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The Food and Drug Administration has approved the biosimilar tocilizumab-bavi (Tofidence), Biogen, the drug’s manufacturer, announced on Sept. 29.

It is the first tocilizumab biosimilar approved by the FDA. The reference product, Actemra (Genentech), was first approved by the agency in 2010.

“The approval of Tofidence in the U.S. marks another positive step toward helping more people with chronic autoimmune conditions gain access to leading therapies,” Ian Henshaw, global head of biosimilars at Biogen, said in a statement. “With the increasing numbers of approved biosimilars, we expect increased savings and sustainability for health care systems and an increase in physician choice and patient access to biologics.”

Biogen’s pricing for tocilizumab-bavi will be available closer to the product’s launch date, which has yet to be determined, a company spokesman said. The U.S. average monthly cost of Actemra for rheumatoid arthritis, administered intravenously, is $2,134-$4,268 depending on dosage, according to a Genentech spokesperson.

Tocilizumab-bavi is an intravenous formulation (20 mg/mL) indicated for treatment of moderately to severely active RA, polyarticular juvenile idiopathic arthritis (PJIA), and systemic juvenile idiopathic arthritis (SJIA). The medication is administered every 4 weeks in RA and PJIA and every 8 weeks in SJIA as a single intravenous drip infusion over 1 hour.

The European Commission approved its first tocilizumab biosimilar, Tyenne (Fresenius Kabi), earlier in 2023 in both subcutaneous and intravenous formulations. Biogen did not comment on whether the company is working on a subcutaneous formulation for tocilizumab-bavi.

A version of this article appeared on Medscape.com.

The Food and Drug Administration has approved the biosimilar tocilizumab-bavi (Tofidence), Biogen, the drug’s manufacturer, announced on Sept. 29.

It is the first tocilizumab biosimilar approved by the FDA. The reference product, Actemra (Genentech), was first approved by the agency in 2010.

“The approval of Tofidence in the U.S. marks another positive step toward helping more people with chronic autoimmune conditions gain access to leading therapies,” Ian Henshaw, global head of biosimilars at Biogen, said in a statement. “With the increasing numbers of approved biosimilars, we expect increased savings and sustainability for health care systems and an increase in physician choice and patient access to biologics.”

Biogen’s pricing for tocilizumab-bavi will be available closer to the product’s launch date, which has yet to be determined, a company spokesman said. The U.S. average monthly cost of Actemra for rheumatoid arthritis, administered intravenously, is $2,134-$4,268 depending on dosage, according to a Genentech spokesperson.

Tocilizumab-bavi is an intravenous formulation (20 mg/mL) indicated for treatment of moderately to severely active RA, polyarticular juvenile idiopathic arthritis (PJIA), and systemic juvenile idiopathic arthritis (SJIA). The medication is administered every 4 weeks in RA and PJIA and every 8 weeks in SJIA as a single intravenous drip infusion over 1 hour.

The European Commission approved its first tocilizumab biosimilar, Tyenne (Fresenius Kabi), earlier in 2023 in both subcutaneous and intravenous formulations. Biogen did not comment on whether the company is working on a subcutaneous formulation for tocilizumab-bavi.

A version of this article appeared on Medscape.com.

The Food and Drug Administration has approved the biosimilar tocilizumab-bavi (Tofidence), Biogen, the drug’s manufacturer, announced on Sept. 29.

It is the first tocilizumab biosimilar approved by the FDA. The reference product, Actemra (Genentech), was first approved by the agency in 2010.

“The approval of Tofidence in the U.S. marks another positive step toward helping more people with chronic autoimmune conditions gain access to leading therapies,” Ian Henshaw, global head of biosimilars at Biogen, said in a statement. “With the increasing numbers of approved biosimilars, we expect increased savings and sustainability for health care systems and an increase in physician choice and patient access to biologics.”

Biogen’s pricing for tocilizumab-bavi will be available closer to the product’s launch date, which has yet to be determined, a company spokesman said. The U.S. average monthly cost of Actemra for rheumatoid arthritis, administered intravenously, is $2,134-$4,268 depending on dosage, according to a Genentech spokesperson.

Tocilizumab-bavi is an intravenous formulation (20 mg/mL) indicated for treatment of moderately to severely active RA, polyarticular juvenile idiopathic arthritis (PJIA), and systemic juvenile idiopathic arthritis (SJIA). The medication is administered every 4 weeks in RA and PJIA and every 8 weeks in SJIA as a single intravenous drip infusion over 1 hour.

The European Commission approved its first tocilizumab biosimilar, Tyenne (Fresenius Kabi), earlier in 2023 in both subcutaneous and intravenous formulations. Biogen did not comment on whether the company is working on a subcutaneous formulation for tocilizumab-bavi.

A version of this article appeared on Medscape.com.

Click to view more from Federal Health Care Data Trends 2023.

Click to view more from Federal Health Care Data Trends 2023.

Click to view more from Federal Health Care Data Trends 2023.

