A 65-year-old African American man presented to an Otolaryngology Head and Neck Surgery clinic at a tertiary Veterans Health Administration (VHA) facility for evaluation. The patient recalled a past diagnosis of oropharyngeal cancer (OPC), possibly associated with the human papillomavirus (HPV). After receiving the diagnosis at another VHA facility, the patient opted to seek care at a local, non-VHA facility and received approximately 7 weeks of daily radiation and weekly infusions of chemotherapy.

Six years after his initial diagnosis and treatment, the patient said he had a persistent cough with any meaningful attempts to eat or drink. He also noted he lost at least 10 lbs in the last 3 months and had been hospitalized twice during the past winter. During his second hospitalization he spent 4 days on a ventilator in the intensive care unit.

On examination, the patient appeared frail and cachectic, with significant fibrosis of the neck skin and moderate trismus. His dentition was in poor health, and an in-clinic flexible endoscopy demonstrated clear silent aspiration of oral secretions. Given his failure to thrive, the patient was urgently admitted to the hospital. A modified barium swallow study performed by the head and neck Speech Pathology team demonstrated gross aspiration with all consistencies. After extensive counseling, the patient agreed to the placement of a gastrostomy tube. He was discharged in stable condition with adequate supplies and self-care training. He was advised to continue follow-up in the Head and Neck Cancer Survivorship clinic.

Two years later, in the early phase of the COVID-19 pandemic, the patient was admitted to the hospital with COVID pneumonia. Given the damage to his lungs over the previous decade from recurrent episodes of aspiration pneumonia, the patient succumbed.

An Unexpected, Unrelenting Epidemic

Shifting population dynamics and behaviors have led to an explosion in the incidence of cancers associated with infection by oncogenic subtypes of HPV, among which cancer of the oropharynx represents the most common malignancy.^1,2 OPC now afflicts more than 30,000 new patients in the United States each year.³ Given current vaccination rates against oncogenic HPV, the overall trend of increasing incidence is not expected to stabilize until the 2040s.³ Traditional cancers of the head and neck region were previously fatal after 5 years in more than 60% of cases; however, today patients with HPV-associated OPC can expect a more than 80% chance of being alive 5 years after treatment.^4-7 Combining the increasing incidence of OPC with a high chance of oncologic cure has led to an ever-expanding cohort of OPC survivors.

Enthusiasm about a high rate of survival after an HPV-associated OPC diagnosis is now partially dampened by an increasing realization that neither oncologists nor healthcare systems are remotely prepared for this rapidly expanding cohort of OPC survivors. Their unique needs and problems have yet to be objectively defined and quantified.

Relationship Between Survival and Long-Term Toxicity in HPV-Associated OPC

Survivorship care after OPC treatment is a growing challenge in terms of the number of patients affected, the negative impact on quality of life (QOL), and the potential burden on the healthcare system. The rapidly growing number of OPC survivors who are living long enough to develop delayed adverse effects related to their past OPC treatment^1,2,8 includes many patients in whom toxicities can be truly debilitating,^9,10 generating significant unmet needs.

Tumor and Treatment Toxicity

Although HPV-associated OPC demonstrates an excellent response to conventional chemoradiotherapy (CRT), this finding cannot be interpreted to mean that reducing treatment intensity is safe for patients with this disease. Prospective trials have now demonstrated that neither replacing or eliminating conventional chemotherapy, nor significantly reducing radiation doses, can be considered safe at this time.^11-15 As a result, a patient with newly diagnosed HPV-associated OPC in 2025, and potentially even 2030, is likely to receive the same treatment as patients who were treated in the late 2010s.¹⁴

Three decades ago, the chronic effects of tumor and treatment were largely limited to a small cohort of survivors; however, today they affect more patients.^1,2,7 Chronic xerostomia, dysphagia, trismus, radiation fibrosis, and osteoradionecrosis (ORN) now confront tens of thousands of OPC survivors; over the coming decades, these treatment effects have the potential to affect millions of patients.^16-22

While most acute toxicities resolve within several months of completing CRT, late CRT sequelae tend to be dynamic and can progress silently over many years.^16,23 Adverse effects vary widely, with many toxicities (eg, dysphagia, ORN) being particularly debilitating. Many of these effects occur in a radiation dose–dependent fashion, but radiation dose does not fully predict late toxicities, pointing to a role for other, yet unidentified contributing factors.^24,25

Dysphagia in Survivors of OPC

About two-thirds of survivors of head and neck cancer (HNC) who seek follow-up care 5 years after treatment report dysphagia and at least partial dependence on a feeding tube.²⁶ The incidence of dysphagia increases proportionately with higher radiation doses delivered to the pharyngeal constrictors and supraglottic larynx.¹⁸ Dysphagia can severely reduce QOL years after treatment, necessitating substantial changes in diet and social behavior among OPC survivors. Often, patients are forced to choose between chronic malnutrition or starvation and feeding tube dependence.²⁷ Loss of a normal oral diet is frequently one of the most affected QOL measures for OPC survivors.²⁸

In addition to effects on QOL, dysphagia can have life-threatening consequences. In a recent systematic review and meta-analysis, life-threatening aspiration occurred after > 24 months at a reported incidence ranging from 3% to nearly 35%. Although a reduction in radiation dose to the pharyngeal constrictors can reduce chronic dysphagia,²⁷ whether this can be done safely in most OPC patients, particularly those with bulky primary tumors, remains unclear.

Osteoradionecrosis (ORN) in Survivors of OPC

ORN is one of the most potentially serious complications of CRT and may not manifest for years after treatment. Its median time of onset after radiotherapy is 8 years in patients with OPC.²⁴ Bone injury and impaired healing of the alveolar mucosa are signs of ORN, which occurs in ~7% of patients receiving intensity-modulated radiation therapy for OPC.¹⁷ ORN is accompanied by pain, difficulties with chewing, exacerbation of concomitant dysphagia and, in the advanced stage—gross cosmetic deformity secondary to mandibular or maxillary fracture and/or decay.²⁹ Despite the severity of this complication, we are just beginning to understand why ORN develops in a subset of patients. Although ORN is generally more common in patients with advanced-stage OPC who receive higher doses of radiation to a larger overall bone volume,^17,19,24,30 comprehensive translational research efforts focused on ORN (as well as other late toxicities of OPC treatment) are still in their infancy.

Unmet Needs in Predicting and Evaluating Late Toxicities

Predicting which patients will experience long-term treatment toxicities or which types of late toxicities they may develop is not yet possible. Whereas increased data collection and prognostic models can help inform healthcare systems as to the expected frequencies of toxicity, they are unlikely to be prognostic at the individual patient level. As such, there is a critical need for individualized biomarker strategies that can predict one’s risk of toxicity and identify normal tissue shifts in biology and function early in the process to initiate interventions before significant deterioration. Adding to the complexity of predicting late toxicities is the lack of standardization in instruments used to categorize them. Examples of tools that may be used to categorize dysphagia include the Common Terminology Criteria for Adverse Events v4.0 grading scale, the Radiation Therapy Oncology Group grading system, and the European Organization for Research and Treatment of Cancer Performance Status Scale for Head and Neck Cancer.²⁰ The MD Anderson Symptom Inventory for head and neck cancer may also be used to catalog dysphagia and other common symptoms of HNC, as well as treatment-related concerns.³¹ Magnetic resonance imaging-based techniques coupled with machine learning approaches represent emerging tools that may have a role in identifying early radiation-induced bone changes that can facilitate early detection of ORN.^32,33 Although conventional and newer tools can be used to generate objective metrics of treatment-related toxicity, consistent and appropriate deployment across the entire cohort of OPC survivors in the United States remains a distant goal.

Calibrating Treatment Intensity to Disease Intensity 

Given the risk of severe and potentially life-threatening consequences of radiation-based treatment, there is a large unmet need to better calibrate treatment intensity to the intensity of HPV-associated OPC.^14,34 In light of the good prognosis of the disease in most patients, recent efforts have focused on identifying ways to de-escalate treatment intensity while preserving the good outcomes known to be possible for patients with HPV-associated OPC. Improving tolerability and limiting the risk of late effects of radiation-based treatment is especially important with the aging population of HPV-associated OPC survivors, who would also be expected to have unrelated comorbidities.¹

Various modes of de-escalation have been studied, including adding surgery to CRT, reducing radiation dose, and modifying systemic therapy regimens. Most of these efforts have largely failed to identify a safe regimen for treatment de-escalation that applies to a majority or even a significant plurality of patients with OPC.^14,35,36 Although CheckMate 141 and KEYNOTE-048 garnered excitement when immune checkpoint inhibitors (ICIs) significantly prolonged overall survival and had a more favorable safety profile than standard systemic therapy in recurrent and metastatic OPC,^11,37,38 adding definitive frontline avelumab to CRT failed to prolong progression-free survival versus CRT alone in the phase 3 JAVELIN Head and Neck 100 trial.¹³ Combined with additional recent trial data, these findings make it unlikely that an ICI-based regimen will provide previously unavailable de-escalation options for patients with OPC in the near future.

Considering continued de-escalation efforts, it is important to remember that survival is not uniform among all patients with HPV-associated OPC. For example, patients with HPV-associated OPC and a history of current or prior heavy tobacco use have not experienced the same dramatic prolongation in overall survival as their nonsmoking counterparts.³⁶ Patients with recurrent disease also face a dismal prognosis, with failure rates of about 70% with salvage treatment with surgery, re-irradiation, or systemic therapy.^38-41 Therefore, de-escalation may not be appropriate in all patients, but identifying which patients are at risk of overtreatment is not straightforward. Better risk stratification of patients may provide part of the solution but will require rigorous testing and long-term follow-up to establish.

Discussion

There is an urgent need to carefully consider how to manage long-term survivors of HPV-associated OPC. With ever-increasing numbers of patients who are living years beyond their OPC treatment, continual reevaluation of treatment strategies in certain subsets of patients and making concerted efforts to identify and manage late toxicities early is paramount. Yet there remains a critical gap in knowledge due to insufficient metrics for both toxicity intensity and the frequency of debilitating, life-threatening toxicity. Unfortunately, the lack of tools available combined with the mismatch in disease intensity with treatment intensity likely results in excessive treatment-induced toxicity for many patients.

In the absence of clear evidence about which treatment strategy to use for individual patients, clinicians are tasked with making therapeutic choices without being fully able to predict outcomes. Patient preference is important to consider, but these conversations can be complicated. How does one talk to a patient about their willingness to risk a cancer recurrence and potentially risk late toxicities when the clinician does not know whether that individual patient will develop late toxicities, or know how severe they will be? It is a tradeoff between QOL (ie, possible feeding tube dependence) and survival—yet the magnitude of the effect on QOL remains impossible to predict at present for the individual patient.

Moreover, the needs of individual OPC survivors vary. A cross-sectional study performed at Princess Margaret Cancer Centre found that 61% of the 158 participants had unmet needs related to their cancer survivorship.⁴² Meeting the needs of survivors may require the development of better screening instruments that can manage various complications early and effectively. Continuing to follow OPC survivors with a multidisciplinary team would most certainly be beneficial and has been reported to improve QOL.⁴³ Continual Speech Pathology management and therapy from the time of diagnosis into the survivorship phase of care has been suggested as one way to improve functional outcomes.⁴⁴ Given that coordinating long-term care teams is logistically challenging, well-planned research is warranted to equip these teams to provide OPC survivors with the care they need. These efforts will be particularly important considering the large number of survivors who will need this type of care in the coming decades. The time to start is now well past.

Click to read more from 2023 Rare Diseases Report: Cancers

A 65-year-old African American man presented to an Otolaryngology Head and Neck Surgery clinic at a tertiary Veterans Health Administration (VHA) facility for evaluation. The patient recalled a past diagnosis of oropharyngeal cancer (OPC), possibly associated with the human papillomavirus (HPV). After receiving the diagnosis at another VHA facility, the patient opted to seek care at a local, non-VHA facility and received approximately 7 weeks of daily radiation and weekly infusions of chemotherapy.

Six years after his initial diagnosis and treatment, the patient said he had a persistent cough with any meaningful attempts to eat or drink. He also noted he lost at least 10 lbs in the last 3 months and had been hospitalized twice during the past winter. During his second hospitalization he spent 4 days on a ventilator in the intensive care unit.

On examination, the patient appeared frail and cachectic, with significant fibrosis of the neck skin and moderate trismus. His dentition was in poor health, and an in-clinic flexible endoscopy demonstrated clear silent aspiration of oral secretions. Given his failure to thrive, the patient was urgently admitted to the hospital. A modified barium swallow study performed by the head and neck Speech Pathology team demonstrated gross aspiration with all consistencies. After extensive counseling, the patient agreed to the placement of a gastrostomy tube. He was discharged in stable condition with adequate supplies and self-care training. He was advised to continue follow-up in the Head and Neck Cancer Survivorship clinic.

Two years later, in the early phase of the COVID-19 pandemic, the patient was admitted to the hospital with COVID pneumonia. Given the damage to his lungs over the previous decade from recurrent episodes of aspiration pneumonia, the patient succumbed.

An Unexpected, Unrelenting Epidemic

Shifting population dynamics and behaviors have led to an explosion in the incidence of cancers associated with infection by oncogenic subtypes of HPV, among which cancer of the oropharynx represents the most common malignancy.^1,2 OPC now afflicts more than 30,000 new patients in the United States each year.³ Given current vaccination rates against oncogenic HPV, the overall trend of increasing incidence is not expected to stabilize until the 2040s.³ Traditional cancers of the head and neck region were previously fatal after 5 years in more than 60% of cases; however, today patients with HPV-associated OPC can expect a more than 80% chance of being alive 5 years after treatment.^4-7 Combining the increasing incidence of OPC with a high chance of oncologic cure has led to an ever-expanding cohort of OPC survivors.

Enthusiasm about a high rate of survival after an HPV-associated OPC diagnosis is now partially dampened by an increasing realization that neither oncologists nor healthcare systems are remotely prepared for this rapidly expanding cohort of OPC survivors. Their unique needs and problems have yet to be objectively defined and quantified.

Relationship Between Survival and Long-Term Toxicity in HPV-Associated OPC

Survivorship care after OPC treatment is a growing challenge in terms of the number of patients affected, the negative impact on quality of life (QOL), and the potential burden on the healthcare system. The rapidly growing number of OPC survivors who are living long enough to develop delayed adverse effects related to their past OPC treatment^1,2,8 includes many patients in whom toxicities can be truly debilitating,^9,10 generating significant unmet needs.

Tumor and Treatment Toxicity

Although HPV-associated OPC demonstrates an excellent response to conventional chemoradiotherapy (CRT), this finding cannot be interpreted to mean that reducing treatment intensity is safe for patients with this disease. Prospective trials have now demonstrated that neither replacing or eliminating conventional chemotherapy, nor significantly reducing radiation doses, can be considered safe at this time.^11-15 As a result, a patient with newly diagnosed HPV-associated OPC in 2025, and potentially even 2030, is likely to receive the same treatment as patients who were treated in the late 2010s.¹⁴

Three decades ago, the chronic effects of tumor and treatment were largely limited to a small cohort of survivors; however, today they affect more patients.^1,2,7 Chronic xerostomia, dysphagia, trismus, radiation fibrosis, and osteoradionecrosis (ORN) now confront tens of thousands of OPC survivors; over the coming decades, these treatment effects have the potential to affect millions of patients.^16-22

While most acute toxicities resolve within several months of completing CRT, late CRT sequelae tend to be dynamic and can progress silently over many years.^16,23 Adverse effects vary widely, with many toxicities (eg, dysphagia, ORN) being particularly debilitating. Many of these effects occur in a radiation dose–dependent fashion, but radiation dose does not fully predict late toxicities, pointing to a role for other, yet unidentified contributing factors.^24,25

Dysphagia in Survivors of OPC

About two-thirds of survivors of head and neck cancer (HNC) who seek follow-up care 5 years after treatment report dysphagia and at least partial dependence on a feeding tube.²⁶ The incidence of dysphagia increases proportionately with higher radiation doses delivered to the pharyngeal constrictors and supraglottic larynx.¹⁸ Dysphagia can severely reduce QOL years after treatment, necessitating substantial changes in diet and social behavior among OPC survivors. Often, patients are forced to choose between chronic malnutrition or starvation and feeding tube dependence.²⁷ Loss of a normal oral diet is frequently one of the most affected QOL measures for OPC survivors.²⁸

In addition to effects on QOL, dysphagia can have life-threatening consequences. In a recent systematic review and meta-analysis, life-threatening aspiration occurred after > 24 months at a reported incidence ranging from 3% to nearly 35%. Although a reduction in radiation dose to the pharyngeal constrictors can reduce chronic dysphagia,²⁷ whether this can be done safely in most OPC patients, particularly those with bulky primary tumors, remains unclear.

Osteoradionecrosis (ORN) in Survivors of OPC

ORN is one of the most potentially serious complications of CRT and may not manifest for years after treatment. Its median time of onset after radiotherapy is 8 years in patients with OPC.²⁴ Bone injury and impaired healing of the alveolar mucosa are signs of ORN, which occurs in ~7% of patients receiving intensity-modulated radiation therapy for OPC.¹⁷ ORN is accompanied by pain, difficulties with chewing, exacerbation of concomitant dysphagia and, in the advanced stage—gross cosmetic deformity secondary to mandibular or maxillary fracture and/or decay.²⁹ Despite the severity of this complication, we are just beginning to understand why ORN develops in a subset of patients. Although ORN is generally more common in patients with advanced-stage OPC who receive higher doses of radiation to a larger overall bone volume,^17,19,24,30 comprehensive translational research efforts focused on ORN (as well as other late toxicities of OPC treatment) are still in their infancy.

Unmet Needs in Predicting and Evaluating Late Toxicities

Predicting which patients will experience long-term treatment toxicities or which types of late toxicities they may develop is not yet possible. Whereas increased data collection and prognostic models can help inform healthcare systems as to the expected frequencies of toxicity, they are unlikely to be prognostic at the individual patient level. As such, there is a critical need for individualized biomarker strategies that can predict one’s risk of toxicity and identify normal tissue shifts in biology and function early in the process to initiate interventions before significant deterioration. Adding to the complexity of predicting late toxicities is the lack of standardization in instruments used to categorize them. Examples of tools that may be used to categorize dysphagia include the Common Terminology Criteria for Adverse Events v4.0 grading scale, the Radiation Therapy Oncology Group grading system, and the European Organization for Research and Treatment of Cancer Performance Status Scale for Head and Neck Cancer.²⁰ The MD Anderson Symptom Inventory for head and neck cancer may also be used to catalog dysphagia and other common symptoms of HNC, as well as treatment-related concerns.³¹ Magnetic resonance imaging-based techniques coupled with machine learning approaches represent emerging tools that may have a role in identifying early radiation-induced bone changes that can facilitate early detection of ORN.^32,33 Although conventional and newer tools can be used to generate objective metrics of treatment-related toxicity, consistent and appropriate deployment across the entire cohort of OPC survivors in the United States remains a distant goal.

