means to purchase a bicycle. We also understand that regular cycling requires living in an area where it is reasonably safe, and we celebrate the installation of more bike lanes, particularly protected lanes, in many cities around the world.”

But, despite the limitations of an observational study and possible selection bias of people who are able to cycle, “it is important to share this evidence for the potentially large health benefits of cycling, which almost surely generalize to persons without diabetes.”
 

Cycling tied to lower all-cause and CVD mortality

The prospective cohort study included 7,459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition. All were assessed during 1992-1998 and again in 1996-2011, with a mean follow-up of roughly 15 years. During that time, there were 1,673 deaths from all causes, with 811 attributed to CVD.

Compared with no cycling, those who reported any cycling had a 24% lower risk of death from any cause over a 5-year period, after adjustment for confounders and for other physical activity. The greatest risk reduction was seen in those who reported cycling between 150-299 minutes per week, particularly in CVD mortality.

In a subanalysis of 5,423 individuals with 10.7 years of follow-up, there were 975 all-cause deaths and 429 from CVD. Individuals who began or continued cycling during follow-up experienced reductions of about 35% for both all-cause and CVD mortality, compared with those who never cycled.

Dr. Redberg and colleagues added that “there are environmental benefits to increasing the use of cycling for commuting and other transport because cycling helps to decrease the adverse environmental and health effects of automobile exhaust.”

They concluded: “As avid and/or aspiring cyclists ourselves, we are sold on the mental and physical benefits of getting to work and seeing the world on two wheels, self-propelled, and think it is well worth a try.”

The study work was supported by the Health Research Fund of Instituto de Salud Carlos III; the Spanish regional governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra; and the Catalan Institute of Oncology. The Centre for Physical Activity Research is supported by a grant from TrygFonden. Dr. Ried-Larsen reported personal fees from Novo Nordisk. Dr. Redberg reported receiving grants from Arnold Ventures; the Greenwall Foundation; and the National Heart, Lung, and Blood Institute.