Nearly half of patients undergoing drug-induced sleep endoscopy (DISE) experienced a sentinel central event after an average of 6 minutes in a study of 103 individuals with obstructive sleep apnea (OSA).

DISE has become the top choice for surgical selection in patients with OSA, but it has a variable effect on surgical outcomes, Julianna G. Rodin, MD, of the University of Pennsylvania, Philadelphia, and colleagues explained.

The University of Pennsylvania sleep surgery team developed a comprehensive DISE platform that includes simultaneous collection of respiratory airflow and effort measurements, airway collapsibility, and videoendoscopy.

“This home sleep study-style setup has allowed us to better characterize the upper airway during DISE, and even helped our team diagnose a patient with Cheyne-Stokes breathing/central sleep apnea,” Dr. Rodin said in an interview.

“With it, we also began to notice relatively frequent central and/or mixed sleep disordered breathing events during DISE after propofol dosing initiation,” she said.

In a study presented at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Dr. Rodin and colleagues measured both the frequency and timing of sentinel central and/or mixed events (SCent) in adults undergoing DISE to assess the prevalence and impact on DISE.

The researchers also assessed differences in VOTE classification (velum, oropharynx, tongue base, and epiglottis) in sentinel central events, compared with obstructive events. VOTE scores were calculated using a grade of 0 for no obstruction, 1 for partial obstruction, and 2 for total obstruction.

The study population included 103 adults with OSA who underwent DISE with propofol sedation at a single tertiary academic medical center between June 2020 and November 2022. The mean age of the participants was 53.5 years, the mean body mass index (BMI) was 29.7 kg/m², and 67% were male. The average apnea-hypopnea index (AHI) was 30.7 events per hour. The researchers used a polysomnography platform to capture data on nasal airflow, thoraco-abdominal effort belt signals, and videoendoscopy.

A total of 47 patients (46%) had at least one SCent. The average time to the first SCent was just under 6 minutes, and average transition to obstructive pathology in these patients occurred between 7 and 8 minutes. Using the one-sided prediction interval, at least 95% of patients were expected to transition to obstructive pathology within 12-13 minutes, Dr. Rodin said.

In addition, 29 of the 46 patients with SCent (63%) showed significant variability between central/mixed VOTE scores and obstructive VOTE scores.

No statistically significant differences were noted between patients with and without SCent in terms of demographics or AHI.
 

Surprising prevalence of SCents

“We anecdotally noted that SCents seemed to be somewhat common during the initial period of DISE, but were surprised that we saw at least one SCent in almost 50% of our DISE population,” Dr. Rodin said. “We also saw that the majority of these SCents eventually transitioned to obstructive events after approximately 12 minutes, which is often past the average duration of normal DISE exams.”

The high frequency of differing VOTE scores between SCents and obstructive events also was unexpected, she added. Within the changes in VOTE scores as defined in the study, “there was a higher tendency for SCents to have more complete tongue base collapse compared to no or partial collapse in obstructive events, and to transition from anterior-posterior velum to concentric velum collapse during the obstructive event.”

This outcome could potentially affect a patient’s candidacy for hypoglossal nerve stimulator therapy, she explained.

The takeaway from the current study is an increased awareness of the prevalence and timing of SCents in OSA patients, said Dr. Rodin. Clinicians who offer DISE and PAP alternatives also should be mindful of clinical signs of effort, by monitoring the chest and abdomen during DISE in the absence of respiratory effort belts.

The study findings also suggest that clinicians consider extending the minimum DISE duration to 10 minutes to ensure that the majority of SCents have passed, and delay VOTE scoring until patients transition to obstructive events, she added.

As for additional research, Dr. Rodin said: “If we could repeat the study with a standardized protocol of target-controlled infusion (TCI) of propofol, that would further bolster the data.” However, TCI is not approved in the United States.

“Our propofol dosing technique was not standardized across all patients, which in theory could account for more SCents if patients were more sedated,” Dr. Rodin noted. “However, we did not see a difference in average bispectral index levels across all patients.”

Other limitations of the current study included an inability to visualize the entire upper airway to achieve a complete VOTE score for every patient, which could have led to underestimation of the VOTE difference frequency, she added.
 

Data inform team approaches to DISE

As DISE procedures become more widespread, “it is paramount that we understand the risks associated with these procedures to increase safety, improve shared decision-making, and encourage a team-based approach in the operating room with our anesthesia colleagues,” said Daniel M. Zeitler, MD, from the University of Washington and Virgina Mason Medical Center, both in Seattle, who served as a moderator for the session in which the study was presented.

“I was surprised by these data for two reasons,” Dr. Zeitler said in an interview. “We typically don’t wait more than a few minutes between induction of anesthesia and the initiation of the airway procedure. This study calls that practice into question, and the duration of time before the onset of a sentinel event was much longer than I would have expected,” he said.

Second, “I was quite surprised that there were no differences in the demographics or AHI between the two groups; this reminds us that AHI and BMI alone may not be themselves predictive of risk and all patients should be assessed similarly.”