Calibrating Treatment Intensity to Disease Intensity 

Given the risk of severe and potentially life-threatening consequences of radiation-based treatment, there is a large unmet need to better calibrate treatment intensity to the intensity of HPV-associated OPC.^14,34 In light of the good prognosis of the disease in most patients, recent efforts have focused on identifying ways to de-escalate treatment intensity while preserving the good outcomes known to be possible for patients with HPV-associated OPC. Improving tolerability and limiting the risk of late effects of radiation-based treatment is especially important with the aging population of HPV-associated OPC survivors, who would also be expected to have unrelated comorbidities.¹

Various modes of de-escalation have been studied, including adding surgery to CRT, reducing radiation dose, and modifying systemic therapy regimens. Most of these efforts have largely failed to identify a safe regimen for treatment de-escalation that applies to a majority or even a significant plurality of patients with OPC.^14,35,36 Although CheckMate 141 and KEYNOTE-048 garnered excitement when immune checkpoint inhibitors (ICIs) significantly prolonged overall survival and had a more favorable safety profile than standard systemic therapy in recurrent and metastatic OPC,^11,37,38 adding definitive frontline avelumab to CRT failed to prolong progression-free survival versus CRT alone in the phase 3 JAVELIN Head and Neck 100 trial.¹³ Combined with additional recent trial data, these findings make it unlikely that an ICI-based regimen will provide previously unavailable de-escalation options for patients with OPC in the near future.

Considering continued de-escalation efforts, it is important to remember that survival is not uniform among all patients with HPV-associated OPC. For example, patients with HPV-associated OPC and a history of current or prior heavy tobacco use have not experienced the same dramatic prolongation in overall survival as their nonsmoking counterparts.³⁶ Patients with recurrent disease also face a dismal prognosis, with failure rates of about 70% with salvage treatment with surgery, re-irradiation, or systemic therapy.^38-41 Therefore, de-escalation may not be appropriate in all patients, but identifying which patients are at risk of overtreatment is not straightforward. Better risk stratification of patients may provide part of the solution but will require rigorous testing and long-term follow-up to establish.

Discussion

There is an urgent need to carefully consider how to manage long-term survivors of HPV-associated OPC. With ever-increasing numbers of patients who are living years beyond their OPC treatment, continual reevaluation of treatment strategies in certain subsets of patients and making concerted efforts to identify and manage late toxicities early is paramount. Yet there remains a critical gap in knowledge due to insufficient metrics for both toxicity intensity and the frequency of debilitating, life-threatening toxicity. Unfortunately, the lack of tools available combined with the mismatch in disease intensity with treatment intensity likely results in excessive treatment-induced toxicity for many patients.

In the absence of clear evidence about which treatment strategy to use for individual patients, clinicians are tasked with making therapeutic choices without being fully able to predict outcomes. Patient preference is important to consider, but these conversations can be complicated. How does one talk to a patient about their willingness to risk a cancer recurrence and potentially risk late toxicities when the clinician does not know whether that individual patient will develop late toxicities, or know how severe they will be? It is a tradeoff between QOL (ie, possible feeding tube dependence) and survival—yet the magnitude of the effect on QOL remains impossible to predict at present for the individual patient.

Moreover, the needs of individual OPC survivors vary. A cross-sectional study performed at Princess Margaret Cancer Centre found that 61% of the 158 participants had unmet needs related to their cancer survivorship.⁴² Meeting the needs of survivors may require the development of better screening instruments that can manage various complications early and effectively. Continuing to follow OPC survivors with a multidisciplinary team would most certainly be beneficial and has been reported to improve QOL.⁴³ Continual Speech Pathology management and therapy from the time of diagnosis into the survivorship phase of care has been suggested as one way to improve functional outcomes.⁴⁴ Given that coordinating long-term care teams is logistically challenging, well-planned research is warranted to equip these teams to provide OPC survivors with the care they need. These efforts will be particularly important considering the large number of survivors who will need this type of care in the coming decades. The time to start is now well past.

Click to read more from 2023 Rare Diseases Report: Cancers

A 65-year-old African American man presented to an Otolaryngology Head and Neck Surgery clinic at a tertiary Veterans Health Administration (VHA) facility for evaluation. The patient recalled a past diagnosis of oropharyngeal cancer (OPC), possibly associated with the human papillomavirus (HPV). After receiving the diagnosis at another VHA facility, the patient opted to seek care at a local, non-VHA facility and received approximately 7 weeks of daily radiation and weekly infusions of chemotherapy.

Six years after his initial diagnosis and treatment, the patient said he had a persistent cough with any meaningful attempts to eat or drink. He also noted he lost at least 10 lbs in the last 3 months and had been hospitalized twice during the past winter. During his second hospitalization he spent 4 days on a ventilator in the intensive care unit.

On examination, the patient appeared frail and cachectic, with significant fibrosis of the neck skin and moderate trismus. His dentition was in poor health, and an in-clinic flexible endoscopy demonstrated clear silent aspiration of oral secretions. Given his failure to thrive, the patient was urgently admitted to the hospital. A modified barium swallow study performed by the head and neck Speech Pathology team demonstrated gross aspiration with all consistencies. After extensive counseling, the patient agreed to the placement of a gastrostomy tube. He was discharged in stable condition with adequate supplies and self-care training. He was advised to continue follow-up in the Head and Neck Cancer Survivorship clinic.

Two years later, in the early phase of the COVID-19 pandemic, the patient was admitted to the hospital with COVID pneumonia. Given the damage to his lungs over the previous decade from recurrent episodes of aspiration pneumonia, the patient succumbed.

An Unexpected, Unrelenting Epidemic

Shifting population dynamics and behaviors have led to an explosion in the incidence of cancers associated with infection by oncogenic subtypes of HPV, among which cancer of the oropharynx represents the most common malignancy.^1,2 OPC now afflicts more than 30,000 new patients in the United States each year.³ Given current vaccination rates against oncogenic HPV, the overall trend of increasing incidence is not expected to stabilize until the 2040s.³ Traditional cancers of the head and neck region were previously fatal after 5 years in more than 60% of cases; however, today patients with HPV-associated OPC can expect a more than 80% chance of being alive 5 years after treatment.^4-7 Combining the increasing incidence of OPC with a high chance of oncologic cure has led to an ever-expanding cohort of OPC survivors.

Enthusiasm about a high rate of survival after an HPV-associated OPC diagnosis is now partially dampened by an increasing realization that neither oncologists nor healthcare systems are remotely prepared for this rapidly expanding cohort of OPC survivors. Their unique needs and problems have yet to be objectively defined and quantified.

Relationship Between Survival and Long-Term Toxicity in HPV-Associated OPC

Survivorship care after OPC treatment is a growing challenge in terms of the number of patients affected, the negative impact on quality of life (QOL), and the potential burden on the healthcare system. The rapidly growing number of OPC survivors who are living long enough to develop delayed adverse effects related to their past OPC treatment^1,2,8 includes many patients in whom toxicities can be truly debilitating,^9,10 generating significant unmet needs.

Tumor and Treatment Toxicity

Although HPV-associated OPC demonstrates an excellent response to conventional chemoradiotherapy (CRT), this finding cannot be interpreted to mean that reducing treatment intensity is safe for patients with this disease. Prospective trials have now demonstrated that neither replacing or eliminating conventional chemotherapy, nor significantly reducing radiation doses, can be considered safe at this time.^11-15 As a result, a patient with newly diagnosed HPV-associated OPC in 2025, and potentially even 2030, is likely to receive the same treatment as patients who were treated in the late 2010s.¹⁴

Three decades ago, the chronic effects of tumor and treatment were largely limited to a small cohort of survivors; however, today they affect more patients.^1,2,7 Chronic xerostomia, dysphagia, trismus, radiation fibrosis, and osteoradionecrosis (ORN) now confront tens of thousands of OPC survivors; over the coming decades, these treatment effects have the potential to affect millions of patients.^16-22

While most acute toxicities resolve within several months of completing CRT, late CRT sequelae tend to be dynamic and can progress silently over many years.^16,23 Adverse effects vary widely, with many toxicities (eg, dysphagia, ORN) being particularly debilitating. Many of these effects occur in a radiation dose–dependent fashion, but radiation dose does not fully predict late toxicities, pointing to a role for other, yet unidentified contributing factors.^24,25

Dysphagia in Survivors of OPC

About two-thirds of survivors of head and neck cancer (HNC) who seek follow-up care 5 years after treatment report dysphagia and at least partial dependence on a feeding tube.²⁶ The incidence of dysphagia increases proportionately with higher radiation doses delivered to the pharyngeal constrictors and supraglottic larynx.¹⁸ Dysphagia can severely reduce QOL years after treatment, necessitating substantial changes in diet and social behavior among OPC survivors. Often, patients are forced to choose between chronic malnutrition or starvation and feeding tube dependence.²⁷ Loss of a normal oral diet is frequently one of the most affected QOL measures for OPC survivors.²⁸

In addition to effects on QOL, dysphagia can have life-threatening consequences. In a recent systematic review and meta-analysis, life-threatening aspiration occurred after > 24 months at a reported incidence ranging from 3% to nearly 35%. Although a reduction in radiation dose to the pharyngeal constrictors can reduce chronic dysphagia,²⁷ whether this can be done safely in most OPC patients, particularly those with bulky primary tumors, remains unclear.

Osteoradionecrosis (ORN) in Survivors of OPC

ORN is one of the most potentially serious complications of CRT and may not manifest for years after treatment. Its median time of onset after radiotherapy is 8 years in patients with OPC.²⁴ Bone injury and impaired healing of the alveolar mucosa are signs of ORN, which occurs in ~7% of patients receiving intensity-modulated radiation therapy for OPC.¹⁷ ORN is accompanied by pain, difficulties with chewing, exacerbation of concomitant dysphagia and, in the advanced stage—gross cosmetic deformity secondary to mandibular or maxillary fracture and/or decay.²⁹ Despite the severity of this complication, we are just beginning to understand why ORN develops in a subset of patients. Although ORN is generally more common in patients with advanced-stage OPC who receive higher doses of radiation to a larger overall bone volume,^17,19,24,30 comprehensive translational research efforts focused on ORN (as well as other late toxicities of OPC treatment) are still in their infancy.

Unmet Needs in Predicting and Evaluating Late Toxicities

Predicting which patients will experience long-term treatment toxicities or which types of late toxicities they may develop is not yet possible. Whereas increased data collection and prognostic models can help inform healthcare systems as to the expected frequencies of toxicity, they are unlikely to be prognostic at the individual patient level. As such, there is a critical need for individualized biomarker strategies that can predict one’s risk of toxicity and identify normal tissue shifts in biology and function early in the process to initiate interventions before significant deterioration. Adding to the complexity of predicting late toxicities is the lack of standardization in instruments used to categorize them. Examples of tools that may be used to categorize dysphagia include the Common Terminology Criteria for Adverse Events v4.0 grading scale, the Radiation Therapy Oncology Group grading system, and the European Organization for Research and Treatment of Cancer Performance Status Scale for Head and Neck Cancer.²⁰ The MD Anderson Symptom Inventory for head and neck cancer may also be used to catalog dysphagia and other common symptoms of HNC, as well as treatment-related concerns.³¹ Magnetic resonance imaging-based techniques coupled with machine learning approaches represent emerging tools that may have a role in identifying early radiation-induced bone changes that can facilitate early detection of ORN.^32,33 Although conventional and newer tools can be used to generate objective metrics of treatment-related toxicity, consistent and appropriate deployment across the entire cohort of OPC survivors in the United States remains a distant goal.

Calibrating Treatment Intensity to Disease Intensity 

Given the risk of severe and potentially life-threatening consequences of radiation-based treatment, there is a large unmet need to better calibrate treatment intensity to the intensity of HPV-associated OPC.^14,34 In light of the good prognosis of the disease in most patients, recent efforts have focused on identifying ways to de-escalate treatment intensity while preserving the good outcomes known to be possible for patients with HPV-associated OPC. Improving tolerability and limiting the risk of late effects of radiation-based treatment is especially important with the aging population of HPV-associated OPC survivors, who would also be expected to have unrelated comorbidities.¹

Various modes of de-escalation have been studied, including adding surgery to CRT, reducing radiation dose, and modifying systemic therapy regimens. Most of these efforts have largely failed to identify a safe regimen for treatment de-escalation that applies to a majority or even a significant plurality of patients with OPC.^14,35,36 Although CheckMate 141 and KEYNOTE-048 garnered excitement when immune checkpoint inhibitors (ICIs) significantly prolonged overall survival and had a more favorable safety profile than standard systemic therapy in recurrent and metastatic OPC,^11,37,38 adding definitive frontline avelumab to CRT failed to prolong progression-free survival versus CRT alone in the phase 3 JAVELIN Head and Neck 100 trial.¹³ Combined with additional recent trial data, these findings make it unlikely that an ICI-based regimen will provide previously unavailable de-escalation options for patients with OPC in the near future.

Considering continued de-escalation efforts, it is important to remember that survival is not uniform among all patients with HPV-associated OPC. For example, patients with HPV-associated OPC and a history of current or prior heavy tobacco use have not experienced the same dramatic prolongation in overall survival as their nonsmoking counterparts.³⁶ Patients with recurrent disease also face a dismal prognosis, with failure rates of about 70% with salvage treatment with surgery, re-irradiation, or systemic therapy.^38-41 Therefore, de-escalation may not be appropriate in all patients, but identifying which patients are at risk of overtreatment is not straightforward. Better risk stratification of patients may provide part of the solution but will require rigorous testing and long-term follow-up to establish.

Discussion

There is an urgent need to carefully consider how to manage long-term survivors of HPV-associated OPC. With ever-increasing numbers of patients who are living years beyond their OPC treatment, continual reevaluation of treatment strategies in certain subsets of patients and making concerted efforts to identify and manage late toxicities early is paramount. Yet there remains a critical gap in knowledge due to insufficient metrics for both toxicity intensity and the frequency of debilitating, life-threatening toxicity. Unfortunately, the lack of tools available combined with the mismatch in disease intensity with treatment intensity likely results in excessive treatment-induced toxicity for many patients.

In the absence of clear evidence about which treatment strategy to use for individual patients, clinicians are tasked with making therapeutic choices without being fully able to predict outcomes. Patient preference is important to consider, but these conversations can be complicated. How does one talk to a patient about their willingness to risk a cancer recurrence and potentially risk late toxicities when the clinician does not know whether that individual patient will develop late toxicities, or know how severe they will be? It is a tradeoff between QOL (ie, possible feeding tube dependence) and survival—yet the magnitude of the effect on QOL remains impossible to predict at present for the individual patient.

Moreover, the needs of individual OPC survivors vary. A cross-sectional study performed at Princess Margaret Cancer Centre found that 61% of the 158 participants had unmet needs related to their cancer survivorship.⁴² Meeting the needs of survivors may require the development of better screening instruments that can manage various complications early and effectively. Continuing to follow OPC survivors with a multidisciplinary team would most certainly be beneficial and has been reported to improve QOL.⁴³ Continual Speech Pathology management and therapy from the time of diagnosis into the survivorship phase of care has been suggested as one way to improve functional outcomes.⁴⁴ Given that coordinating long-term care teams is logistically challenging, well-planned research is warranted to equip these teams to provide OPC survivors with the care they need. These efforts will be particularly important considering the large number of survivors who will need this type of care in the coming decades. The time to start is now well past.

Click to read more from 2023 Rare Diseases Report: Cancers

Higher doses of oral semaglutide than the 14-mg/day dose that is currently approved for type 2 diabetes may be additional options for patients with prediabetes or diabetes and obesity, according to the results of two new phase 3 clinical trials.

The two trials, OASIS in patients with overweight or obesity without diabetes and PIONEER PLUS in patients with inadequately controlled type 2 diabetes, were presented at the annual scientific sessions of the American Diabetes Association and simultaneously published in The Lancet.

Filip K. Knop, MD, PhD, University of Copenhagen, presented highlights of the OASIS-1 results, and Vanita R. Aroda, MD, Brigham and Women’s Hospital and Harvard University, Boston, presented key findings of PIONEER PLUS, during a press briefing prior to the ADA session.

OASIS-1 showed that “oral semaglutide 50 mg may represent an effective option for the treatment of obesity, particularly in patients who prefer oral administration,” Dr. Knop summarized.

And “the PIONEER PLUS trial showed superior glycemic control and body-weight loss and improvement in cardiometabolic risk factors, with higher doses of once-daily oral semaglutide (25 mg and 50 mg) compared with the currently [highest] approved 14-mg dose,” said Dr. Aroda.

Session chair Marion Pragnell, PhD, vice president of research & science at ADA, said in an interview there is a need for multiple treatment options, as different patients respond differently to individual drugs. The oral dose of semaglutide has to be higher than that approved for subcutaneous injection (as Ozempic or Wegovy) because of bioavailability, but small-molecule research is advancing such that in future lower doses of oral drugs may have the same effect as the current lower subcutaneous doses of the drug.

The oral version of semaglutide (Rybelsus) was approved in the United States for type 2 diabetes in doses of 7 mg or 14 mg per day in 2019; it has not been approved for use in obesity.

Dr. Knop remarked that, in his clinical practice, about 25% of patients with type 2 diabetes prefer daily oral semaglutide and the rest prefer weekly injected semaglutide.

“Having an oral formulation of semaglutide in addition to the subcutaneous, or injectable, formula available will allow people who struggle to lose weight with diet and physical activity alone to take this effective medication in a way that best suits them,” he added.

Participants in OASIS and PIONEER PLUS were instructed to take the once-daily study drug tablet in the morning, in the fasting state, with up to half a glass of water (120 mL) at least 30 minutes before intake of any other food, beverage, or oral medication.
 

OASIS: 50-mg daily pill in adults with overweight or obesity

OASIS is, to their knowledge, “the first trial to assess the bodyweight-lowering effect of an oral GLP-1 agonist (semaglutide 50 mg taken once per day) in adults with overweight or obesity, without type 2 diabetes,” Dr. Knop and colleagues wrote.

The 50-mg dose induced clinically meaningful reductions in bodyweight, with accompanying improvements in cardiometabolic risk factors, consistent with results reported for subcutaneous semaglutide 2.4 mg once weekly (Wegovy) in a similar population.

As an adjunct to diet and physical activity, oral semaglutide 50 mg led to a mean bodyweight reduction of 15.1%, compared with 2.4% in the placebo group, and greater percentages of participants reaching bodyweight reduction targets of at least 5%, 10%, 15%, and 20%.