“Otolaryngologists performing DISE need to be aware of these data, communicate them to the involved teams, including anesthesia, nursing, and postanesthesia care units, and remember to delay the manipulation of the airway long enough to minimize the risk of a sentinel event,” Dr. Zeitler said. “Perhaps this also means we need improved intraoperative monitoring for these patients, including respiratory airflow and effort monitoring.”

For further research, “we need to increase the number of patients, perform a multicenter study, and expand the study to a wider range of ages, BMI, and AHI,” he added. A recommended algorithm for these cases in order to standardize the practice would be useful.

The study received no outside funding. Dr. Rodin and Dr. Zeitler reported no relevant financial relationships. Several coauthors disclosed funding and relationships with multiple companies unrelated to the current study.

A version of this article appeared on Medscape.com.

Nearly half of patients undergoing drug-induced sleep endoscopy (DISE) experienced a sentinel central event after an average of 6 minutes in a study of 103 individuals with obstructive sleep apnea (OSA).

DISE has become the top choice for surgical selection in patients with OSA, but it has a variable effect on surgical outcomes, Julianna G. Rodin, MD, of the University of Pennsylvania, Philadelphia, and colleagues explained.

The University of Pennsylvania sleep surgery team developed a comprehensive DISE platform that includes simultaneous collection of respiratory airflow and effort measurements, airway collapsibility, and videoendoscopy.

“This home sleep study-style setup has allowed us to better characterize the upper airway during DISE, and even helped our team diagnose a patient with Cheyne-Stokes breathing/central sleep apnea,” Dr. Rodin said in an interview.

“With it, we also began to notice relatively frequent central and/or mixed sleep disordered breathing events during DISE after propofol dosing initiation,” she said.

In a study presented at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Dr. Rodin and colleagues measured both the frequency and timing of sentinel central and/or mixed events (SCent) in adults undergoing DISE to assess the prevalence and impact on DISE.

The researchers also assessed differences in VOTE classification (velum, oropharynx, tongue base, and epiglottis) in sentinel central events, compared with obstructive events. VOTE scores were calculated using a grade of 0 for no obstruction, 1 for partial obstruction, and 2 for total obstruction.

The study population included 103 adults with OSA who underwent DISE with propofol sedation at a single tertiary academic medical center between June 2020 and November 2022. The mean age of the participants was 53.5 years, the mean body mass index (BMI) was 29.7 kg/m², and 67% were male. The average apnea-hypopnea index (AHI) was 30.7 events per hour. The researchers used a polysomnography platform to capture data on nasal airflow, thoraco-abdominal effort belt signals, and videoendoscopy.

A total of 47 patients (46%) had at least one SCent. The average time to the first SCent was just under 6 minutes, and average transition to obstructive pathology in these patients occurred between 7 and 8 minutes. Using the one-sided prediction interval, at least 95% of patients were expected to transition to obstructive pathology within 12-13 minutes, Dr. Rodin said.

In addition, 29 of the 46 patients with SCent (63%) showed significant variability between central/mixed VOTE scores and obstructive VOTE scores.

No statistically significant differences were noted between patients with and without SCent in terms of demographics or AHI.
 

Surprising prevalence of SCents

“We anecdotally noted that SCents seemed to be somewhat common during the initial period of DISE, but were surprised that we saw at least one SCent in almost 50% of our DISE population,” Dr. Rodin said. “We also saw that the majority of these SCents eventually transitioned to obstructive events after approximately 12 minutes, which is often past the average duration of normal DISE exams.”

The high frequency of differing VOTE scores between SCents and obstructive events also was unexpected, she added. Within the changes in VOTE scores as defined in the study, “there was a higher tendency for SCents to have more complete tongue base collapse compared to no or partial collapse in obstructive events, and to transition from anterior-posterior velum to concentric velum collapse during the obstructive event.”

This outcome could potentially affect a patient’s candidacy for hypoglossal nerve stimulator therapy, she explained.

The takeaway from the current study is an increased awareness of the prevalence and timing of SCents in OSA patients, said Dr. Rodin. Clinicians who offer DISE and PAP alternatives also should be mindful of clinical signs of effort, by monitoring the chest and abdomen during DISE in the absence of respiratory effort belts.

The study findings also suggest that clinicians consider extending the minimum DISE duration to 10 minutes to ensure that the majority of SCents have passed, and delay VOTE scoring until patients transition to obstructive events, she added.

As for additional research, Dr. Rodin said: “If we could repeat the study with a standardized protocol of target-controlled infusion (TCI) of propofol, that would further bolster the data.” However, TCI is not approved in the United States.

“Our propofol dosing technique was not standardized across all patients, which in theory could account for more SCents if patients were more sedated,” Dr. Rodin noted. “However, we did not see a difference in average bispectral index levels across all patients.”

Other limitations of the current study included an inability to visualize the entire upper airway to achieve a complete VOTE score for every patient, which could have led to underestimation of the VOTE difference frequency, she added.
 