Body-weight reductions were accompanied by significant improvements in cardiometabolic risk factors, compared with placebo.

“These results indicate that oral semaglutide 50 mg could provide an effective, future option for people with overweight or obesity who would benefit from a GLP-1 receptor agonist,” they concluded.
 

PIONEER PLUS: Inadequately controlled type 2 diabetes

Reporting the PIONEER PLUS data, Dr. Aroda and colleagues said: “For people with inadequately controlled type 2 diabetes on a stable dose of one to three oral glucose-lowering drugs, higher doses (25 mg and 50 mg) of once-daily oral semaglutide provided more effective glycemic control and greater bodyweight loss than 14 mg semaglutide, without additional safety concerns.”

PIONEER PLUS is the first study to indicate that these bigger doses of semaglutide might provide a highly effective oral option to improve both glycemic control and weight loss in type 2 diabetes.

“This trial provides compelling evidence that the availability of a wider range of doses of oral semaglutide will allow for individualized dosing to the desired effect, and the ability to intensify treatment as needed,” said Dr. Aroda. “We are hopeful that these results encourage earlier effective management of type 2 diabetes and allow for broader management in the primary care setting.”

In an accompanying editorial Christina H. Sherrill, PharmD, and Andrew Y. Hwang, PharmD, write: “This expansion in dosing titration might provide clinicians with more opportunities to obtain the maximum efficacy of this oral GLP-1 agonist.”

But additional investigations “to establish whether the superior glycemic reduction seen at these higher doses translates into cardiovascular risk reduction” are needed, said Dr. Sherrill, of High Point (N.C.) University, and Dr. Hwang, of Massachusetts College of Pharmacy and Health Sciences University, Boston.

Such investigations “would further elucidate the place in therapy of high-dose oral semaglutide,” they concluded.

Dr. Aroda and colleagues agreed: “Future real-world studies will be needed to investigate the clinical impact of the availability of higher doses of oral semaglutide.”

The trials were funded by Novo Nordisk.

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

Higher doses of oral semaglutide than the 14-mg/day dose that is currently approved for type 2 diabetes may be additional options for patients with prediabetes or diabetes and obesity, according to the results of two new phase 3 clinical trials.

The two trials, OASIS in patients with overweight or obesity without diabetes and PIONEER PLUS in patients with inadequately controlled type 2 diabetes, were presented at the annual scientific sessions of the American Diabetes Association and simultaneously published in The Lancet.

Filip K. Knop, MD, PhD, University of Copenhagen, presented highlights of the OASIS-1 results, and Vanita R. Aroda, MD, Brigham and Women’s Hospital and Harvard University, Boston, presented key findings of PIONEER PLUS, during a press briefing prior to the ADA session.

OASIS-1 showed that “oral semaglutide 50 mg may represent an effective option for the treatment of obesity, particularly in patients who prefer oral administration,” Dr. Knop summarized.

And “the PIONEER PLUS trial showed superior glycemic control and body-weight loss and improvement in cardiometabolic risk factors, with higher doses of once-daily oral semaglutide (25 mg and 50 mg) compared with the currently [highest] approved 14-mg dose,” said Dr. Aroda.

Session chair Marion Pragnell, PhD, vice president of research & science at ADA, said in an interview there is a need for multiple treatment options, as different patients respond differently to individual drugs. The oral dose of semaglutide has to be higher than that approved for subcutaneous injection (as Ozempic or Wegovy) because of bioavailability, but small-molecule research is advancing such that in future lower doses of oral drugs may have the same effect as the current lower subcutaneous doses of the drug.

The oral version of semaglutide (Rybelsus) was approved in the United States for type 2 diabetes in doses of 7 mg or 14 mg per day in 2019; it has not been approved for use in obesity.

Dr. Knop remarked that, in his clinical practice, about 25% of patients with type 2 diabetes prefer daily oral semaglutide and the rest prefer weekly injected semaglutide.

“Having an oral formulation of semaglutide in addition to the subcutaneous, or injectable, formula available will allow people who struggle to lose weight with diet and physical activity alone to take this effective medication in a way that best suits them,” he added.

Participants in OASIS and PIONEER PLUS were instructed to take the once-daily study drug tablet in the morning, in the fasting state, with up to half a glass of water (120 mL) at least 30 minutes before intake of any other food, beverage, or oral medication.
 

OASIS: 50-mg daily pill in adults with overweight or obesity

OASIS is, to their knowledge, “the first trial to assess the bodyweight-lowering effect of an oral GLP-1 agonist (semaglutide 50 mg taken once per day) in adults with overweight or obesity, without type 2 diabetes,” Dr. Knop and colleagues wrote.

The 50-mg dose induced clinically meaningful reductions in bodyweight, with accompanying improvements in cardiometabolic risk factors, consistent with results reported for subcutaneous semaglutide 2.4 mg once weekly (Wegovy) in a similar population.

As an adjunct to diet and physical activity, oral semaglutide 50 mg led to a mean bodyweight reduction of 15.1%, compared with 2.4% in the placebo group, and greater percentages of participants reaching bodyweight reduction targets of at least 5%, 10%, 15%, and 20%.

Body-weight reductions were accompanied by significant improvements in cardiometabolic risk factors, compared with placebo.

“These results indicate that oral semaglutide 50 mg could provide an effective, future option for people with overweight or obesity who would benefit from a GLP-1 receptor agonist,” they concluded.
 

PIONEER PLUS: Inadequately controlled type 2 diabetes

Reporting the PIONEER PLUS data, Dr. Aroda and colleagues said: “For people with inadequately controlled type 2 diabetes on a stable dose of one to three oral glucose-lowering drugs, higher doses (25 mg and 50 mg) of once-daily oral semaglutide provided more effective glycemic control and greater bodyweight loss than 14 mg semaglutide, without additional safety concerns.”

PIONEER PLUS is the first study to indicate that these bigger doses of semaglutide might provide a highly effective oral option to improve both glycemic control and weight loss in type 2 diabetes.

“This trial provides compelling evidence that the availability of a wider range of doses of oral semaglutide will allow for individualized dosing to the desired effect, and the ability to intensify treatment as needed,” said Dr. Aroda. “We are hopeful that these results encourage earlier effective management of type 2 diabetes and allow for broader management in the primary care setting.”

In an accompanying editorial Christina H. Sherrill, PharmD, and Andrew Y. Hwang, PharmD, write: “This expansion in dosing titration might provide clinicians with more opportunities to obtain the maximum efficacy of this oral GLP-1 agonist.”

But additional investigations “to establish whether the superior glycemic reduction seen at these higher doses translates into cardiovascular risk reduction” are needed, said Dr. Sherrill, of High Point (N.C.) University, and Dr. Hwang, of Massachusetts College of Pharmacy and Health Sciences University, Boston.

Such investigations “would further elucidate the place in therapy of high-dose oral semaglutide,” they concluded.

Dr. Aroda and colleagues agreed: “Future real-world studies will be needed to investigate the clinical impact of the availability of higher doses of oral semaglutide.”

The trials were funded by Novo Nordisk.

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

Higher doses of oral semaglutide than the 14-mg/day dose that is currently approved for type 2 diabetes may be additional options for patients with prediabetes or diabetes and obesity, according to the results of two new phase 3 clinical trials.

The two trials, OASIS in patients with overweight or obesity without diabetes and PIONEER PLUS in patients with inadequately controlled type 2 diabetes, were presented at the annual scientific sessions of the American Diabetes Association and simultaneously published in The Lancet.

Filip K. Knop, MD, PhD, University of Copenhagen, presented highlights of the OASIS-1 results, and Vanita R. Aroda, MD, Brigham and Women’s Hospital and Harvard University, Boston, presented key findings of PIONEER PLUS, during a press briefing prior to the ADA session.

OASIS-1 showed that “oral semaglutide 50 mg may represent an effective option for the treatment of obesity, particularly in patients who prefer oral administration,” Dr. Knop summarized.

And “the PIONEER PLUS trial showed superior glycemic control and body-weight loss and improvement in cardiometabolic risk factors, with higher doses of once-daily oral semaglutide (25 mg and 50 mg) compared with the currently [highest] approved 14-mg dose,” said Dr. Aroda.

Session chair Marion Pragnell, PhD, vice president of research & science at ADA, said in an interview there is a need for multiple treatment options, as different patients respond differently to individual drugs. The oral dose of semaglutide has to be higher than that approved for subcutaneous injection (as Ozempic or Wegovy) because of bioavailability, but small-molecule research is advancing such that in future lower doses of oral drugs may have the same effect as the current lower subcutaneous doses of the drug.

The oral version of semaglutide (Rybelsus) was approved in the United States for type 2 diabetes in doses of 7 mg or 14 mg per day in 2019; it has not been approved for use in obesity.

Dr. Knop remarked that, in his clinical practice, about 25% of patients with type 2 diabetes prefer daily oral semaglutide and the rest prefer weekly injected semaglutide.

“Having an oral formulation of semaglutide in addition to the subcutaneous, or injectable, formula available will allow people who struggle to lose weight with diet and physical activity alone to take this effective medication in a way that best suits them,” he added.

Participants in OASIS and PIONEER PLUS were instructed to take the once-daily study drug tablet in the morning, in the fasting state, with up to half a glass of water (120 mL) at least 30 minutes before intake of any other food, beverage, or oral medication.
 

OASIS: 50-mg daily pill in adults with overweight or obesity

OASIS is, to their knowledge, “the first trial to assess the bodyweight-lowering effect of an oral GLP-1 agonist (semaglutide 50 mg taken once per day) in adults with overweight or obesity, without type 2 diabetes,” Dr. Knop and colleagues wrote.

The 50-mg dose induced clinically meaningful reductions in bodyweight, with accompanying improvements in cardiometabolic risk factors, consistent with results reported for subcutaneous semaglutide 2.4 mg once weekly (Wegovy) in a similar population.

As an adjunct to diet and physical activity, oral semaglutide 50 mg led to a mean bodyweight reduction of 15.1%, compared with 2.4% in the placebo group, and greater percentages of participants reaching bodyweight reduction targets of at least 5%, 10%, 15%, and 20%.

Body-weight reductions were accompanied by significant improvements in cardiometabolic risk factors, compared with placebo.

“These results indicate that oral semaglutide 50 mg could provide an effective, future option for people with overweight or obesity who would benefit from a GLP-1 receptor agonist,” they concluded.
 

PIONEER PLUS: Inadequately controlled type 2 diabetes

Reporting the PIONEER PLUS data, Dr. Aroda and colleagues said: “For people with inadequately controlled type 2 diabetes on a stable dose of one to three oral glucose-lowering drugs, higher doses (25 mg and 50 mg) of once-daily oral semaglutide provided more effective glycemic control and greater bodyweight loss than 14 mg semaglutide, without additional safety concerns.”

PIONEER PLUS is the first study to indicate that these bigger doses of semaglutide might provide a highly effective oral option to improve both glycemic control and weight loss in type 2 diabetes.

“This trial provides compelling evidence that the availability of a wider range of doses of oral semaglutide will allow for individualized dosing to the desired effect, and the ability to intensify treatment as needed,” said Dr. Aroda. “We are hopeful that these results encourage earlier effective management of type 2 diabetes and allow for broader management in the primary care setting.”

In an accompanying editorial Christina H. Sherrill, PharmD, and Andrew Y. Hwang, PharmD, write: “This expansion in dosing titration might provide clinicians with more opportunities to obtain the maximum efficacy of this oral GLP-1 agonist.”

But additional investigations “to establish whether the superior glycemic reduction seen at these higher doses translates into cardiovascular risk reduction” are needed, said Dr. Sherrill, of High Point (N.C.) University, and Dr. Hwang, of Massachusetts College of Pharmacy and Health Sciences University, Boston.

Such investigations “would further elucidate the place in therapy of high-dose oral semaglutide,” they concluded.

Dr. Aroda and colleagues agreed: “Future real-world studies will be needed to investigate the clinical impact of the availability of higher doses of oral semaglutide.”

The trials were funded by Novo Nordisk.

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

Background 

Of the approximately 80,000 individuals diagnosed annually in the United States with a non-Hodgkin lymphoma (NHL), MCL accounts for an estimated 5%.^1,2 At the time of diagnosis, most of these patients have advanced disease. The diagnosis of MCL is made based on characteristic immunophenotype and the presence of (11;14)(q13;q32) translocation resulting in overexpression of cyclin D1.^3,4 Long-term survival has been observed in a small proportion of patients with MCL, but this disease is generally considered incurable.⁵

Except for the approximately 10% of patients with MCL who present with asymptomatic indolent disease, for whom a watch-and-wait approach is generally used,⁶ there are 2 types of treatment strategies. One is applied to people who are fit and relatively young. In these cases, intensive chemotherapy with or without ASCT has been the dominant approach. In patients who are poor candidates for the toxicities associated with aggressive treatment, less intensive approaches are applied. These strategies include not only better-tolerated combinations of cytotoxic chemotherapies, but also various combinations that involve immunomodulators or small molecule enzyme inhibitors. Although less toxic, these regimens are active, often achieving a complete response (CR) and an extended progression-free survival (PFS).³

These 2 pathways of MCL treatment are reflected in guidelines from the National Comprehensive Cancer Network (NCCN), which describe separate first-line algorithms for stage I and stage II non-bulky disease and stage II bulky and advanced stage disease.⁷ For stage II bulky or advanced stage disease, separate pathways are described for indolent, TP53-mutated, and TP53 wild-type MCL and are further divided into pathways for those who are candidates for ASCT and those who are not.

Currently, “chemotherapy-free” therapies, a term that is sometimes used to identify drug combinations with modest or no cytotoxic effects, though inaccurate, are not preferred for first-line therapy in any group in the NCCN guidelines. However, immunomodulators, such as lenalidomide and targeted therapies, such as Bruton tyrosine kinase inhibitors (BTKis) are being actively tested in the front-line setting with promising results. Practical approaches to the application of these agents are described in trials presented or published in the last year, including TRIANGLE and SHINE.^10,11

Rethinking Front-Line MCL Therapy in the Young and Fit

Case Study

A 52-year-old man with a history of smoking presented with shortness of breath and general fatigue. The medical history included no major chronic diseases. The patient, who was referred after a routine examination, reported a recent decrease in body weight of unknown cause. Enlargement of inguinal, axillary, and submaxillary lymph nodes on examination along with laboratory abnormalities, such as anemia, and elevated lymphoid cells in the peripheral blood, raised suspicion of a lymphoproliferative disorder. A diagnosis of MCL was reached based on characteristic lymphoid cell morphology and immunotyping positive for CCND1 on lymph node biopsy. Ki-67 was 50% with wild-type TP53 on next-generation sequencing. The disease was characterized as stage III with intermediate risk MIPI (Mantle Cell Lymphoma International Prognostic Index).

For this presentation, one NCCN-guideline recommendation is a cytarabine-containing intensive chemotherapy regimen with rituximab followed by ASCT with maintenance rituximab in patients who are fit for transplant,⁷ but the recent data from the multicenter open-label TRIANGLE study has challenged this paradigm.¹⁰

In TRIANGLE, 870 treatment-naïve patients younger than age 65 (median age 57 years) were randomized to 1 of 3 study arms.¹⁰ In the control arm, patients received the standard-of-care induction with intensive chemoimmunotherapy (CIT) with ASCT consolidation (CIT + ASCT). In 1 of 2 experimental arms, patients received CIT + ibrutinib followed by ASCT consolidation and 2 years of ibrutinib maintenance (CIT + I + ASCT). In the other experimental arm, patients received CIT + ibrutinib followed by 2 years of ibrutinib maintenance with ASCT omitted (CIT + I). Rituximab maintenance as a single dose administered every 2 months for up to 3 years was permitted in all arms.

Most (87%) of the patients in TRIANGLE had stage IV disease and most (85%) had low- or intermediate-risk MIPI. The primary endpoint was failure-free survival (FFS). Rates of FFS at 3 years were 72% for the CIT+ ASCT arm, 88% for the CIT + I + ASCT arm, and 86% for the CIT + I arm. Overall survival (OS) at 3 years, during which time the trial was amended to permit rituximab maintenance in all 3 study arms, numerically favored ibrutinib arms (92% for CIT + I and 91% for CIT + I + ASCT), over chemotherapy alone (86% for CIT + ASCT).

The TRIANGLE trial does not yet establish a new standard for the types of patients enrolled, but it does show clearly that the use of ibrutinib with CIT was not inferior to the standard intensive approach integrating ASCT, and most types of adverse events occurred with less frequency in the ibrutinib-only arm.

There are numerous questions to pose and a broader understanding of applicability to be gained as more follow-up of this study and other studies utilizing targeted therapies, including other BTK inhibitors, provide mor data. Of particular interest is whether the presence of minimal residual disease (MRD) and the prognostic implications of MRD are affected by the use of a BTKi and/or ASCT. The E4151 and E4181 clinical trials may collectively provide greater insight here.^12,13

Rethinking Front-Line MCL Therapy in Older Patients

Case Study

A 74-year-old man with a history of cardiovascular disease, including a prior ST-elevated myocardial infarction, presents with nonspecific symptoms, including night sweats, intermittent fevers, and fatigue. Despite his symptoms, he continues to work 3 days per week and participates in a weekly game of doubles tennis. Axillary swelling leads him to seek medical attention. Imaging demonstrates diffuse lymphadenopathy. An axillary lymph node biopsy confirms a diagnosis of MC with FISH (fluorescence in situ hybridization) positive for t(11;14). He is of intermediate risk on MIPI scoring.

Due to his age and concurrent heart disease, he is not a candidate for aggressive chemotherapy and ASCT. Less aggressive therapies including bendamustine plus rituximab (BR),^14,15 lenalidomide plus rituximab (RR),⁸ and rituximab, bendamustine, and cytarabine (R-BAC) are discussed with this patient.¹⁶

Based on STiL data and BRIGHT studies, BR has become a widely used regimen.^14,15 However, attempts are being made to improve upon the BR backbone with the addition of BTK inhibitors.¹¹ In SHINE, BR plus ibrutinib further improved PFS relative to BR alone. SHINE was a 2-arm study, which was restricted to patients 65 years of age or older (median age 71 years); 523 previously untreated patients with good performance status and acceptable organ function were randomized to BR or BR plus ibrutinib. Most patients had intermediate- (~48%) or high- (~34%) risk MIPI. More than 90% had advanced-stage disease. Of patients in whom the TP53 mutation status was established, only about 10% were positive.