Data inform team approaches to DISE

As DISE procedures become more widespread, “it is paramount that we understand the risks associated with these procedures to increase safety, improve shared decision-making, and encourage a team-based approach in the operating room with our anesthesia colleagues,” said Daniel M. Zeitler, MD, from the University of Washington and Virgina Mason Medical Center, both in Seattle, who served as a moderator for the session in which the study was presented.

“I was surprised by these data for two reasons,” Dr. Zeitler said in an interview. “We typically don’t wait more than a few minutes between induction of anesthesia and the initiation of the airway procedure. This study calls that practice into question, and the duration of time before the onset of a sentinel event was much longer than I would have expected,” he said.

Second, “I was quite surprised that there were no differences in the demographics or AHI between the two groups; this reminds us that AHI and BMI alone may not be themselves predictive of risk and all patients should be assessed similarly.”

“Otolaryngologists performing DISE need to be aware of these data, communicate them to the involved teams, including anesthesia, nursing, and postanesthesia care units, and remember to delay the manipulation of the airway long enough to minimize the risk of a sentinel event,” Dr. Zeitler said. “Perhaps this also means we need improved intraoperative monitoring for these patients, including respiratory airflow and effort monitoring.”

For further research, “we need to increase the number of patients, perform a multicenter study, and expand the study to a wider range of ages, BMI, and AHI,” he added. A recommended algorithm for these cases in order to standardize the practice would be useful.

The study received no outside funding. Dr. Rodin and Dr. Zeitler reported no relevant financial relationships. Several coauthors disclosed funding and relationships with multiple companies unrelated to the current study.

A version of this article appeared on Medscape.com.

Nearly half of patients undergoing drug-induced sleep endoscopy (DISE) experienced a sentinel central event after an average of 6 minutes in a study of 103 individuals with obstructive sleep apnea (OSA).

DISE has become the top choice for surgical selection in patients with OSA, but it has a variable effect on surgical outcomes, Julianna G. Rodin, MD, of the University of Pennsylvania, Philadelphia, and colleagues explained.

The University of Pennsylvania sleep surgery team developed a comprehensive DISE platform that includes simultaneous collection of respiratory airflow and effort measurements, airway collapsibility, and videoendoscopy.

“This home sleep study-style setup has allowed us to better characterize the upper airway during DISE, and even helped our team diagnose a patient with Cheyne-Stokes breathing/central sleep apnea,” Dr. Rodin said in an interview.

“With it, we also began to notice relatively frequent central and/or mixed sleep disordered breathing events during DISE after propofol dosing initiation,” she said.

In a study presented at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Dr. Rodin and colleagues measured both the frequency and timing of sentinel central and/or mixed events (SCent) in adults undergoing DISE to assess the prevalence and impact on DISE.

The researchers also assessed differences in VOTE classification (velum, oropharynx, tongue base, and epiglottis) in sentinel central events, compared with obstructive events. VOTE scores were calculated using a grade of 0 for no obstruction, 1 for partial obstruction, and 2 for total obstruction.

The study population included 103 adults with OSA who underwent DISE with propofol sedation at a single tertiary academic medical center between June 2020 and November 2022. The mean age of the participants was 53.5 years, the mean body mass index (BMI) was 29.7 kg/m², and 67% were male. The average apnea-hypopnea index (AHI) was 30.7 events per hour. The researchers used a polysomnography platform to capture data on nasal airflow, thoraco-abdominal effort belt signals, and videoendoscopy.

A total of 47 patients (46%) had at least one SCent. The average time to the first SCent was just under 6 minutes, and average transition to obstructive pathology in these patients occurred between 7 and 8 minutes. Using the one-sided prediction interval, at least 95% of patients were expected to transition to obstructive pathology within 12-13 minutes, Dr. Rodin said.

In addition, 29 of the 46 patients with SCent (63%) showed significant variability between central/mixed VOTE scores and obstructive VOTE scores.

No statistically significant differences were noted between patients with and without SCent in terms of demographics or AHI.
 

Surprising prevalence of SCents

“We anecdotally noted that SCents seemed to be somewhat common during the initial period of DISE, but were surprised that we saw at least one SCent in almost 50% of our DISE population,” Dr. Rodin said. “We also saw that the majority of these SCents eventually transitioned to obstructive events after approximately 12 minutes, which is often past the average duration of normal DISE exams.”

The high frequency of differing VOTE scores between SCents and obstructive events also was unexpected, she added. Within the changes in VOTE scores as defined in the study, “there was a higher tendency for SCents to have more complete tongue base collapse compared to no or partial collapse in obstructive events, and to transition from anterior-posterior velum to concentric velum collapse during the obstructive event.”

This outcome could potentially affect a patient’s candidacy for hypoglossal nerve stimulator therapy, she explained.

The takeaway from the current study is an increased awareness of the prevalence and timing of SCents in OSA patients, said Dr. Rodin. Clinicians who offer DISE and PAP alternatives also should be mindful of clinical signs of effort, by monitoring the chest and abdomen during DISE in the absence of respiratory effort belts.

The study findings also suggest that clinicians consider extending the minimum DISE duration to 10 minutes to ensure that the majority of SCents have passed, and delay VOTE scoring until patients transition to obstructive events, she added.

As for additional research, Dr. Rodin said: “If we could repeat the study with a standardized protocol of target-controlled infusion (TCI) of propofol, that would further bolster the data.” However, TCI is not approved in the United States.

“Our propofol dosing technique was not standardized across all patients, which in theory could account for more SCents if patients were more sedated,” Dr. Rodin noted. “However, we did not see a difference in average bispectral index levels across all patients.”

Other limitations of the current study included an inability to visualize the entire upper airway to achieve a complete VOTE score for every patient, which could have led to underestimation of the VOTE difference frequency, she added.
 

Data inform team approaches to DISE

As DISE procedures become more widespread, “it is paramount that we understand the risks associated with these procedures to increase safety, improve shared decision-making, and encourage a team-based approach in the operating room with our anesthesia colleagues,” said Daniel M. Zeitler, MD, from the University of Washington and Virgina Mason Medical Center, both in Seattle, who served as a moderator for the session in which the study was presented.

“I was surprised by these data for two reasons,” Dr. Zeitler said in an interview. “We typically don’t wait more than a few minutes between induction of anesthesia and the initiation of the airway procedure. This study calls that practice into question, and the duration of time before the onset of a sentinel event was much longer than I would have expected,” he said.

Second, “I was quite surprised that there were no differences in the demographics or AHI between the two groups; this reminds us that AHI and BMI alone may not be themselves predictive of risk and all patients should be assessed similarly.”

“Otolaryngologists performing DISE need to be aware of these data, communicate them to the involved teams, including anesthesia, nursing, and postanesthesia care units, and remember to delay the manipulation of the airway long enough to minimize the risk of a sentinel event,” Dr. Zeitler said. “Perhaps this also means we need improved intraoperative monitoring for these patients, including respiratory airflow and effort monitoring.”

For further research, “we need to increase the number of patients, perform a multicenter study, and expand the study to a wider range of ages, BMI, and AHI,” he added. A recommended algorithm for these cases in order to standardize the practice would be useful.

The study received no outside funding. Dr. Rodin and Dr. Zeitler reported no relevant financial relationships. Several coauthors disclosed funding and relationships with multiple companies unrelated to the current study.

A version of this article appeared on Medscape.com.

Click to read more from Federal Health Care Data Trends 2023.

Click to read more from Federal Health Care Data Trends 2023.

Click to read more from Federal Health Care Data Trends 2023.

Semaglutide and liraglutide are glucagon-like peptide 1 receptor agonists (GLP-1 RAs) that are approved by the US Food and Drug Administration as subcutaneous injections for patients with type 2 diabetes mellitus (T2DM). Both are recommended by the American Diabetes Association (ADA) as first-line options for patients with concomitant atherosclerotic cardiovascular (CV) disease and exert therapeutic effect via incretin-like mechanisms.¹ These agents lower blood glucose levels by stimulating insulin release, increasing the body’s sensitivity to insulin, and inhibiting inappropriate glucagon secretion.^2,3 They also slow gastric emptying, resulting in decreased appetite and potential weight loss.⁴

The SUSTAIN (1-7) trials concluded that semaglutide presented an equivalent safety profile and greater efficacy compared with other GLP-1 RAs, including exenatide and dulaglutide.² The SUSTAIN-10 open-label, head-to-head trial evaluating 1 mg semaglutide once weekly vs 1.2 mg liraglutide daily concluded that semaglutide was superior in hemoglobin A_1c (HbA_1c) and body weight reduction compared with liraglutide, with slightly increased gastrointestinal (GI) adverse effects (AEs).⁵ Similar to the LEADER trial assessing liraglutide, SUSTAIN-6 evaluated semaglutide in patients at increased CV risk and found that compared with placebo, semaglutide decreased rates of serious CV events, such as CV death, myocardial infarction, and stroke and were similar to the CV outcomes in the LEADER trial.^2,6 Although initial results of the SUSTAIN-6 trial were thought to be nearly equivalent to the LEADER trial, analyses later published comparing both trials noted that semaglutide had more potent HbA_1c lowering and weight loss benefit when compared with liraglutide.^2,6 The cardioprotective outcomes of SUSTAIN-6 qualified semaglutide for inclusion in the current ADA Standards of Medical Care recommendations for CV risk reduction.^6,7 However, despite the CV safety profile and efficacy associated with semaglutide, the SUSTAIN-6 trial noted an increased risk of diabetic retinopathy (DR) complications in 50 of 1648 patients (3%) treated with semaglutide compared with 29 of 1649 (1.8%) who received placebo (P = .02; hazard ratio, 1.76; 95% CI, 1.11-2.78).⁶ Of the 79 total patients who experienced retinopathy complications, 66 had retinopathy at baseline (42 of 50 [84%]) in the semaglutide group; 24 of 29 [83%] in the placebo group).⁶ Worsening of DR became one of the most notable AEs of semaglutide evaluated in clinical trials. This further deemed the effect as a warning in the semaglutide package insert to assist clinicians with treatment decisions.