In the arm receiving BR alone, the median PFS was 52.9 months. With the addition of 560 mg once-daily ibrutinib to 6 cycles of BR followed by maintenance rituximab and continued ibrutinib, the median PFS, which was the primary endpoint, climbed to a median of 80.6 months. BR plus ibrutini was associated with a 41% reduction in the hazard ratio (HR) for progression or death (HR 0.75; P=.01). When stratified by risk factors, the advantage of BR plus ibrutinib was particularly pronounced in patients with intermediate-risk, (although not high-risk) nonmutated TP53, and less bulky disease.¹¹

There was no significant effect of the addition of ibrutinib on OS at the last analysis, but the longer PFS was achieved with only a modest increase in adverse events (AEs). For AEs of grade 3 or higher, the AE rates for BR plus ibrutinib and BR alone were 81.5% and 77.3%, respectively. Rates of cytopenias, including grade 3 or higher, were similar in the 2 arms. Rash and gastrointestinal AEs, such as diarrhea, nausea, and abdominal pain, occurred more frequently among patients who received ibrutinib.¹¹

Without an OS advantage, the SHINE trial does not establish a new standard of care, particularly given that it was voluntarily revoked from the market for the treatment of MCL. However, results are likely to accelerate interest in evaluating other targeted therapies, in combination with other relatively well-tolerated treatments. In patients with MCL unfit for ASCT, there is interest in pursuing other BTK inhibitors, particularly with ibrutinib being revoked as an indication for MCL. including the newer noncovalent pirtobrutinib, which was recently approved for MCL in the relapsed/refractory setting,¹⁷ and bispecific T-cell engagers (BiTEs) such as glofitamab.¹⁸

Rethinking Front-Line in TP53-Mutated MCL

Case Study

A previously healthy 62-year-old woman who presents with rapidly progressing lymphadenopathy and constitutional symptoms is diagnosed with MCL that has multiple adverse features. She has a Ki-67 level higher than 30%, a TP53 mutation, and blastoid morphology.¹⁹

The NCCN guidelines strongly recommend a clinical trial for patients with a TP53 mutation.⁷ Despite various high-intensity combinations to control disease in these patients, the 2017 pooled analysis demonstrated that most patients with TP53 mutations have a poor or no response to chemotherapy with a high side effect burden.¹⁹ In particular, such patients derive little benefit from high-intensity chemotherapy using ASCT.¹⁹

Nonetheless, for TP53-mutated MCL, several regimens have demonstrated activity. Most of these have used highly targeted therapies that offer the potential for low relative rates of toxicity. Two “chemotherapy-free” combinations involving venetoclax, the CD20-targeted obinutuzumab, and BTK inhibitors have completed phase 2 trials with promising results.^20,21 In a study evaluating the BOVen regimen (the second-generation BTK inhibitor zanubrutinib, obinutuzumab, and venetoclax) as time-limited therapy in TP53-mutated patients, 89% of patients achieved MRD at 26 months of follow-up.²⁰

Several novel therapies being tested in the relapsed/refractory setting have generated interest for evaluation in front-line clinical studies. These strategies include the BiTE glofitamab,¹⁸ the antibody-drug conjugate zilovertamab vedotin,²² and the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (brexu-cel).²³ Brexu-cel is already approved in relapsed/refractory MCL.²³ Given the poor response to available treatments seen in patients with TP53 mutations, these novel therapies have the potential to improve outcomes in this population of high unmet need.

Summary

Durable remissions of MCL can be achieved with aggressive combinations of chemotherapy, but recent studies suggest a momentum away from cytotoxic drugs toward therapies with more targeted effects. In at least some patient populations, these therapies can rival the degree and duration of disease control achieved with less well-tolerated treatment. If ongoing trials corroborate the long-term efficacy and safety of these approaches, these therapies may represent an important evolution in MCL management.

Click to read more from 2023 Rare Diseases Report: Cancers

Background 

Of the approximately 80,000 individuals diagnosed annually in the United States with a non-Hodgkin lymphoma (NHL), MCL accounts for an estimated 5%.^1,2 At the time of diagnosis, most of these patients have advanced disease. The diagnosis of MCL is made based on characteristic immunophenotype and the presence of (11;14)(q13;q32) translocation resulting in overexpression of cyclin D1.^3,4 Long-term survival has been observed in a small proportion of patients with MCL, but this disease is generally considered incurable.⁵

Except for the approximately 10% of patients with MCL who present with asymptomatic indolent disease, for whom a watch-and-wait approach is generally used,⁶ there are 2 types of treatment strategies. One is applied to people who are fit and relatively young. In these cases, intensive chemotherapy with or without ASCT has been the dominant approach. In patients who are poor candidates for the toxicities associated with aggressive treatment, less intensive approaches are applied. These strategies include not only better-tolerated combinations of cytotoxic chemotherapies, but also various combinations that involve immunomodulators or small molecule enzyme inhibitors. Although less toxic, these regimens are active, often achieving a complete response (CR) and an extended progression-free survival (PFS).³

These 2 pathways of MCL treatment are reflected in guidelines from the National Comprehensive Cancer Network (NCCN), which describe separate first-line algorithms for stage I and stage II non-bulky disease and stage II bulky and advanced stage disease.⁷ For stage II bulky or advanced stage disease, separate pathways are described for indolent, TP53-mutated, and TP53 wild-type MCL and are further divided into pathways for those who are candidates for ASCT and those who are not.

Currently, “chemotherapy-free” therapies, a term that is sometimes used to identify drug combinations with modest or no cytotoxic effects, though inaccurate, are not preferred for first-line therapy in any group in the NCCN guidelines. However, immunomodulators, such as lenalidomide and targeted therapies, such as Bruton tyrosine kinase inhibitors (BTKis) are being actively tested in the front-line setting with promising results. Practical approaches to the application of these agents are described in trials presented or published in the last year, including TRIANGLE and SHINE.^10,11

Rethinking Front-Line MCL Therapy in the Young and Fit

Case Study

A 52-year-old man with a history of smoking presented with shortness of breath and general fatigue. The medical history included no major chronic diseases. The patient, who was referred after a routine examination, reported a recent decrease in body weight of unknown cause. Enlargement of inguinal, axillary, and submaxillary lymph nodes on examination along with laboratory abnormalities, such as anemia, and elevated lymphoid cells in the peripheral blood, raised suspicion of a lymphoproliferative disorder. A diagnosis of MCL was reached based on characteristic lymphoid cell morphology and immunotyping positive for CCND1 on lymph node biopsy. Ki-67 was 50% with wild-type TP53 on next-generation sequencing. The disease was characterized as stage III with intermediate risk MIPI (Mantle Cell Lymphoma International Prognostic Index).

For this presentation, one NCCN-guideline recommendation is a cytarabine-containing intensive chemotherapy regimen with rituximab followed by ASCT with maintenance rituximab in patients who are fit for transplant,⁷ but the recent data from the multicenter open-label TRIANGLE study has challenged this paradigm.¹⁰

In TRIANGLE, 870 treatment-naïve patients younger than age 65 (median age 57 years) were randomized to 1 of 3 study arms.¹⁰ In the control arm, patients received the standard-of-care induction with intensive chemoimmunotherapy (CIT) with ASCT consolidation (CIT + ASCT). In 1 of 2 experimental arms, patients received CIT + ibrutinib followed by ASCT consolidation and 2 years of ibrutinib maintenance (CIT + I + ASCT). In the other experimental arm, patients received CIT + ibrutinib followed by 2 years of ibrutinib maintenance with ASCT omitted (CIT + I). Rituximab maintenance as a single dose administered every 2 months for up to 3 years was permitted in all arms.

Most (87%) of the patients in TRIANGLE had stage IV disease and most (85%) had low- or intermediate-risk MIPI. The primary endpoint was failure-free survival (FFS). Rates of FFS at 3 years were 72% for the CIT+ ASCT arm, 88% for the CIT + I + ASCT arm, and 86% for the CIT + I arm. Overall survival (OS) at 3 years, during which time the trial was amended to permit rituximab maintenance in all 3 study arms, numerically favored ibrutinib arms (92% for CIT + I and 91% for CIT + I + ASCT), over chemotherapy alone (86% for CIT + ASCT).

The TRIANGLE trial does not yet establish a new standard for the types of patients enrolled, but it does show clearly that the use of ibrutinib with CIT was not inferior to the standard intensive approach integrating ASCT, and most types of adverse events occurred with less frequency in the ibrutinib-only arm.

There are numerous questions to pose and a broader understanding of applicability to be gained as more follow-up of this study and other studies utilizing targeted therapies, including other BTK inhibitors, provide mor data. Of particular interest is whether the presence of minimal residual disease (MRD) and the prognostic implications of MRD are affected by the use of a BTKi and/or ASCT. The E4151 and E4181 clinical trials may collectively provide greater insight here.^12,13

Rethinking Front-Line MCL Therapy in Older Patients

Case Study

A 74-year-old man with a history of cardiovascular disease, including a prior ST-elevated myocardial infarction, presents with nonspecific symptoms, including night sweats, intermittent fevers, and fatigue. Despite his symptoms, he continues to work 3 days per week and participates in a weekly game of doubles tennis. Axillary swelling leads him to seek medical attention. Imaging demonstrates diffuse lymphadenopathy. An axillary lymph node biopsy confirms a diagnosis of MC with FISH (fluorescence in situ hybridization) positive for t(11;14). He is of intermediate risk on MIPI scoring.

Due to his age and concurrent heart disease, he is not a candidate for aggressive chemotherapy and ASCT. Less aggressive therapies including bendamustine plus rituximab (BR),^14,15 lenalidomide plus rituximab (RR),⁸ and rituximab, bendamustine, and cytarabine (R-BAC) are discussed with this patient.¹⁶

Based on STiL data and BRIGHT studies, BR has become a widely used regimen.^14,15 However, attempts are being made to improve upon the BR backbone with the addition of BTK inhibitors.¹¹ In SHINE, BR plus ibrutinib further improved PFS relative to BR alone. SHINE was a 2-arm study, which was restricted to patients 65 years of age or older (median age 71 years); 523 previously untreated patients with good performance status and acceptable organ function were randomized to BR or BR plus ibrutinib. Most patients had intermediate- (~48%) or high- (~34%) risk MIPI. More than 90% had advanced-stage disease. Of patients in whom the TP53 mutation status was established, only about 10% were positive.

In the arm receiving BR alone, the median PFS was 52.9 months. With the addition of 560 mg once-daily ibrutinib to 6 cycles of BR followed by maintenance rituximab and continued ibrutinib, the median PFS, which was the primary endpoint, climbed to a median of 80.6 months. BR plus ibrutini was associated with a 41% reduction in the hazard ratio (HR) for progression or death (HR 0.75; P=.01). When stratified by risk factors, the advantage of BR plus ibrutinib was particularly pronounced in patients with intermediate-risk, (although not high-risk) nonmutated TP53, and less bulky disease.¹¹

There was no significant effect of the addition of ibrutinib on OS at the last analysis, but the longer PFS was achieved with only a modest increase in adverse events (AEs). For AEs of grade 3 or higher, the AE rates for BR plus ibrutinib and BR alone were 81.5% and 77.3%, respectively. Rates of cytopenias, including grade 3 or higher, were similar in the 2 arms. Rash and gastrointestinal AEs, such as diarrhea, nausea, and abdominal pain, occurred more frequently among patients who received ibrutinib.¹¹

Without an OS advantage, the SHINE trial does not establish a new standard of care, particularly given that it was voluntarily revoked from the market for the treatment of MCL. However, results are likely to accelerate interest in evaluating other targeted therapies, in combination with other relatively well-tolerated treatments. In patients with MCL unfit for ASCT, there is interest in pursuing other BTK inhibitors, particularly with ibrutinib being revoked as an indication for MCL. including the newer noncovalent pirtobrutinib, which was recently approved for MCL in the relapsed/refractory setting,¹⁷ and bispecific T-cell engagers (BiTEs) such as glofitamab.¹⁸

Rethinking Front-Line in TP53-Mutated MCL

Case Study

A previously healthy 62-year-old woman who presents with rapidly progressing lymphadenopathy and constitutional symptoms is diagnosed with MCL that has multiple adverse features. She has a Ki-67 level higher than 30%, a TP53 mutation, and blastoid morphology.¹⁹

The NCCN guidelines strongly recommend a clinical trial for patients with a TP53 mutation.⁷ Despite various high-intensity combinations to control disease in these patients, the 2017 pooled analysis demonstrated that most patients with TP53 mutations have a poor or no response to chemotherapy with a high side effect burden.¹⁹ In particular, such patients derive little benefit from high-intensity chemotherapy using ASCT.¹⁹

Nonetheless, for TP53-mutated MCL, several regimens have demonstrated activity. Most of these have used highly targeted therapies that offer the potential for low relative rates of toxicity. Two “chemotherapy-free” combinations involving venetoclax, the CD20-targeted obinutuzumab, and BTK inhibitors have completed phase 2 trials with promising results.^20,21 In a study evaluating the BOVen regimen (the second-generation BTK inhibitor zanubrutinib, obinutuzumab, and venetoclax) as time-limited therapy in TP53-mutated patients, 89% of patients achieved MRD at 26 months of follow-up.²⁰

Several novel therapies being tested in the relapsed/refractory setting have generated interest for evaluation in front-line clinical studies. These strategies include the BiTE glofitamab,¹⁸ the antibody-drug conjugate zilovertamab vedotin,²² and the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (brexu-cel).²³ Brexu-cel is already approved in relapsed/refractory MCL.²³ Given the poor response to available treatments seen in patients with TP53 mutations, these novel therapies have the potential to improve outcomes in this population of high unmet need.

Summary

Durable remissions of MCL can be achieved with aggressive combinations of chemotherapy, but recent studies suggest a momentum away from cytotoxic drugs toward therapies with more targeted effects. In at least some patient populations, these therapies can rival the degree and duration of disease control achieved with less well-tolerated treatment. If ongoing trials corroborate the long-term efficacy and safety of these approaches, these therapies may represent an important evolution in MCL management.

Click to read more from 2023 Rare Diseases Report: Cancers

Background 

Of the approximately 80,000 individuals diagnosed annually in the United States with a non-Hodgkin lymphoma (NHL), MCL accounts for an estimated 5%.^1,2 At the time of diagnosis, most of these patients have advanced disease. The diagnosis of MCL is made based on characteristic immunophenotype and the presence of (11;14)(q13;q32) translocation resulting in overexpression of cyclin D1.^3,4 Long-term survival has been observed in a small proportion of patients with MCL, but this disease is generally considered incurable.⁵

Except for the approximately 10% of patients with MCL who present with asymptomatic indolent disease, for whom a watch-and-wait approach is generally used,⁶ there are 2 types of treatment strategies. One is applied to people who are fit and relatively young. In these cases, intensive chemotherapy with or without ASCT has been the dominant approach. In patients who are poor candidates for the toxicities associated with aggressive treatment, less intensive approaches are applied. These strategies include not only better-tolerated combinations of cytotoxic chemotherapies, but also various combinations that involve immunomodulators or small molecule enzyme inhibitors. Although less toxic, these regimens are active, often achieving a complete response (CR) and an extended progression-free survival (PFS).³

These 2 pathways of MCL treatment are reflected in guidelines from the National Comprehensive Cancer Network (NCCN), which describe separate first-line algorithms for stage I and stage II non-bulky disease and stage II bulky and advanced stage disease.⁷ For stage II bulky or advanced stage disease, separate pathways are described for indolent, TP53-mutated, and TP53 wild-type MCL and are further divided into pathways for those who are candidates for ASCT and those who are not.

Currently, “chemotherapy-free” therapies, a term that is sometimes used to identify drug combinations with modest or no cytotoxic effects, though inaccurate, are not preferred for first-line therapy in any group in the NCCN guidelines. However, immunomodulators, such as lenalidomide and targeted therapies, such as Bruton tyrosine kinase inhibitors (BTKis) are being actively tested in the front-line setting with promising results. Practical approaches to the application of these agents are described in trials presented or published in the last year, including TRIANGLE and SHINE.^10,11

Rethinking Front-Line MCL Therapy in the Young and Fit

Case Study

A 52-year-old man with a history of smoking presented with shortness of breath and general fatigue. The medical history included no major chronic diseases. The patient, who was referred after a routine examination, reported a recent decrease in body weight of unknown cause. Enlargement of inguinal, axillary, and submaxillary lymph nodes on examination along with laboratory abnormalities, such as anemia, and elevated lymphoid cells in the peripheral blood, raised suspicion of a lymphoproliferative disorder. A diagnosis of MCL was reached based on characteristic lymphoid cell morphology and immunotyping positive for CCND1 on lymph node biopsy. Ki-67 was 50% with wild-type TP53 on next-generation sequencing. The disease was characterized as stage III with intermediate risk MIPI (Mantle Cell Lymphoma International Prognostic Index).

For this presentation, one NCCN-guideline recommendation is a cytarabine-containing intensive chemotherapy regimen with rituximab followed by ASCT with maintenance rituximab in patients who are fit for transplant,⁷ but the recent data from the multicenter open-label TRIANGLE study has challenged this paradigm.¹⁰

In TRIANGLE, 870 treatment-naïve patients younger than age 65 (median age 57 years) were randomized to 1 of 3 study arms.¹⁰ In the control arm, patients received the standard-of-care induction with intensive chemoimmunotherapy (CIT) with ASCT consolidation (CIT + ASCT). In 1 of 2 experimental arms, patients received CIT + ibrutinib followed by ASCT consolidation and 2 years of ibrutinib maintenance (CIT + I + ASCT). In the other experimental arm, patients received CIT + ibrutinib followed by 2 years of ibrutinib maintenance with ASCT omitted (CIT + I). Rituximab maintenance as a single dose administered every 2 months for up to 3 years was permitted in all arms.

Most (87%) of the patients in TRIANGLE had stage IV disease and most (85%) had low- or intermediate-risk MIPI. The primary endpoint was failure-free survival (FFS). Rates of FFS at 3 years were 72% for the CIT+ ASCT arm, 88% for the CIT + I + ASCT arm, and 86% for the CIT + I arm. Overall survival (OS) at 3 years, during which time the trial was amended to permit rituximab maintenance in all 3 study arms, numerically favored ibrutinib arms (92% for CIT + I and 91% for CIT + I + ASCT), over chemotherapy alone (86% for CIT + ASCT).

The TRIANGLE trial does not yet establish a new standard for the types of patients enrolled, but it does show clearly that the use of ibrutinib with CIT was not inferior to the standard intensive approach integrating ASCT, and most types of adverse events occurred with less frequency in the ibrutinib-only arm.