As part of a US Department of Veterans Affairs (VA) National Lost Opportunity Cost Savings Initiative, which encompasses administrative efforts to promote more cost-effective yet safe and efficacious therapy options for veterans, the Michael E. DeBakey VA Medical Center (MEDVAMC) in Houston, Texas, converted a portion of patients with T2DM established on liraglutide to semaglutide. The 30-day supply cost of the 2-pack liraglutide 6 mg/mL (3 mL) injection pens for the MEDVAMC was $197.64. The 30-day supply cost for the singular multidose semaglutide 0.5 mg/0.375 mL (1.5 mL) injection pen was $115.15. Cost savings for the MEDVAMC facility were initially estimated to reach $642,522.

The subset of patients converted had to have undergone teleretinal imaging and not have a diagnosis of nonproliferative DR (NPDR), proliferative DR (PDR), or PDR with or without diabetic macular edema. These recommendations excluding various forms of retinopathy were implemented per local institution guidance supporting clinical data from the SUSTAIN trials. Patients diagnosed with these conditions were continued on liraglutide due to an increased risk of DR complications associated with semaglutide.

In the fall of 2021, there was also a standing list of patients on liraglutide who were not converted due to a lack of teleretinal imaging. As a result, there was potential for a quality improvement (QI) intervention to target this patient population, which could result in further cost savings for MEDVAMC and improved glycemic control because of increased conversion from liraglutide to semaglutide. The purpose of this project was to perform a QI assessment on this subset of patients both initially converted from liraglutide to semaglutide, and those who were yet to be converted due to a lack of teleretinal imaging to determine the impact on glycemic control and cost savings.

Methods

This QI project was a single-center, prospective cohort study with a retrospective chart review of veterans with T2DM converted from liraglutide to semaglutide at the MEDVAMC. Patient data were collected from the Computerized Patient Record System (CPRS) between March 1, 2021, and November 30, 2021. An initial subset of patients was converted to semaglutide in March and April 2021. Patients initially excluded underwent a second chart review to determine whether they truly met exclusion criteria. Patients who did not have a definitive diagnosis of NPDR or PDR, those due for updated teleretinal imaging, as well as those with updated teleretinal imaging that excluded NPDR or PDR were targeted for clinician education interventions.

Following this intervention, a subset of patients with negative DR findings were converted from liraglutide to semaglutide. Primary care and endocrinology clinicians were notified that patients who met the criteria should be referred for teleretinal imaging if no updated results were present or that patients were eligible for semaglutide conversion based on negative findings. Both patients who were initially converted as well as those converted following education were included for data collection/analysis of glycemic control via HbA_1c and blood glucose levels.

Cost savings were evaluated using outpatient pharmacy procurement pricing data. This project was approved by the MEDVAMC Quality Assurance and Regulatory Affairs Office.

Participants

Patients included in the study were adults aged ≥ 18 years with T2DM, converted from liraglutide 0.6 and 1.2 mg daily to semaglutide 0.25 mg weekly (titrated to 0.5 mg weekly after 4 weeks), and had an active prescription for semaglutide, with or without insulin or other oral antihyperglycemics. Patients with NPDR or PDR, type 1 DM, no HbA_1c data, no filled semaglutide prescriptions, insulin pumps, and those without teleretinal imaging within the postintervention period or who died during the study period were excluded.

Patient baseline characteristics collected included demographic data, CV comorbidities, antihyperglycemic medications, and changes in insulin doses. Parameters analyzed at baseline and 3 to 12 months postconversion included body weight, HbA_1c, and blood glucose levels.

Outcomes

The primary objectives of this QI project were to assess glycemic control (via changes in HbA_1c levels) and cost savings following patient conversion from liraglutide to semaglutide. A second objective was to educate clinicians for referral of T2DM patients without teleretinal imaging in the past 2 years.

The purpose of the latter objective was to encourage conversion from liraglutide to semaglutide in the absence of DR. We predicted that 50% of patients with clinician education would be converted. Secondary objectives included assessing body weight differences, evaluating modifications in diabetes regimen, and documenting AEs. We predicted that glycemic control would either remain stable or improve with conversion to semaglutide.

Statistical Analysis

Patient demographic data were analyzed using descriptive statistics. Quantitative data (HbA_1c, blood glucose, and body weight differences as continuous variables) were analyzed using a paired Student t test, and categorical variables were analyzed using the χ² test.

During the study period, 692 patients were identified with active liraglutide prescriptions (Figure). Of these, 49 patients who were initially excluded due to outdated teleretinal imaging or negative findings met the criteria for clinician education, and 14 of those 49 patients (28.6%) were converted from liraglutide to semaglutide. Thirty-three patients (67.3%) did not schedule teleretinal imaging or did not convert to semaglutide following negative teleretinal findings. Two patients (4.1%) either scheduled or proceeded with teleretinal imaging, without any further action from the clinician.

Including the 14 patients converted posteducational intervention, 425 patients were converted to semaglutide. Excluded from analysis were 121 patients: 57 for incomplete HbA_1c data or no filled semaglutide prescription; 30 for HbA_1c and weight data outside of the study timeframe; 25 died of causes unrelated to the project; 8 had insulin pumps; and 1 was diagnosed with late-onset type 1 DM. The final sample was 304 patients who underwent analysis.

Two hundred seventy-three patients (89.8%) were male, and 180 (59.2%) were White (Table 1). The mean (SD) age of patients was 65.9 (9.6) years, and 236 (77.6%) were established on insulin therapy (either basal, bolus, or a combination). The 3 most common antihyperglycemic agents (other than insulin) that patients used included 185 metformin (60.9%), 104 empagliflozin (34.2%), and 50 glipizide (16.4%) prescriptions.

Most patients had CV disease. Three hundred patients (98.7%) had comorbid hypertension, 298 (98.0%) had hyperlipidemia, and 114 (37.5%) had coronary artery disease (Table 2). Other diseases that patients were concomitantly diagnosed with included peripheral vascular disease, heart failure, history of stroke or transient ischemic attack, and history of myocardial infarction.

Documented AEs included 83 patients (27.3%) with hypoglycemia at any point within 3 to 12 months of conversion and 25 patients (8.2%) with mainly GI-related events, including nausea, vomiting, diarrhea, decreased appetite, and abdominal pain. Six patients (2.0%) had a new diagnosis of DR 3 to 12 months postconversion.

Glycemic Control and Weight Changes

At baseline, mean (SD) HbA_1c was 8.1% (1.5), blood glucose was 187.4 (44.2) mg/dL, and body weight was 112.9 (23.0) kg (Table 3). In the timeframe evaluated (3 to 12 months postconversion), patients’ mean (SD) HbA_1c was found to have significantly decreased to 7.6% (1.4) (P < .001; 95% CI, -0.7 to -0.3), blood glucose decreased to 172.6 (39.0) mg/dL (P < .001; 95% CI, -19.3 to -10.2), and body weight decreased to 105.2 (32.3) kg (P < .001; 95% CI, -10.6 to -4.8). All parameters evaluated were deemed statistically significant.

Further analyses evaluating specific changes in HbA_1c observed postconversion are as follows: 199 patients (65.5%) experienced a decrease, 92 (30.3%) experienced an increase, and 13 (4.3%) experienced no change in their HbA_1c.

As the timeframe was fairly broad to assess HbA_1c changes, a prespecified subgroup analysis was conducted to determine specific changes in HbA_1c within 3 to 6, 6 to 9, and 9 to 12 months postconversion (Table 4). At 3 to 6 months postconversion, patient mean (SD) HbA_1c levels significantly decreased from 8.2% (1.5) at baseline to 7.6% (1.3) postconversion (P = .002; 95% CI, -1.0 to -0.2). At 6 to 9 months postconversion, the mean (SD) HbA_1c significantly decreased from 8.1% (1.5) at baseline to 7.6% (1.4) postconversion (P = .002; 95% CI, -0.8 to -0.2).

Glucose-Lowering Agent Adjustments

One hundred thirteen patients (37.2%) required no changes to their antihyperglycemic regimen with the conversion, 85 (28.0%) required increased insulin doses, and 77 (25.3%) required decreased insulin doses (Table 5). Forty-five (14.8%) patients underwent discontinuation of either insulin or other antihyperglycemic agents; 44 (14.5%) had other antihyperglycemic agents dose increased, 39 (12.8%) required adding other glucose-lowering agents, 28 (9.2%) discontinued semaglutide, and 10 (3.3%) had other glucose-lowering medication doses decreased.

Cost Savings

Cost savings were evaluated using the MEDVAMC outpatient pharmacy procurement service. The total cost savings per patient per month was $82.49. For the 411 preclinician education patients converted to semaglutide, this resulted in a prospective annual cost savings of $406,840.68. An additional $13,858.32 was saved due to the intervention/clinician education for 14 patients converted to semaglutide. The total annual cost savings was $420,699.00.

Discussion

Overall, glycemic control significantly improved with veterans’ conversion from liraglutide to semaglutide. Not only were significant changes noted with HbA_1c levels and weight, but consistencies were noted with mean HbA_1c decrease and weight loss expected of GLP-1 RAs noted in clinical trials. The typical range for HbA_1c changes expected is -1% to -2% and weight loss of 1 to 6 kg.^4,7 Data from the LEAD-5 and SUSTAIN-4 trials, evaluating glycemic control in liraglutide and semaglutide, respectively, have noted comparable yet slightly more potent HbA_1c decreases (-1.33% for liraglutide 1.8 mg daily vs -1.2% and -1.6% for semaglutide 0.5 mg and 1 mg weekly, respectively).^8,9 However, more robust weight loss has been noted with semaglutide vs liraglutide (-4.62 kg for semaglutide 0.5 mg weekly and -6.33 kg for semaglutide 1 mg weekly vs -3.43 kg for liraglutide 1.8 mg daily).^8,9 Results from the SUSTAIN-10 trial also noted mean changes in HbA_1c of -1.7% for semaglutide 1 mg weekly vs -1.0% for liraglutide 1.2 mg daily; mean body weight differences were -5.8 kg for semaglutide and -1.9 kg for liraglutide at their respective doses.⁵ The mean weight loss noted with this QI project is consistent with prior trials of semaglutide.