There are numerous questions to pose and a broader understanding of applicability to be gained as more follow-up of this study and other studies utilizing targeted therapies, including other BTK inhibitors, provide mor data. Of particular interest is whether the presence of minimal residual disease (MRD) and the prognostic implications of MRD are affected by the use of a BTKi and/or ASCT. The E4151 and E4181 clinical trials may collectively provide greater insight here.^12,13

Rethinking Front-Line MCL Therapy in Older Patients

Case Study

A 74-year-old man with a history of cardiovascular disease, including a prior ST-elevated myocardial infarction, presents with nonspecific symptoms, including night sweats, intermittent fevers, and fatigue. Despite his symptoms, he continues to work 3 days per week and participates in a weekly game of doubles tennis. Axillary swelling leads him to seek medical attention. Imaging demonstrates diffuse lymphadenopathy. An axillary lymph node biopsy confirms a diagnosis of MC with FISH (fluorescence in situ hybridization) positive for t(11;14). He is of intermediate risk on MIPI scoring.

Due to his age and concurrent heart disease, he is not a candidate for aggressive chemotherapy and ASCT. Less aggressive therapies including bendamustine plus rituximab (BR),^14,15 lenalidomide plus rituximab (RR),⁸ and rituximab, bendamustine, and cytarabine (R-BAC) are discussed with this patient.¹⁶

Based on STiL data and BRIGHT studies, BR has become a widely used regimen.^14,15 However, attempts are being made to improve upon the BR backbone with the addition of BTK inhibitors.¹¹ In SHINE, BR plus ibrutinib further improved PFS relative to BR alone. SHINE was a 2-arm study, which was restricted to patients 65 years of age or older (median age 71 years); 523 previously untreated patients with good performance status and acceptable organ function were randomized to BR or BR plus ibrutinib. Most patients had intermediate- (~48%) or high- (~34%) risk MIPI. More than 90% had advanced-stage disease. Of patients in whom the TP53 mutation status was established, only about 10% were positive.

In the arm receiving BR alone, the median PFS was 52.9 months. With the addition of 560 mg once-daily ibrutinib to 6 cycles of BR followed by maintenance rituximab and continued ibrutinib, the median PFS, which was the primary endpoint, climbed to a median of 80.6 months. BR plus ibrutini was associated with a 41% reduction in the hazard ratio (HR) for progression or death (HR 0.75; P=.01). When stratified by risk factors, the advantage of BR plus ibrutinib was particularly pronounced in patients with intermediate-risk, (although not high-risk) nonmutated TP53, and less bulky disease.¹¹

There was no significant effect of the addition of ibrutinib on OS at the last analysis, but the longer PFS was achieved with only a modest increase in adverse events (AEs). For AEs of grade 3 or higher, the AE rates for BR plus ibrutinib and BR alone were 81.5% and 77.3%, respectively. Rates of cytopenias, including grade 3 or higher, were similar in the 2 arms. Rash and gastrointestinal AEs, such as diarrhea, nausea, and abdominal pain, occurred more frequently among patients who received ibrutinib.¹¹

Without an OS advantage, the SHINE trial does not establish a new standard of care, particularly given that it was voluntarily revoked from the market for the treatment of MCL. However, results are likely to accelerate interest in evaluating other targeted therapies, in combination with other relatively well-tolerated treatments. In patients with MCL unfit for ASCT, there is interest in pursuing other BTK inhibitors, particularly with ibrutinib being revoked as an indication for MCL. including the newer noncovalent pirtobrutinib, which was recently approved for MCL in the relapsed/refractory setting,¹⁷ and bispecific T-cell engagers (BiTEs) such as glofitamab.¹⁸

Rethinking Front-Line in TP53-Mutated MCL

Case Study

A previously healthy 62-year-old woman who presents with rapidly progressing lymphadenopathy and constitutional symptoms is diagnosed with MCL that has multiple adverse features. She has a Ki-67 level higher than 30%, a TP53 mutation, and blastoid morphology.¹⁹

The NCCN guidelines strongly recommend a clinical trial for patients with a TP53 mutation.⁷ Despite various high-intensity combinations to control disease in these patients, the 2017 pooled analysis demonstrated that most patients with TP53 mutations have a poor or no response to chemotherapy with a high side effect burden.¹⁹ In particular, such patients derive little benefit from high-intensity chemotherapy using ASCT.¹⁹

Nonetheless, for TP53-mutated MCL, several regimens have demonstrated activity. Most of these have used highly targeted therapies that offer the potential for low relative rates of toxicity. Two “chemotherapy-free” combinations involving venetoclax, the CD20-targeted obinutuzumab, and BTK inhibitors have completed phase 2 trials with promising results.^20,21 In a study evaluating the BOVen regimen (the second-generation BTK inhibitor zanubrutinib, obinutuzumab, and venetoclax) as time-limited therapy in TP53-mutated patients, 89% of patients achieved MRD at 26 months of follow-up.²⁰

Several novel therapies being tested in the relapsed/refractory setting have generated interest for evaluation in front-line clinical studies. These strategies include the BiTE glofitamab,¹⁸ the antibody-drug conjugate zilovertamab vedotin,²² and the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (brexu-cel).²³ Brexu-cel is already approved in relapsed/refractory MCL.²³ Given the poor response to available treatments seen in patients with TP53 mutations, these novel therapies have the potential to improve outcomes in this population of high unmet need.

Summary

Durable remissions of MCL can be achieved with aggressive combinations of chemotherapy, but recent studies suggest a momentum away from cytotoxic drugs toward therapies with more targeted effects. In at least some patient populations, these therapies can rival the degree and duration of disease control achieved with less well-tolerated treatment. If ongoing trials corroborate the long-term efficacy and safety of these approaches, these therapies may represent an important evolution in MCL management.

Click to read more from 2023 Rare Diseases Report: Cancers

New data suggest a significantly stronger link in women compared with men between atrial fibrillation (AF) and mild cognitive impairment (MCI) and dementia.

“Our findings imply that women with AF may be at higher risk for MCI and dementia with potentially more rapid disease progression from normal cognition to MCI or dementia than women without AF or men with and without AF,” wrote authors of a new study led by Kathryn A. Wood, PhD, RN, Neil Hodgson Woodruff School of Nursing at Emory University in Atlanta.

The findings were published online in Alzheimer’s & Dementia.

Researchers used the National Alzheimer’s Coordinating Center data with 43,630 patients and analyzed sex differences between men and women with AF and their performance on neuropsychological tests and cognitive disease progression.

Higher odds of dementia, MCI in women

According to the paper, AF is associated with higher odds of dementia (odds ratio [OR], 3.00; 95% confidence interval [CI], 1.22-7.37) in women and MCI in women (OR, 3.43; 95% CI, 1.55-7.55) compared with men.

Women with AF and normal cognition at baseline had a higher risk of disease progression (hazard ratio [HR], 1.26; 95% CI, 1.06-1.50) from normal to MCI and from MCI to vascular dementia (HR, 3.27; 95% CI, 1.89-5.65) than that of men with AF or men and women without AF. 

AF is a major public health problem linked with stroke and heart failure, and is an independent risk factor of increased mortality. It is associated with higher risk of cognitive impairment and dementia independent of stroke history.
 

Cognitive screening for AF patients

The authors wrote that cognitive screening, especially in women, should be part of yearly cardiology visits for patients with AF to help identify early those at highest risk for cognitive disease.

T. Jared Bunch, MD, professor of medicine in the division of cardiovascular medicine at University of Utah in Salt Lake City, said in an interview, “We have learned that how we treat atrial fibrillation can influence risk.”

First, he said, outcomes, including brain health, are better when rhythm control approaches are used within the first year of diagnosis. 

“Restoring a normal heart rhythm improves brain perfusion and cognitive function. Next, aggressive rhythm control – such as catheter ablation – is associated with much lower long-term risks of dementia in the [patients].  Finally, early and effective use of anticoagulation in patients with atrial fibrillation lowers risk of stroke, dementia, and cognitive decline.”
 

Several factors unknown

Dr. Bunch said there are some unknowns in the study, such as how long patients were in atrial fibrillation. 

He said one way to address the inequities is to refer women earlier as women are often referred later in disease to specialty care, which can have consequences.

He said it is not known how many people underwent early and effective rhythm control. 

“Women also are less likely to receive catheter ablation, a cardioversion, or be placed on antiarrhythmic drugs,” said Dr. Bunch, who was not part of the study. “These also represent potential opportunities to improve outcomes by treating the rhythm in a similar and aggressive manner in both men and women.”

Also unknown is how many people were on effective oral anticoagulation, Dr. Bunch noted.

The study importantly highlights a significant problem surrounding the care of women with AF, he said, but there are strategies to improve outcomes.

In addition to earlier screening and referral for women, providers should recognize that men and women may present differently with different AF symptoms. He added that physicians should offer catheter ablation, the most effective treatment, equally to men and women who are candidates.

In all people, he said, it’s important “to start anticoagulation very early in the disease to lower the risk of micro- and macrothrombotic events that lead to poor brain health and function.”

The study authors and Dr. Bunch declared no relevant financial relationships.

New data suggest a significantly stronger link in women compared with men between atrial fibrillation (AF) and mild cognitive impairment (MCI) and dementia.

“Our findings imply that women with AF may be at higher risk for MCI and dementia with potentially more rapid disease progression from normal cognition to MCI or dementia than women without AF or men with and without AF,” wrote authors of a new study led by Kathryn A. Wood, PhD, RN, Neil Hodgson Woodruff School of Nursing at Emory University in Atlanta.

The findings were published online in Alzheimer’s & Dementia.

Researchers used the National Alzheimer’s Coordinating Center data with 43,630 patients and analyzed sex differences between men and women with AF and their performance on neuropsychological tests and cognitive disease progression.

Higher odds of dementia, MCI in women

According to the paper, AF is associated with higher odds of dementia (odds ratio [OR], 3.00; 95% confidence interval [CI], 1.22-7.37) in women and MCI in women (OR, 3.43; 95% CI, 1.55-7.55) compared with men.

Women with AF and normal cognition at baseline had a higher risk of disease progression (hazard ratio [HR], 1.26; 95% CI, 1.06-1.50) from normal to MCI and from MCI to vascular dementia (HR, 3.27; 95% CI, 1.89-5.65) than that of men with AF or men and women without AF. 

AF is a major public health problem linked with stroke and heart failure, and is an independent risk factor of increased mortality. It is associated with higher risk of cognitive impairment and dementia independent of stroke history.
 

Cognitive screening for AF patients

The authors wrote that cognitive screening, especially in women, should be part of yearly cardiology visits for patients with AF to help identify early those at highest risk for cognitive disease.

T. Jared Bunch, MD, professor of medicine in the division of cardiovascular medicine at University of Utah in Salt Lake City, said in an interview, “We have learned that how we treat atrial fibrillation can influence risk.”

First, he said, outcomes, including brain health, are better when rhythm control approaches are used within the first year of diagnosis. 

“Restoring a normal heart rhythm improves brain perfusion and cognitive function. Next, aggressive rhythm control – such as catheter ablation – is associated with much lower long-term risks of dementia in the [patients].  Finally, early and effective use of anticoagulation in patients with atrial fibrillation lowers risk of stroke, dementia, and cognitive decline.”
 

Several factors unknown

Dr. Bunch said there are some unknowns in the study, such as how long patients were in atrial fibrillation. 

He said one way to address the inequities is to refer women earlier as women are often referred later in disease to specialty care, which can have consequences.

He said it is not known how many people underwent early and effective rhythm control. 

“Women also are less likely to receive catheter ablation, a cardioversion, or be placed on antiarrhythmic drugs,” said Dr. Bunch, who was not part of the study. “These also represent potential opportunities to improve outcomes by treating the rhythm in a similar and aggressive manner in both men and women.”

Also unknown is how many people were on effective oral anticoagulation, Dr. Bunch noted.

The study importantly highlights a significant problem surrounding the care of women with AF, he said, but there are strategies to improve outcomes.

In addition to earlier screening and referral for women, providers should recognize that men and women may present differently with different AF symptoms. He added that physicians should offer catheter ablation, the most effective treatment, equally to men and women who are candidates.

In all people, he said, it’s important “to start anticoagulation very early in the disease to lower the risk of micro- and macrothrombotic events that lead to poor brain health and function.”

The study authors and Dr. Bunch declared no relevant financial relationships.

New data suggest a significantly stronger link in women compared with men between atrial fibrillation (AF) and mild cognitive impairment (MCI) and dementia.

“Our findings imply that women with AF may be at higher risk for MCI and dementia with potentially more rapid disease progression from normal cognition to MCI or dementia than women without AF or men with and without AF,” wrote authors of a new study led by Kathryn A. Wood, PhD, RN, Neil Hodgson Woodruff School of Nursing at Emory University in Atlanta.

The findings were published online in Alzheimer’s & Dementia.

Researchers used the National Alzheimer’s Coordinating Center data with 43,630 patients and analyzed sex differences between men and women with AF and their performance on neuropsychological tests and cognitive disease progression.

Higher odds of dementia, MCI in women

According to the paper, AF is associated with higher odds of dementia (odds ratio [OR], 3.00; 95% confidence interval [CI], 1.22-7.37) in women and MCI in women (OR, 3.43; 95% CI, 1.55-7.55) compared with men.

Women with AF and normal cognition at baseline had a higher risk of disease progression (hazard ratio [HR], 1.26; 95% CI, 1.06-1.50) from normal to MCI and from MCI to vascular dementia (HR, 3.27; 95% CI, 1.89-5.65) than that of men with AF or men and women without AF. 

AF is a major public health problem linked with stroke and heart failure, and is an independent risk factor of increased mortality. It is associated with higher risk of cognitive impairment and dementia independent of stroke history.
 

Cognitive screening for AF patients

The authors wrote that cognitive screening, especially in women, should be part of yearly cardiology visits for patients with AF to help identify early those at highest risk for cognitive disease.

T. Jared Bunch, MD, professor of medicine in the division of cardiovascular medicine at University of Utah in Salt Lake City, said in an interview, “We have learned that how we treat atrial fibrillation can influence risk.”

First, he said, outcomes, including brain health, are better when rhythm control approaches are used within the first year of diagnosis. 

“Restoring a normal heart rhythm improves brain perfusion and cognitive function. Next, aggressive rhythm control – such as catheter ablation – is associated with much lower long-term risks of dementia in the [patients].  Finally, early and effective use of anticoagulation in patients with atrial fibrillation lowers risk of stroke, dementia, and cognitive decline.”
 

Several factors unknown

Dr. Bunch said there are some unknowns in the study, such as how long patients were in atrial fibrillation. 

He said one way to address the inequities is to refer women earlier as women are often referred later in disease to specialty care, which can have consequences.

He said it is not known how many people underwent early and effective rhythm control. 

“Women also are less likely to receive catheter ablation, a cardioversion, or be placed on antiarrhythmic drugs,” said Dr. Bunch, who was not part of the study. “These also represent potential opportunities to improve outcomes by treating the rhythm in a similar and aggressive manner in both men and women.”

Also unknown is how many people were on effective oral anticoagulation, Dr. Bunch noted.

The study importantly highlights a significant problem surrounding the care of women with AF, he said, but there are strategies to improve outcomes.

In addition to earlier screening and referral for women, providers should recognize that men and women may present differently with different AF symptoms. He added that physicians should offer catheter ablation, the most effective treatment, equally to men and women who are candidates.

In all people, he said, it’s important “to start anticoagulation very early in the disease to lower the risk of micro- and macrothrombotic events that lead to poor brain health and function.”

The study authors and Dr. Bunch declared no relevant financial relationships.

More than 140 million Americans use artificial sweeteners, a habit driven by the irrefutable fact that excess sugar is harmful. But I’m continually amazed by alarmist headlines on the topic.

In May, the World Health Organization (WHO) released a report to support its “conditional recommendation” against the use of non-sugar sweeteners (NSS) for weight control. Despite the WHO’s goal “to provide evidence-informed guidance,” the report includes the disclaimer that “The recommendation is based on evidence of low certainty.”

Low certainty is an accurate descriptor for the findings of many of the 280-plus studies in the report. That the guidance does not apply to patients with diabetes was easily lost in the repeated mentions of the perceived dangers of these sugar alternatives.

The review included various table-top and beverage sweeteners, including acesulfame K, aspartame, saccharin, sucralose, stevia, and stevia derivatives. Low-calorie sugars and sugar alcohols such as erythritol were excluded.

The WHO looked at long- and short-term trials, randomized controlled trials (RCTs), prospective studies, and case-control studies measuring a wide range of endpoints, from dental caries to cancer. The report highlighted that some findings cannot be attributed directly to NSS use but may simply be due to their substitution for sugar. Differences in outcomes due to sex, ethnicity, and body weight status could not be assessed either. And the WHO conceded the possibility of reverse causation in observational studies wherein higher-risk individuals may consume more NSS.

Nonnutritive sweeteners are given little credit for weight loss. “A significant difference in body weight and BMI was only observed in trials that reported a reduction in energy intake ... rather than primarily by an inherent property of NSS that can modulate body weight (independently of energy intake),” the report reads. But isn’t the desired effect of using an artificial sweetener instead of table sugar that you lower your calorie intake?

The WHO noted that weight loss was not sustained – a finding in nearly every weight loss trial in history and something more attributable to human nature than the sweetener one chooses.

The document outlines that meta-analyses of prospective cohort studies show that higher intakes of NSS were associated with an increased risk for type 2 diabetes and elevated fasting glucose, while meta-analyses of randomized trials suggest no significant effect on “biomarkers used in the assessment and diagnosis of diabetes and insulin resistance, including fasting glucose, fasting insulin and hemoglobin A1c.”

Similar disparities are noted with cardiovascular risk. Prospective trials suggest an increased risk for CVD, including stroke and its precursor, hypertension; but again, the RCT data found no evidence to suggest a significant effect “on biomarkers used in the assessment and diagnosis of CVDs, including blood pressure, low-density lipoprotein cholesterol and other blood lipids.”
 

Splenda and stevia under fire

Predictably, some in the nonnutritive sweetener industry are incensed.

Ted Gelov, CEO of Heartland Food Products Group, maker of Splenda, responded in a press release, “Every few years now it seems I have to come to you and clarify misleading headlines ... Suggesting that sweeteners like Splenda cannot have long-term benefits is a disservice to healthcare providers, their patients, and all consumers.”

Splenda has been on the U.S. market since 1999, and Mr. Gelov reportedly uses three to eight packets daily in his coffee and tea.

I reached out to Heartland and they sent me an eight-page document consisting of over 50 statements, summaries, and clinical trials supporting the safety of artificial sweeteners, including sucralose, an ingredient in Splenda. In 2016, Mr. Gelov rebutted claims that sucralose was linked to cancer in Swiss male mice. These “dramatized headlines are based on one flawed study by an isolated Italian research laboratory, the Ramazzini Institute,” Mr. Gelov wrote.

Another recent headline was about the DNA-damaging effects of sucralose-6-acetate (S6A) seen in an in vitro study published in the Journal of Toxicology and Environmental Health. According to the authors, commercial sucralose samples contain up to 0.67% S6A, a manufacturing impurity.

Despite many reports linking this study to Splenda, Heartland wrote that “Splenda and its ingredients were never studied or tested in this research. We, and our suppliers, rigorously and routinely test and monitor for any impurities in our products. We can confirm that S6A is not present in Splenda Brand sucralose down to the lowest detection limit possible, which is .001% sensitivity level.”

F. Perry Wilson, MD, director of Clinical and Translational Research Accelerator at Yale and a regular contributor to this news organization, took to Twitter to put this study in context: “The human exposure equivalent to sucralose would be 60 packets per day,” he pointed out. And the blood levels of S6A with normal consumption would not “come close to the DNA damage threshold noted in the article.”

Perhaps the most concerning scientific data suggesting a link between artificial sweetener use and ill health is a Cleveland Clinic study showing an association between higher blood levels of erythritol and adverse cardiovascular outcomes such as heart attack, stroke, or death. The researchers also found that erythritol, which is found in stevia and some keto food products, made platelet activation and clot formation easier.

When I asked about these findings, Heartland stated, “The study was primarily conducted on patients who were at an elevated risk of cardiovascular events due to their advanced age, elevated body mass and presence of pre-existing health conditions ... the stated findings were only an association and cannot imply causation.”

The main conclusion I’ve drawn on the topic of artificial sweeteners is that a lot of resources were wasted in performing underpowered, poorly designed trials on compounds that are already generally regarded as safe (GRAS) by the FDA. The WHO “conditional guideline” is, by its own description, based on a plethora of “low certainty” to “very low certainty” evidence.

The monies to produce the WHO report and many of these trials would have been better spent educating the public on the difference between simple and complex carbohydrates; the inflammatory and disease-producing effects of excess sugars; and how to prevent, diagnose, and treat diabetes.

If more trials on artificial sweeteners are planned, they should be performed on people doing human things – which does not include ingesting 60 packets of any sweetener in a single day.

In my personal N-of-1 trial, consuming sugar makes me crave more, feel sluggish, and gain weight. I don’t believe that NSS alone will control my weight. But I’ll continue to drink two cups of stevia-laced coffee every morning, take walks, avoid alcohol, eat my vegetables, and hope for the best.

Dr. Walton-Shirley is a clinical cardiologist in Nashville, Tenn. She disclosed no relevant conflicts of interest.

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

More than 140 million Americans use artificial sweeteners, a habit driven by the irrefutable fact that excess sugar is harmful. But I’m continually amazed by alarmist headlines on the topic.

In May, the World Health Organization (WHO) released a report to support its “conditional recommendation” against the use of non-sugar sweeteners (NSS) for weight control. Despite the WHO’s goal “to provide evidence-informed guidance,” the report includes the disclaimer that “The recommendation is based on evidence of low certainty.”

Low certainty is an accurate descriptor for the findings of many of the 280-plus studies in the report. That the guidance does not apply to patients with diabetes was easily lost in the repeated mentions of the perceived dangers of these sugar alternatives.

The review included various table-top and beverage sweeteners, including acesulfame K, aspartame, saccharin, sucralose, stevia, and stevia derivatives. Low-calorie sugars and sugar alcohols such as erythritol were excluded.

The WHO looked at long- and short-term trials, randomized controlled trials (RCTs), prospective studies, and case-control studies measuring a wide range of endpoints, from dental caries to cancer. The report highlighted that some findings cannot be attributed directly to NSS use but may simply be due to their substitution for sugar. Differences in outcomes due to sex, ethnicity, and body weight status could not be assessed either. And the WHO conceded the possibility of reverse causation in observational studies wherein higher-risk individuals may consume more NSS.

Nonnutritive sweeteners are given little credit for weight loss. “A significant difference in body weight and BMI was only observed in trials that reported a reduction in energy intake ... rather than primarily by an inherent property of NSS that can modulate body weight (independently of energy intake),” the report reads. But isn’t the desired effect of using an artificial sweetener instead of table sugar that you lower your calorie intake?

The WHO noted that weight loss was not sustained – a finding in nearly every weight loss trial in history and something more attributable to human nature than the sweetener one chooses.

The document outlines that meta-analyses of prospective cohort studies show that higher intakes of NSS were associated with an increased risk for type 2 diabetes and elevated fasting glucose, while meta-analyses of randomized trials suggest no significant effect on “biomarkers used in the assessment and diagnosis of diabetes and insulin resistance, including fasting glucose, fasting insulin and hemoglobin A1c.”

Similar disparities are noted with cardiovascular risk. Prospective trials suggest an increased risk for CVD, including stroke and its precursor, hypertension; but again, the RCT data found no evidence to suggest a significant effect “on biomarkers used in the assessment and diagnosis of CVDs, including blood pressure, low-density lipoprotein cholesterol and other blood lipids.”
 

Splenda and stevia under fire

Predictably, some in the nonnutritive sweetener industry are incensed.

Ted Gelov, CEO of Heartland Food Products Group, maker of Splenda, responded in a press release, “Every few years now it seems I have to come to you and clarify misleading headlines ... Suggesting that sweeteners like Splenda cannot have long-term benefits is a disservice to healthcare providers, their patients, and all consumers.”

Splenda has been on the U.S. market since 1999, and Mr. Gelov reportedly uses three to eight packets daily in his coffee and tea.

I reached out to Heartland and they sent me an eight-page document consisting of over 50 statements, summaries, and clinical trials supporting the safety of artificial sweeteners, including sucralose, an ingredient in Splenda. In 2016, Mr. Gelov rebutted claims that sucralose was linked to cancer in Swiss male mice. These “dramatized headlines are based on one flawed study by an isolated Italian research laboratory, the Ramazzini Institute,” Mr. Gelov wrote.

Another recent headline was about the DNA-damaging effects of sucralose-6-acetate (S6A) seen in an in vitro study published in the Journal of Toxicology and Environmental Health. According to the authors, commercial sucralose samples contain up to 0.67% S6A, a manufacturing impurity.

Despite many reports linking this study to Splenda, Heartland wrote that “Splenda and its ingredients were never studied or tested in this research. We, and our suppliers, rigorously and routinely test and monitor for any impurities in our products. We can confirm that S6A is not present in Splenda Brand sucralose down to the lowest detection limit possible, which is .001% sensitivity level.”

F. Perry Wilson, MD, director of Clinical and Translational Research Accelerator at Yale and a regular contributor to this news organization, took to Twitter to put this study in context: “The human exposure equivalent to sucralose would be 60 packets per day,” he pointed out. And the blood levels of S6A with normal consumption would not “come close to the DNA damage threshold noted in the article.”

Perhaps the most concerning scientific data suggesting a link between artificial sweetener use and ill health is a Cleveland Clinic study showing an association between higher blood levels of erythritol and adverse cardiovascular outcomes such as heart attack, stroke, or death. The researchers also found that erythritol, which is found in stevia and some keto food products, made platelet activation and clot formation easier.

When I asked about these findings, Heartland stated, “The study was primarily conducted on patients who were at an elevated risk of cardiovascular events due to their advanced age, elevated body mass and presence of pre-existing health conditions ... the stated findings were only an association and cannot imply causation.”

The main conclusion I’ve drawn on the topic of artificial sweeteners is that a lot of resources were wasted in performing underpowered, poorly designed trials on compounds that are already generally regarded as safe (GRAS) by the FDA. The WHO “conditional guideline” is, by its own description, based on a plethora of “low certainty” to “very low certainty” evidence.

The monies to produce the WHO report and many of these trials would have been better spent educating the public on the difference between simple and complex carbohydrates; the inflammatory and disease-producing effects of excess sugars; and how to prevent, diagnose, and treat diabetes.

If more trials on artificial sweeteners are planned, they should be performed on people doing human things – which does not include ingesting 60 packets of any sweetener in a single day.

In my personal N-of-1 trial, consuming sugar makes me crave more, feel sluggish, and gain weight. I don’t believe that NSS alone will control my weight. But I’ll continue to drink two cups of stevia-laced coffee every morning, take walks, avoid alcohol, eat my vegetables, and hope for the best.

Dr. Walton-Shirley is a clinical cardiologist in Nashville, Tenn. She disclosed no relevant conflicts of interest.

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

More than 140 million Americans use artificial sweeteners, a habit driven by the irrefutable fact that excess sugar is harmful. But I’m continually amazed by alarmist headlines on the topic.

In May, the World Health Organization (WHO) released a report to support its “conditional recommendation” against the use of non-sugar sweeteners (NSS) for weight control. Despite the WHO’s goal “to provide evidence-informed guidance,” the report includes the disclaimer that “The recommendation is based on evidence of low certainty.”

Low certainty is an accurate descriptor for the findings of many of the 280-plus studies in the report. That the guidance does not apply to patients with diabetes was easily lost in the repeated mentions of the perceived dangers of these sugar alternatives.

The review included various table-top and beverage sweeteners, including acesulfame K, aspartame, saccharin, sucralose, stevia, and stevia derivatives. Low-calorie sugars and sugar alcohols such as erythritol were excluded.

The WHO looked at long- and short-term trials, randomized controlled trials (RCTs), prospective studies, and case-control studies measuring a wide range of endpoints, from dental caries to cancer. The report highlighted that some findings cannot be attributed directly to NSS use but may simply be due to their substitution for sugar. Differences in outcomes due to sex, ethnicity, and body weight status could not be assessed either. And the WHO conceded the possibility of reverse causation in observational studies wherein higher-risk individuals may consume more NSS.

Nonnutritive sweeteners are given little credit for weight loss. “A significant difference in body weight and BMI was only observed in trials that reported a reduction in energy intake ... rather than primarily by an inherent property of NSS that can modulate body weight (independently of energy intake),” the report reads. But isn’t the desired effect of using an artificial sweetener instead of table sugar that you lower your calorie intake?

The WHO noted that weight loss was not sustained – a finding in nearly every weight loss trial in history and something more attributable to human nature than the sweetener one chooses.

The document outlines that meta-analyses of prospective cohort studies show that higher intakes of NSS were associated with an increased risk for type 2 diabetes and elevated fasting glucose, while meta-analyses of randomized trials suggest no significant effect on “biomarkers used in the assessment and diagnosis of diabetes and insulin resistance, including fasting glucose, fasting insulin and hemoglobin A1c.”

Similar disparities are noted with cardiovascular risk. Prospective trials suggest an increased risk for CVD, including stroke and its precursor, hypertension; but again, the RCT data found no evidence to suggest a significant effect “on biomarkers used in the assessment and diagnosis of CVDs, including blood pressure, low-density lipoprotein cholesterol and other blood lipids.”
 

Splenda and stevia under fire

Predictably, some in the nonnutritive sweetener industry are incensed.

Ted Gelov, CEO of Heartland Food Products Group, maker of Splenda, responded in a press release, “Every few years now it seems I have to come to you and clarify misleading headlines ... Suggesting that sweeteners like Splenda cannot have long-term benefits is a disservice to healthcare providers, their patients, and all consumers.”

Splenda has been on the U.S. market since 1999, and Mr. Gelov reportedly uses three to eight packets daily in his coffee and tea.

I reached out to Heartland and they sent me an eight-page document consisting of over 50 statements, summaries, and clinical trials supporting the safety of artificial sweeteners, including sucralose, an ingredient in Splenda. In 2016, Mr. Gelov rebutted claims that sucralose was linked to cancer in Swiss male mice. These “dramatized headlines are based on one flawed study by an isolated Italian research laboratory, the Ramazzini Institute,” Mr. Gelov wrote.

Another recent headline was about the DNA-damaging effects of sucralose-6-acetate (S6A) seen in an in vitro study published in the Journal of Toxicology and Environmental Health. According to the authors, commercial sucralose samples contain up to 0.67% S6A, a manufacturing impurity.

Despite many reports linking this study to Splenda, Heartland wrote that “Splenda and its ingredients were never studied or tested in this research. We, and our suppliers, rigorously and routinely test and monitor for any impurities in our products. We can confirm that S6A is not present in Splenda Brand sucralose down to the lowest detection limit possible, which is .001% sensitivity level.”

F. Perry Wilson, MD, director of Clinical and Translational Research Accelerator at Yale and a regular contributor to this news organization, took to Twitter to put this study in context: “The human exposure equivalent to sucralose would be 60 packets per day,” he pointed out. And the blood levels of S6A with normal consumption would not “come close to the DNA damage threshold noted in the article.”

Perhaps the most concerning scientific data suggesting a link between artificial sweetener use and ill health is a Cleveland Clinic study showing an association between higher blood levels of erythritol and adverse cardiovascular outcomes such as heart attack, stroke, or death. The researchers also found that erythritol, which is found in stevia and some keto food products, made platelet activation and clot formation easier.

When I asked about these findings, Heartland stated, “The study was primarily conducted on patients who were at an elevated risk of cardiovascular events due to their advanced age, elevated body mass and presence of pre-existing health conditions ... the stated findings were only an association and cannot imply causation.”

The main conclusion I’ve drawn on the topic of artificial sweeteners is that a lot of resources were wasted in performing underpowered, poorly designed trials on compounds that are already generally regarded as safe (GRAS) by the FDA. The WHO “conditional guideline” is, by its own description, based on a plethora of “low certainty” to “very low certainty” evidence.

The monies to produce the WHO report and many of these trials would have been better spent educating the public on the difference between simple and complex carbohydrates; the inflammatory and disease-producing effects of excess sugars; and how to prevent, diagnose, and treat diabetes.

If more trials on artificial sweeteners are planned, they should be performed on people doing human things – which does not include ingesting 60 packets of any sweetener in a single day.

In my personal N-of-1 trial, consuming sugar makes me crave more, feel sluggish, and gain weight. I don’t believe that NSS alone will control my weight. But I’ll continue to drink two cups of stevia-laced coffee every morning, take walks, avoid alcohol, eat my vegetables, and hope for the best.

Dr. Walton-Shirley is a clinical cardiologist in Nashville, Tenn. She disclosed no relevant conflicts of interest.

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

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

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

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

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

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

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

PHOENIX – The way Jennifer Barton, PhD, sees it, optical coherence tomography (OCT), laser-induced fluorescence, and multiphoton microscopy are poised to revolutionize the future of cancer detection.

Chris Richards/University of Arizona

In a lecture during a multispecialty roundup of cutting-edge energy-based device applications at the annual conference of the American Society for Laser Medicine and Surgery, Dr. Barton, a biomedical engineer who directs the BIO5 Institute at the University of Arizona, Tucson, said that while no current modality exists to enable physicians in dermatology and other specialties to view internal structures throughout the entire body with cellular resolution, refining existing technologies is a good way to start.

In 2011, renowned cancer researchers Douglas Hanahan, PhD, and Robert A. Weinberg, PhD, proposed six hallmarks of cancer, which include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Each hallmark poses unique imaging challenges. For example, enabling replicative immortality “means that the cell nuclei change size and shape; they change their position,” said Dr. Barton, who is also professor of biomedical engineering and optical sciences at the university. “If we want to see that, we’re going to need an imaging modality that’s subcellular in resolution.”

Similarly, if clinicians want to view how proliferative signaling is changing, “that means being able to visualize the cell surface receptors; those are even smaller to actually visualize,” she said. “But we have technologies where we can target those receptors with fluorophores. And then we can look at large areas very quickly.” Meanwhile, the ability of cancer cells to resist cell death and evade growth suppressors often results in thickening of epithelium throughout the body. “So, if we can measure the thickness of the epithelium, we can see that there’s something wrong with that tissue,” she said.

As for cancer’s propensity for invasion and metastasis, “here, we’re looking at how the collagen structure [between the cells] has changed and whether there’s layer breakdown or not. Optical imaging can detect cancer. However, high resolution optical techniques can only image about 1 mm deep, so unless you’re looking at the skin or the eye, you’re going to have to develop an endoscope to be able to view these hallmarks.”

OCT images the tissue microstructure, generally in a resolution of 2-20 microns, at a depth of 1-2 mm, and it measures reflected light. When possible, Dr. Barton combines OCT with laser-induced fluorescence for enhanced accuracy of detection of cancer. Induced fluorescence senses molecular information with the natural fluorophores in the body or with targeted exogenous agents. Then there’s multiphoton microscopy, an advanced imaging technique that enables clinicians to view cellular and subcellular events within living tissue. Early models of this technology “took up entire benches” in physics labs, Dr. Barton said, but she and other investigators are designing smaller devices for use in clinics. “This is exciting, because not only do we [view] subcellular structure with this modality, but it can also be highly sensitive to collagen structure,” she said.
 

Ovarian cancer model

In a model of ovarian cancer, she and colleagues externalized the ovaries of a mouse, imaged the organs, put them back in, and reassessed them at 8 weeks. “This model develops cancer very quickly,” said Dr. Barton, who once worked for McDonnell Douglas on the Space Station program. At 8 weeks, using fluorescence and targeted agents with a tabletop multiphoton microscopy system, they observed that the proliferation signals of cancer had begun. “So, with an agent targeted to the folate receptor or to other receptors that are implicated in cancer development, we can see that ovaries and fallopian tubes are lighting up,” she said.

With proof of concept established with the mouse study, she and other researchers are drawing from technological advances to create tiny laser systems for use in the clinic to image a variety of structures in the human body. Optics advances include bulk optics and all-fiber designs where engineers can create an imaging probe that’s only 125 microns in diameter, “or maybe even as small as 70 microns in diameter,” she said. “We can do fabrications on the tips of endoscopes to redirect the light and focus it. We can also do 3-D printing and spiral scanning to create miniature devices to make new advances. That means that instead of just white light imaging of the colon or the lung like we have had in the past, we can start moving into smaller structures, such as the eustachian tube, the fallopian tube, the bile ducts, or making miniature devices for brain biopsies, lung biopsies, and maybe being able to get into bronchioles and arterioles.”

According to Dr. Barton, prior research has demonstrated that cerebral vasculature can be imaged with a catheter 400 microns in diameter, the spaces in the lungs can be imaged with a needle that is 310 microns in diameter, and the inner structures of the eustachian tube can be viewed with an endoscope 1 mm in diameter.

She and her colleagues are developing an OCT/fluorescence imaging falloposcope that is 0.8 mm in diameter, flexible, and steerable, as a tool for early detection of ovarian cancer in humans. “It’s now known that most ovarian cancer starts in the fallopian tubes,” Dr. Barton said. “It’s metastatic disease when those cells break off from the fallopian tubes and go to the ovaries. We wanted to create an imaging system where we created a fiber bundle that we could navigate with white light and with fluorescence so that we can see these early stages of cancer [and] how they fluoresce differently. We also wanted to have an OCT system so that we could image through the wall of the fallopian tube and look for that layer thickening and other precursors to ovarian cancer.”

To date, in vivo testing in healthy women has demonstrated that the miniature endoscope is able to reach the fallopian tubes through the natural orifice of the vagina and uterus. “That is pretty exciting,” she said. “The images may not be of the highest quality, but we are advancing.”

Dr. Barton reported having no relevant financial disclosures.

PHOENIX – The way Jennifer Barton, PhD, sees it, optical coherence tomography (OCT), laser-induced fluorescence, and multiphoton microscopy are poised to revolutionize the future of cancer detection.

Chris Richards/University of Arizona

In a lecture during a multispecialty roundup of cutting-edge energy-based device applications at the annual conference of the American Society for Laser Medicine and Surgery, Dr. Barton, a biomedical engineer who directs the BIO5 Institute at the University of Arizona, Tucson, said that while no current modality exists to enable physicians in dermatology and other specialties to view internal structures throughout the entire body with cellular resolution, refining existing technologies is a good way to start.

In 2011, renowned cancer researchers Douglas Hanahan, PhD, and Robert A. Weinberg, PhD, proposed six hallmarks of cancer, which include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Each hallmark poses unique imaging challenges. For example, enabling replicative immortality “means that the cell nuclei change size and shape; they change their position,” said Dr. Barton, who is also professor of biomedical engineering and optical sciences at the university. “If we want to see that, we’re going to need an imaging modality that’s subcellular in resolution.”

Similarly, if clinicians want to view how proliferative signaling is changing, “that means being able to visualize the cell surface receptors; those are even smaller to actually visualize,” she said. “But we have technologies where we can target those receptors with fluorophores. And then we can look at large areas very quickly.” Meanwhile, the ability of cancer cells to resist cell death and evade growth suppressors often results in thickening of epithelium throughout the body. “So, if we can measure the thickness of the epithelium, we can see that there’s something wrong with that tissue,” she said.

As for cancer’s propensity for invasion and metastasis, “here, we’re looking at how the collagen structure [between the cells] has changed and whether there’s layer breakdown or not. Optical imaging can detect cancer. However, high resolution optical techniques can only image about 1 mm deep, so unless you’re looking at the skin or the eye, you’re going to have to develop an endoscope to be able to view these hallmarks.”

OCT images the tissue microstructure, generally in a resolution of 2-20 microns, at a depth of 1-2 mm, and it measures reflected light. When possible, Dr. Barton combines OCT with laser-induced fluorescence for enhanced accuracy of detection of cancer. Induced fluorescence senses molecular information with the natural fluorophores in the body or with targeted exogenous agents. Then there’s multiphoton microscopy, an advanced imaging technique that enables clinicians to view cellular and subcellular events within living tissue. Early models of this technology “took up entire benches” in physics labs, Dr. Barton said, but she and other investigators are designing smaller devices for use in clinics. “This is exciting, because not only do we [view] subcellular structure with this modality, but it can also be highly sensitive to collagen structure,” she said.
 

Ovarian cancer model

In a model of ovarian cancer, she and colleagues externalized the ovaries of a mouse, imaged the organs, put them back in, and reassessed them at 8 weeks. “This model develops cancer very quickly,” said Dr. Barton, who once worked for McDonnell Douglas on the Space Station program. At 8 weeks, using fluorescence and targeted agents with a tabletop multiphoton microscopy system, they observed that the proliferation signals of cancer had begun. “So, with an agent targeted to the folate receptor or to other receptors that are implicated in cancer development, we can see that ovaries and fallopian tubes are lighting up,” she said.

With proof of concept established with the mouse study, she and other researchers are drawing from technological advances to create tiny laser systems for use in the clinic to image a variety of structures in the human body. Optics advances include bulk optics and all-fiber designs where engineers can create an imaging probe that’s only 125 microns in diameter, “or maybe even as small as 70 microns in diameter,” she said. “We can do fabrications on the tips of endoscopes to redirect the light and focus it. We can also do 3-D printing and spiral scanning to create miniature devices to make new advances. That means that instead of just white light imaging of the colon or the lung like we have had in the past, we can start moving into smaller structures, such as the eustachian tube, the fallopian tube, the bile ducts, or making miniature devices for brain biopsies, lung biopsies, and maybe being able to get into bronchioles and arterioles.”

According to Dr. Barton, prior research has demonstrated that cerebral vasculature can be imaged with a catheter 400 microns in diameter, the spaces in the lungs can be imaged with a needle that is 310 microns in diameter, and the inner structures of the eustachian tube can be viewed with an endoscope 1 mm in diameter.

She and her colleagues are developing an OCT/fluorescence imaging falloposcope that is 0.8 mm in diameter, flexible, and steerable, as a tool for early detection of ovarian cancer in humans. “It’s now known that most ovarian cancer starts in the fallopian tubes,” Dr. Barton said. “It’s metastatic disease when those cells break off from the fallopian tubes and go to the ovaries. We wanted to create an imaging system where we created a fiber bundle that we could navigate with white light and with fluorescence so that we can see these early stages of cancer [and] how they fluoresce differently. We also wanted to have an OCT system so that we could image through the wall of the fallopian tube and look for that layer thickening and other precursors to ovarian cancer.”

To date, in vivo testing in healthy women has demonstrated that the miniature endoscope is able to reach the fallopian tubes through the natural orifice of the vagina and uterus. “That is pretty exciting,” she said. “The images may not be of the highest quality, but we are advancing.”

Dr. Barton reported having no relevant financial disclosures.

PHOENIX – The way Jennifer Barton, PhD, sees it, optical coherence tomography (OCT), laser-induced fluorescence, and multiphoton microscopy are poised to revolutionize the future of cancer detection.

Chris Richards/University of Arizona

In a lecture during a multispecialty roundup of cutting-edge energy-based device applications at the annual conference of the American Society for Laser Medicine and Surgery, Dr. Barton, a biomedical engineer who directs the BIO5 Institute at the University of Arizona, Tucson, said that while no current modality exists to enable physicians in dermatology and other specialties to view internal structures throughout the entire body with cellular resolution, refining existing technologies is a good way to start.

In 2011, renowned cancer researchers Douglas Hanahan, PhD, and Robert A. Weinberg, PhD, proposed six hallmarks of cancer, which include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Each hallmark poses unique imaging challenges. For example, enabling replicative immortality “means that the cell nuclei change size and shape; they change their position,” said Dr. Barton, who is also professor of biomedical engineering and optical sciences at the university. “If we want to see that, we’re going to need an imaging modality that’s subcellular in resolution.”

Similarly, if clinicians want to view how proliferative signaling is changing, “that means being able to visualize the cell surface receptors; those are even smaller to actually visualize,” she said. “But we have technologies where we can target those receptors with fluorophores. And then we can look at large areas very quickly.” Meanwhile, the ability of cancer cells to resist cell death and evade growth suppressors often results in thickening of epithelium throughout the body. “So, if we can measure the thickness of the epithelium, we can see that there’s something wrong with that tissue,” she said.

As for cancer’s propensity for invasion and metastasis, “here, we’re looking at how the collagen structure [between the cells] has changed and whether there’s layer breakdown or not. Optical imaging can detect cancer. However, high resolution optical techniques can only image about 1 mm deep, so unless you’re looking at the skin or the eye, you’re going to have to develop an endoscope to be able to view these hallmarks.”

OCT images the tissue microstructure, generally in a resolution of 2-20 microns, at a depth of 1-2 mm, and it measures reflected light. When possible, Dr. Barton combines OCT with laser-induced fluorescence for enhanced accuracy of detection of cancer. Induced fluorescence senses molecular information with the natural fluorophores in the body or with targeted exogenous agents. Then there’s multiphoton microscopy, an advanced imaging technique that enables clinicians to view cellular and subcellular events within living tissue. Early models of this technology “took up entire benches” in physics labs, Dr. Barton said, but she and other investigators are designing smaller devices for use in clinics. “This is exciting, because not only do we [view] subcellular structure with this modality, but it can also be highly sensitive to collagen structure,” she said.
 

Ovarian cancer model

In a model of ovarian cancer, she and colleagues externalized the ovaries of a mouse, imaged the organs, put them back in, and reassessed them at 8 weeks. “This model develops cancer very quickly,” said Dr. Barton, who once worked for McDonnell Douglas on the Space Station program. At 8 weeks, using fluorescence and targeted agents with a tabletop multiphoton microscopy system, they observed that the proliferation signals of cancer had begun. “So, with an agent targeted to the folate receptor or to other receptors that are implicated in cancer development, we can see that ovaries and fallopian tubes are lighting up,” she said.

With proof of concept established with the mouse study, she and other researchers are drawing from technological advances to create tiny laser systems for use in the clinic to image a variety of structures in the human body. Optics advances include bulk optics and all-fiber designs where engineers can create an imaging probe that’s only 125 microns in diameter, “or maybe even as small as 70 microns in diameter,” she said. “We can do fabrications on the tips of endoscopes to redirect the light and focus it. We can also do 3-D printing and spiral scanning to create miniature devices to make new advances. That means that instead of just white light imaging of the colon or the lung like we have had in the past, we can start moving into smaller structures, such as the eustachian tube, the fallopian tube, the bile ducts, or making miniature devices for brain biopsies, lung biopsies, and maybe being able to get into bronchioles and arterioles.”

According to Dr. Barton, prior research has demonstrated that cerebral vasculature can be imaged with a catheter 400 microns in diameter, the spaces in the lungs can be imaged with a needle that is 310 microns in diameter, and the inner structures of the eustachian tube can be viewed with an endoscope 1 mm in diameter.

She and her colleagues are developing an OCT/fluorescence imaging falloposcope that is 0.8 mm in diameter, flexible, and steerable, as a tool for early detection of ovarian cancer in humans. “It’s now known that most ovarian cancer starts in the fallopian tubes,” Dr. Barton said. “It’s metastatic disease when those cells break off from the fallopian tubes and go to the ovaries. We wanted to create an imaging system where we created a fiber bundle that we could navigate with white light and with fluorescence so that we can see these early stages of cancer [and] how they fluoresce differently. We also wanted to have an OCT system so that we could image through the wall of the fallopian tube and look for that layer thickening and other precursors to ovarian cancer.”

To date, in vivo testing in healthy women has demonstrated that the miniature endoscope is able to reach the fallopian tubes through the natural orifice of the vagina and uterus. “That is pretty exciting,” she said. “The images may not be of the highest quality, but we are advancing.”

Dr. Barton reported having no relevant financial disclosures.

Interventions that specifically address diabetes distress can not only improve patient mental health but can also cut costs, according to two new studies in patients with type 1 diabetes presented at the annual scientific sessions of the American Diabetes Association.

Danielle Hessler Jones, PhD, presented findings from Behavioral Approaches to Reducing Diabetes Distress and Improving Glycemic Control (EMBARK) in adults with type 1 diabetes during an oral session.

The three-arm randomized trial found that patients had the greatest improvements in feelings of powerlessness after a 3-month behavioral intervention that combined type 1 diabetes education plus specific attention to diabetes distress.

And in a late-breaking poster, “Do The Right Thing: Behavioral Intervention for At-Risk T1D Youth,” David V. Wagner, PhD, showed that a behavioral intervention not only improved glycemic management but also reduced cost of care in disadvantaged youth.

“Diabetes distress is the emotional response to living with diabetes, the burden of relentless daily self-management, and the prospect of its long-term complications,” said Dr. Hessler Jones, professor and vice chair for research in the department of family and community medicine at the University of California, San Francisco.  

It is common, experienced by 20%-58% of people with type 1 and type 2 diabetes, and is different from depression, as it is associated with glycemic control and disease management. It “is also chronic and does not disappear on its own without intervention,” she stressed.

“It is the expected worries, concerns, and fears that are associated with struggling with a demanding and progressive chronic disease and its management,” she added.

The findings from EMBARK “suggest that distress reductions are greatest when interventions integrate education alongside approaches to address the emotional side of diabetes,” she said.  

The group is also analyzing changes in A1c with the three different interventions in EMBARK, with results expected this fall.

Dr. Hessler Jones said they also just received funding for DDASSIST, which will answer the question: “How do I translate this into care in my clinic?” The aim of the clinic training program is to bring the intervention to the diabetes care team.

“Could this program be delivered by somebody else, other than a psychologist?” an audience member asked. They will be looking at this, she replied.
 

‘Do the right thing’

For the late-breaking poster by Dr. Wagner and colleagues, researchers evaluated direct cost data from three health care systems provided for youth with type 1 diabetes who received an intensive behavioral health intervention, Novel Interventions in Children’s Healthcare (NICH).

Youths were included in the analyses if they had type 1 diabetes and at least 1 year of cost data prior to and following NICH enrollment. Outpatient, emergency department, and inpatient costs were combined. The analysis included 53 youth with the following characteristics: mean age, 14.2 years; 87% Medicaid; 58% female; 32% Black, 29% Non-Hispanic White, 28% Hispanic/Latinx, 7% Pacific Islander, 2% Asian, and 2% other racial and ethnic groups.

Average yearly costs significantly decreased from $20,400 per youth prior to NICH to $9,500 per youth afterward, largely due to inpatient charges.

“These results highlight the benefits of providing access to intensive interventions to pediatric populations experiencing health disparities,” said Dr. Wagner. “Investing early in the lives of youth experiencing health disparities is not only the right thing to do to improve patients’ health but it could also have a positive economic impact down the road.”
 

Three interventions in 300 adults with type 1 diabetes

Meanwhile, EMBARK recruited 300 patients with type 1 diabetes in the United States from clinics and community organizations who were aged 21 and older and had an elevated type 1 diabetes distress score (> 2.0) and A1c greater than or equal to 7.5%.

Participants were a mean age of 46 years, 79% were female, and 89% were White. They had a type 1 diabetes distress score of 2.8, a mean A1c of 8.3%, and 71% used an insulin pump and 79% used a continuous glucose monitor.

Participants were randomized to one of three interventions:

• Streamline: A traditional diabetes educator-led education and management program.
• Tuned-in: A psychologist-led program focused exclusively on reducing diabetes distress.
• Fixit: An integration of the two programs.

Interventions were given virtually over 3 months to small groups of 8-12 individuals and included initial workshops, one-to-one phone calls, and follow-up group meetings. Participants were then followed for 8 months.  

Researchers found statistically significant and substantial reductions in overall diabetes distress in all three interventions, with the greatest reductions in the combined intervention group, which were greater than in the educational approach alone group (P = .005).

The percentage of participants who no longer reported elevated diabetes distress at follow-up was 25% in Streamline, 37% in Tuned-in, and 42% in Fixit.

The percentage of participants who reported a minimal clinically important difference – the smallest change in a treatment outcome that an individual would identify as important – was also greatest in those in the Fixit intervention group (82%) than in the Tuned-in (74%) or Streamline (65%) interventions.
 

‘Adding the psychologist is where the real magic happens’

“The certified diabetes care specialist intervention is really a very standard thing that most clinicians would have access to; they tend to focus on knowledge and problem solving and some of the psychosocial issues,” Robert Gabbay, MD, PhD, chief scientific and medical officer for the ADA, said in an interview.

The EMBARK trial found a “graded response: CDCS alone, psychologist really focused on diabetes distress, and the two together, which would be the ideal practice model,” he noted.

There are these validated ways of measuring diabetes distress using a diabetes distress survey tool, which is also underutilized.  

“Adding the psychologist is really where the real magic happens in terms of diabetes distress,” Dr. Gabbay said.

“As you can imagine, [if] somebody ... feels powerless, it is going to be tough to manage their diabetes and unlikely to be terribly successful,” he observed. Often, these individuals are just not doing well. This study highlighted the importance of identifying this.

“I’m encouraged by the findings from the studies presented during this year’s Scientific Sessions as we continue to seek out innovative, evidence-based solutions that support people living with diabetes when they need it the most,” Dr. Gabbay concluded.

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

Interventions that specifically address diabetes distress can not only improve patient mental health but can also cut costs, according to two new studies in patients with type 1 diabetes presented at the annual scientific sessions of the American Diabetes Association.

Danielle Hessler Jones, PhD, presented findings from Behavioral Approaches to Reducing Diabetes Distress and Improving Glycemic Control (EMBARK) in adults with type 1 diabetes during an oral session.

The three-arm randomized trial found that patients had the greatest improvements in feelings of powerlessness after a 3-month behavioral intervention that combined type 1 diabetes education plus specific attention to diabetes distress.

And in a late-breaking poster, “Do The Right Thing: Behavioral Intervention for At-Risk T1D Youth,” David V. Wagner, PhD, showed that a behavioral intervention not only improved glycemic management but also reduced cost of care in disadvantaged youth.

“Diabetes distress is the emotional response to living with diabetes, the burden of relentless daily self-management, and the prospect of its long-term complications,” said Dr. Hessler Jones, professor and vice chair for research in the department of family and community medicine at the University of California, San Francisco.  

It is common, experienced by 20%-58% of people with type 1 and type 2 diabetes, and is different from depression, as it is associated with glycemic control and disease management. It “is also chronic and does not disappear on its own without intervention,” she stressed.

“It is the expected worries, concerns, and fears that are associated with struggling with a demanding and progressive chronic disease and its management,” she added.

The findings from EMBARK “suggest that distress reductions are greatest when interventions integrate education alongside approaches to address the emotional side of diabetes,” she said.  

The group is also analyzing changes in A1c with the three different interventions in EMBARK, with results expected this fall.

Dr. Hessler Jones said they also just received funding for DDASSIST, which will answer the question: “How do I translate this into care in my clinic?” The aim of the clinic training program is to bring the intervention to the diabetes care team.

“Could this program be delivered by somebody else, other than a psychologist?” an audience member asked. They will be looking at this, she replied.
 

‘Do the right thing’

For the late-breaking poster by Dr. Wagner and colleagues, researchers evaluated direct cost data from three health care systems provided for youth with type 1 diabetes who received an intensive behavioral health intervention, Novel Interventions in Children’s Healthcare (NICH).

Youths were included in the analyses if they had type 1 diabetes and at least 1 year of cost data prior to and following NICH enrollment. Outpatient, emergency department, and inpatient costs were combined. The analysis included 53 youth with the following characteristics: mean age, 14.2 years; 87% Medicaid; 58% female; 32% Black, 29% Non-Hispanic White, 28% Hispanic/Latinx, 7% Pacific Islander, 2% Asian, and 2% other racial and ethnic groups.

Average yearly costs significantly decreased from $20,400 per youth prior to NICH to $9,500 per youth afterward, largely due to inpatient charges.

“These results highlight the benefits of providing access to intensive interventions to pediatric populations experiencing health disparities,” said Dr. Wagner. “Investing early in the lives of youth experiencing health disparities is not only the right thing to do to improve patients’ health but it could also have a positive economic impact down the road.”
 

Three interventions in 300 adults with type 1 diabetes

Meanwhile, EMBARK recruited 300 patients with type 1 diabetes in the United States from clinics and community organizations who were aged 21 and older and had an elevated type 1 diabetes distress score (> 2.0) and A1c greater than or equal to 7.5%.

Participants were a mean age of 46 years, 79% were female, and 89% were White. They had a type 1 diabetes distress score of 2.8, a mean A1c of 8.3%, and 71% used an insulin pump and 79% used a continuous glucose monitor.

Participants were randomized to one of three interventions:

• Streamline: A traditional diabetes educator-led education and management program.
• Tuned-in: A psychologist-led program focused exclusively on reducing diabetes distress.
• Fixit: An integration of the two programs.

Interventions were given virtually over 3 months to small groups of 8-12 individuals and included initial workshops, one-to-one phone calls, and follow-up group meetings. Participants were then followed for 8 months.  

Researchers found statistically significant and substantial reductions in overall diabetes distress in all three interventions, with the greatest reductions in the combined intervention group, which were greater than in the educational approach alone group (P = .005).

The percentage of participants who no longer reported elevated diabetes distress at follow-up was 25% in Streamline, 37% in Tuned-in, and 42% in Fixit.

The percentage of participants who reported a minimal clinically important difference – the smallest change in a treatment outcome that an individual would identify as important – was also greatest in those in the Fixit intervention group (82%) than in the Tuned-in (74%) or Streamline (65%) interventions.
 

‘Adding the psychologist is where the real magic happens’

“The certified diabetes care specialist intervention is really a very standard thing that most clinicians would have access to; they tend to focus on knowledge and problem solving and some of the psychosocial issues,” Robert Gabbay, MD, PhD, chief scientific and medical officer for the ADA, said in an interview.

The EMBARK trial found a “graded response: CDCS alone, psychologist really focused on diabetes distress, and the two together, which would be the ideal practice model,” he noted.

There are these validated ways of measuring diabetes distress using a diabetes distress survey tool, which is also underutilized.  

“Adding the psychologist is really where the real magic happens in terms of diabetes distress,” Dr. Gabbay said.

“As you can imagine, [if] somebody ... feels powerless, it is going to be tough to manage their diabetes and unlikely to be terribly successful,” he observed. Often, these individuals are just not doing well. This study highlighted the importance of identifying this.

“I’m encouraged by the findings from the studies presented during this year’s Scientific Sessions as we continue to seek out innovative, evidence-based solutions that support people living with diabetes when they need it the most,” Dr. Gabbay concluded.

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

Interventions that specifically address diabetes distress can not only improve patient mental health but can also cut costs, according to two new studies in patients with type 1 diabetes presented at the annual scientific sessions of the American Diabetes Association.

Danielle Hessler Jones, PhD, presented findings from Behavioral Approaches to Reducing Diabetes Distress and Improving Glycemic Control (EMBARK) in adults with type 1 diabetes during an oral session.

The three-arm randomized trial found that patients had the greatest improvements in feelings of powerlessness after a 3-month behavioral intervention that combined type 1 diabetes education plus specific attention to diabetes distress.

And in a late-breaking poster, “Do The Right Thing: Behavioral Intervention for At-Risk T1D Youth,” David V. Wagner, PhD, showed that a behavioral intervention not only improved glycemic management but also reduced cost of care in disadvantaged youth.

“Diabetes distress is the emotional response to living with diabetes, the burden of relentless daily self-management, and the prospect of its long-term complications,” said Dr. Hessler Jones, professor and vice chair for research in the department of family and community medicine at the University of California, San Francisco.  

It is common, experienced by 20%-58% of people with type 1 and type 2 diabetes, and is different from depression, as it is associated with glycemic control and disease management. It “is also chronic and does not disappear on its own without intervention,” she stressed.

“It is the expected worries, concerns, and fears that are associated with struggling with a demanding and progressive chronic disease and its management,” she added.

The findings from EMBARK “suggest that distress reductions are greatest when interventions integrate education alongside approaches to address the emotional side of diabetes,” she said.  

The group is also analyzing changes in A1c with the three different interventions in EMBARK, with results expected this fall.

Dr. Hessler Jones said they also just received funding for DDASSIST, which will answer the question: “How do I translate this into care in my clinic?” The aim of the clinic training program is to bring the intervention to the diabetes care team.

“Could this program be delivered by somebody else, other than a psychologist?” an audience member asked. They will be looking at this, she replied.
 

‘Do the right thing’

For the late-breaking poster by Dr. Wagner and colleagues, researchers evaluated direct cost data from three health care systems provided for youth with type 1 diabetes who received an intensive behavioral health intervention, Novel Interventions in Children’s Healthcare (NICH).

Youths were included in the analyses if they had type 1 diabetes and at least 1 year of cost data prior to and following NICH enrollment. Outpatient, emergency department, and inpatient costs were combined. The analysis included 53 youth with the following characteristics: mean age, 14.2 years; 87% Medicaid; 58% female; 32% Black, 29% Non-Hispanic White, 28% Hispanic/Latinx, 7% Pacific Islander, 2% Asian, and 2% other racial and ethnic groups.

Average yearly costs significantly decreased from $20,400 per youth prior to NICH to $9,500 per youth afterward, largely due to inpatient charges.

“These results highlight the benefits of providing access to intensive interventions to pediatric populations experiencing health disparities,” said Dr. Wagner. “Investing early in the lives of youth experiencing health disparities is not only the right thing to do to improve patients’ health but it could also have a positive economic impact down the road.”
 

Three interventions in 300 adults with type 1 diabetes

Meanwhile, EMBARK recruited 300 patients with type 1 diabetes in the United States from clinics and community organizations who were aged 21 and older and had an elevated type 1 diabetes distress score (> 2.0) and A1c greater than or equal to 7.5%.

Participants were a mean age of 46 years, 79% were female, and 89% were White. They had a type 1 diabetes distress score of 2.8, a mean A1c of 8.3%, and 71% used an insulin pump and 79% used a continuous glucose monitor.

Participants were randomized to one of three interventions:

• Streamline: A traditional diabetes educator-led education and management program.
• Tuned-in: A psychologist-led program focused exclusively on reducing diabetes distress.
• Fixit: An integration of the two programs.

Interventions were given virtually over 3 months to small groups of 8-12 individuals and included initial workshops, one-to-one phone calls, and follow-up group meetings. Participants were then followed for 8 months.  

Researchers found statistically significant and substantial reductions in overall diabetes distress in all three interventions, with the greatest reductions in the combined intervention group, which were greater than in the educational approach alone group (P = .005).

The percentage of participants who no longer reported elevated diabetes distress at follow-up was 25% in Streamline, 37% in Tuned-in, and 42% in Fixit.

The percentage of participants who reported a minimal clinically important difference – the smallest change in a treatment outcome that an individual would identify as important – was also greatest in those in the Fixit intervention group (82%) than in the Tuned-in (74%) or Streamline (65%) interventions.
 

‘Adding the psychologist is where the real magic happens’

“The certified diabetes care specialist intervention is really a very standard thing that most clinicians would have access to; they tend to focus on knowledge and problem solving and some of the psychosocial issues,” Robert Gabbay, MD, PhD, chief scientific and medical officer for the ADA, said in an interview.

The EMBARK trial found a “graded response: CDCS alone, psychologist really focused on diabetes distress, and the two together, which would be the ideal practice model,” he noted.

There are these validated ways of measuring diabetes distress using a diabetes distress survey tool, which is also underutilized.  

“Adding the psychologist is really where the real magic happens in terms of diabetes distress,” Dr. Gabbay said.

“As you can imagine, [if] somebody ... feels powerless, it is going to be tough to manage their diabetes and unlikely to be terribly successful,” he observed. Often, these individuals are just not doing well. This study highlighted the importance of identifying this.

“I’m encouraged by the findings from the studies presented during this year’s Scientific Sessions as we continue to seek out innovative, evidence-based solutions that support people living with diabetes when they need it the most,” Dr. Gabbay concluded.

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

SAN DIEGO – A new analysis of a large-scale trial of a novel lipid-lowering agent has shown a particularly large reduction in cardiovascular events in the primary prevention population enrolled in the study, two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.

The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.

This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.

Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.

“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview. 

“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.

But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated. 

“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed. 

Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.” 

“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
 

‘Wake-up call’

He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”

Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels. 

“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”

Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.

He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years. 

“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.

“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.

CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.

Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.

Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”

And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
 

Greater benefit in primary prevention?

In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.

Other key secondary endpoints also showed impressive reductions.

The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.

Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.

“It may seem paradoxical, but there is actually some history that this may be the case,” he said.

He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.

He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.

“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.

Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.

“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”

He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
 

Editorial cautious

In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.

Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.

Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.

“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.

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

SAN DIEGO – A new analysis of a large-scale trial of a novel lipid-lowering agent has shown a particularly large reduction in cardiovascular events in the primary prevention population enrolled in the study, two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.

The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.

This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.

Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.

“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview. 

“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.

But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated. 

“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed. 

Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.” 

“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
 

‘Wake-up call’

He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”

Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels. 

“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”

Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.

He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years. 

“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.

“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.

CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.

Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.

Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”

And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
 

Greater benefit in primary prevention?

In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.

Other key secondary endpoints also showed impressive reductions.

The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.

Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.

“It may seem paradoxical, but there is actually some history that this may be the case,” he said.

He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.

He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.

“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.

Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.

“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”

He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
 

Editorial cautious

In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.

Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.

Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.

“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.

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

SAN DIEGO – A new analysis of a large-scale trial of a novel lipid-lowering agent has shown a particularly large reduction in cardiovascular events in the primary prevention population enrolled in the study, two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.

The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.

This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.

Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.

“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview. 

“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.

But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated. 

“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed. 

Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.” 

“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
 

‘Wake-up call’

He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”

Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels. 

“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”

Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.

He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years. 

“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.

“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.

CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.

Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.

Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”

And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
 

Greater benefit in primary prevention?

In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.

Other key secondary endpoints also showed impressive reductions.

The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.

Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.

“It may seem paradoxical, but there is actually some history that this may be the case,” he said.

He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.

He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.

“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.

Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.

“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”

He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
 

Editorial cautious

In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.

Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.

Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.

“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.

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

SAN DIEGO – Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial, a finding that will likely lead to Food and Drug Administration approval of a new indication for weight loss for tirzepatide.

Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent – a “twincretin” that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor – had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.

Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.

“We anticipate that tirzepatide will be [FDA] approved for weight loss later this year,” W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, said during a press briefing at the annual scientific sessions of the American Diabetes Association.
 

Tirzepatide ‘fills the gap’

Tirzepatide “fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better,” Dr. Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial. 

Mitchel L. Zoler/MDedge News

Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Dr. Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.

“If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss” compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. (Although cross-trial comparisons of different medications often have uncertain reliability.)

“The data suggest an incremental effect from tirzepatide” compared with the GLP-1 agonists now approved for weight loss, said Marlon Pragnell, PhD, vice president, research and science, ADA, who was not involved in the tirzepatide studies.

This is a “step forward for treating people with obesity and type 2 diabetes; it’s a very promising treatment option,” Dr. Pragnell said in an interview.
 

Tirzepatide the ‘most effective agent’

Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings “confirm that tirzepatide is the most effective agent currently on the [U.S.] market to help achieve the two coprimary goals for patients with type 2 diabetes – weight loss and glycemic control – while also having favorable effects on cardiovascular risk factors,” said Dr. Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.

Dr. Lingvay offered as evidence the performance of tirzepatide’s main rival for weight loss semaglutide (Wegovy), delivered at the 2.4 mg/week subcutaneous injected dosage approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.

“It’s fair to say that tirzepatide has an edge,” despite the limitations of cross-trial comparisons, Dr. Lingvay said in an interview.

But she acknowledged that superior weight loss efficacy takes a back seat in U.S. practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive. 
 

Affordability and access will remain a ‘big problem’

Dr. Garvey, too, cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.

“These medications are very expensive – more than $1,000 a dose – and this cost limits access ... [which is] a big problem,” Dr. Garvey noted. U.S. health care payers “do not want to open the gates [to expensive treatments] for a disorder that’s as common as obesity.”

“Access and affordability are always an issue for these medications,” agreed Janet Brown-Friday, RN, president, health care and education, ADA, who had no role in the tirzepatide studies.

SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: Average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5% after 72 weeks.
 

In-trial weight loss of 12.8%-14.7%

The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.

The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.

A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline “will prevent a broad array of complications,” Dr. Garvey noted.

The results were simulatenously published online in The Lancet.
 

Glucose control without severe hypoglycemia

The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.

Dr. Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.

The absence of any severe hypoglycemia was “amazing,” Dr. Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.

The results also showed the benefit of a “big reduction in fasting insulin levels,” which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Dr. Garvey said.

Dr. Garvey disclosed ties to Eli Lilly, which sponsored SURMOUNT-2 and markets tirzepatide (Mounjaro), as well Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Dr. Pragnell and Dr. Brown-Friday have disclosed no relevant financial relationships.



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

SAN DIEGO – Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial, a finding that will likely lead to Food and Drug Administration approval of a new indication for weight loss for tirzepatide.

Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent – a “twincretin” that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor – had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.

Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.

“We anticipate that tirzepatide will be [FDA] approved for weight loss later this year,” W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, said during a press briefing at the annual scientific sessions of the American Diabetes Association.
 

Tirzepatide ‘fills the gap’

Tirzepatide “fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better,” Dr. Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial. 

Mitchel L. Zoler/MDedge News

Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Dr. Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.

“If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss” compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. (Although cross-trial comparisons of different medications often have uncertain reliability.)

“The data suggest an incremental effect from tirzepatide” compared with the GLP-1 agonists now approved for weight loss, said Marlon Pragnell, PhD, vice president, research and science, ADA, who was not involved in the tirzepatide studies.

This is a “step forward for treating people with obesity and type 2 diabetes; it’s a very promising treatment option,” Dr. Pragnell said in an interview.
 

Tirzepatide the ‘most effective agent’

Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings “confirm that tirzepatide is the most effective agent currently on the [U.S.] market to help achieve the two coprimary goals for patients with type 2 diabetes – weight loss and glycemic control – while also having favorable effects on cardiovascular risk factors,” said Dr. Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.

Dr. Lingvay offered as evidence the performance of tirzepatide’s main rival for weight loss semaglutide (Wegovy), delivered at the 2.4 mg/week subcutaneous injected dosage approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.

“It’s fair to say that tirzepatide has an edge,” despite the limitations of cross-trial comparisons, Dr. Lingvay said in an interview.

But she acknowledged that superior weight loss efficacy takes a back seat in U.S. practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive. 
 

Affordability and access will remain a ‘big problem’

Dr. Garvey, too, cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.

“These medications are very expensive – more than $1,000 a dose – and this cost limits access ... [which is] a big problem,” Dr. Garvey noted. U.S. health care payers “do not want to open the gates [to expensive treatments] for a disorder that’s as common as obesity.”

“Access and affordability are always an issue for these medications,” agreed Janet Brown-Friday, RN, president, health care and education, ADA, who had no role in the tirzepatide studies.

SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: Average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5% after 72 weeks.
 

In-trial weight loss of 12.8%-14.7%

The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.

The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.

A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline “will prevent a broad array of complications,” Dr. Garvey noted.

The results were simulatenously published online in The Lancet.
 

Glucose control without severe hypoglycemia

The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.

Dr. Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.

The absence of any severe hypoglycemia was “amazing,” Dr. Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.

The results also showed the benefit of a “big reduction in fasting insulin levels,” which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Dr. Garvey said.

Dr. Garvey disclosed ties to Eli Lilly, which sponsored SURMOUNT-2 and markets tirzepatide (Mounjaro), as well Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Dr. Pragnell and Dr. Brown-Friday have disclosed no relevant financial relationships.



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

SAN DIEGO – Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial, a finding that will likely lead to Food and Drug Administration approval of a new indication for weight loss for tirzepatide.

Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent – a “twincretin” that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor – had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.

Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.

“We anticipate that tirzepatide will be [FDA] approved for weight loss later this year,” W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, said during a press briefing at the annual scientific sessions of the American Diabetes Association.
 

Tirzepatide ‘fills the gap’

Tirzepatide “fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better,” Dr. Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial. 

Mitchel L. Zoler/MDedge News

Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Dr. Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.

“If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss” compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. (Although cross-trial comparisons of different medications often have uncertain reliability.)

“The data suggest an incremental effect from tirzepatide” compared with the GLP-1 agonists now approved for weight loss, said Marlon Pragnell, PhD, vice president, research and science, ADA, who was not involved in the tirzepatide studies.

This is a “step forward for treating people with obesity and type 2 diabetes; it’s a very promising treatment option,” Dr. Pragnell said in an interview.
 

Tirzepatide the ‘most effective agent’

Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings “confirm that tirzepatide is the most effective agent currently on the [U.S.] market to help achieve the two coprimary goals for patients with type 2 diabetes – weight loss and glycemic control – while also having favorable effects on cardiovascular risk factors,” said Dr. Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.

Dr. Lingvay offered as evidence the performance of tirzepatide’s main rival for weight loss semaglutide (Wegovy), delivered at the 2.4 mg/week subcutaneous injected dosage approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.

“It’s fair to say that tirzepatide has an edge,” despite the limitations of cross-trial comparisons, Dr. Lingvay said in an interview.

But she acknowledged that superior weight loss efficacy takes a back seat in U.S. practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive. 
 

Affordability and access will remain a ‘big problem’

Dr. Garvey, too, cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.

“These medications are very expensive – more than $1,000 a dose – and this cost limits access ... [which is] a big problem,” Dr. Garvey noted. U.S. health care payers “do not want to open the gates [to expensive treatments] for a disorder that’s as common as obesity.”

“Access and affordability are always an issue for these medications,” agreed Janet Brown-Friday, RN, president, health care and education, ADA, who had no role in the tirzepatide studies.

SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: Average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5% after 72 weeks.
 

In-trial weight loss of 12.8%-14.7%

The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.

The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.

A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline “will prevent a broad array of complications,” Dr. Garvey noted.

The results were simulatenously published online in The Lancet.
 

Glucose control without severe hypoglycemia

The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.

Dr. Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.

The absence of any severe hypoglycemia was “amazing,” Dr. Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.

The results also showed the benefit of a “big reduction in fasting insulin levels,” which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Dr. Garvey said.

Dr. Garvey disclosed ties to Eli Lilly, which sponsored SURMOUNT-2 and markets tirzepatide (Mounjaro), as well Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Dr. Pragnell and Dr. Brown-Friday have disclosed no relevant financial relationships.



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