Of note, 44 patients (14.5%) required the dosage increase of either one or multiple additional glucose-lowering agents at any time point within the 3- to 12-month period. Of those patients, 38 (86.4%) underwent further semaglutide dose titration to 1 mg weekly. Common reasons for a further dose increase to 1 mg weekly were an indication for more robust HbA_1c lowering, a desire to decrease patients’ either basal or bolus insulin requirements, or a treatment goal of completely titrating patients off insulin.

It is uncertain why 30.3% of patients experienced an increase in HbA_1c and 4.3% experienced no change. However, possibilities for the divergence in HbA_1c outcomes in these subsets of patients may include suboptimal adherence to semaglutide or other antihyperglycemic agents as indicated by clinicians or nonadherence to dietary and lifestyle modifications.

Most patients (65.5%) experienced a decrease in HbA_1c because of conversion to semaglutide, and AEs appeared as follows: 27.3% experienced hypoglycemia, and 8.2% experienced GI intolerance. The semaglutide discontinuation rate neared 10%, a majority due to intolerable AEs as previously described. Overall, patients seemed to tolerate the medication well as their glycemic control and weight loss improved. Adherence was not objectively assessed for this QI project but could be an area of improvement for future studies.

At the MEDVAMC, liraglutide is a nonformulary agent and semaglutide is now the formulary-preferred option. For patients with uncontrolled T2DM, if a GLP-1 RA is desired for therapy, clinicians are to place a prior authorization drug request (PADR) consultation for semaglutide for further evaluation and review of VA Criteria for Use (CFU) by clinical pharmacist practitioners. Liraglutide is the alternative option if patients do not meet the CFU for semaglutide (ie, have a diagnosis of DR among other exclusions). However, the semaglutide CFU was updated in April 2022 to exclude those specifically diagnosed with PDR, severe NPDR, and macular edema unless an ophthalmologist deems semaglutide acceptable. This indicates that patients with mild-to-moderate NPDR (who were originally excluded from this QI project) are now eligible to receive semaglutide. The incidence of new DR diagnoses (2%) observed in this study could indicate an unclear relationship between semaglutide and increased rates of DR; however, no definitive correlation can be established due to the retrospective nature of this project. The implications of the results of this QI project in relation to the updated CFU remain undetermined.

Due to the comparable improvements in HbA_1c and more robust weight loss noted with semaglutide vs liraglutide, we deem it appropriate to select semaglutide as the more cost-efficient GLP-1 RA and formulary preferred option. The data of this QI project supports the overall safety and treatment utility of this option. Although significant cost savings were achieved (> $400,000), the long-term benefit of the liraglutide to semaglutide conversion remains unknown.

Strengths and Limitations

Strengths of this project include the large sample size, its setting in a large VA medical center, and the evaluation of multiple outcomes beyond HbA_1c for assessment of glycemic control (ie, mean blood glucose, insulin titration, and dose adjustment of other glucose-lowering agents).

Limitations of this study include the retrospective chart review used for data collection, limited accuracy of objective data due to the COVID-19 pandemic, and inconsistencies with documentation in patients’ electronic health records. As a protective measure in the height of the pandemic between March 2021 and November 2021, the VA promoted using telephone and virtual-visit clinics to minimize exposure for patients with nonurgent follow-up needs. Patient hesitance to present to the clinic in person due to COVID-19 was also a significant factor in obtaining objective follow-up data. As a result, less accurate and timely baseline and postconversion weight and HbA_1c data resulted, leading to our decision to extend the timeframe evaluated postconversion to 3 to 12 months. We also noted inconsistencies with documentation in CPRS. Unless veterans were closely followed by clinical pharmacist practitioners or endocrine consultation service clinicians, it was more difficult to follow and document trends of insulin titration to assess the impact of semaglutide conversion. The number of AEs, including hypoglycemia and GI intolerance, were also not consistently documented within the CPRS, and the frequency of AEs may be underestimated.

Another possible limitation regarding the interpretation of the results includes the portion of patients titrated up to semaglutide 1 mg weekly. As the focal point of this project was to review changes in glycemic control in the conversion to semaglutide 0.5 mg, this population of patients converted to 1 mg could potentially overestimate the HbA_1c and weight changes described, as it is consistent with the SUSTAIN trials that show more robust decreases in those parameters described earlier.

Conclusions

A subset of patients with T2DM converted from liraglutide to semaglutide experienced significant changes in glycemic control and body weight. Significant differences were noted for a decreased HbA_1c, decreased mean blood glucose, and weight loss. A fair portion of patients’ antihyperglycemic regimens required no changes on conversion to semaglutide. Although the semaglutide discontinuation rate neared 10%, AEs that may have contributed to this discontinuation rate included hypoglycemia and GI intolerance. Clinician education resulted in a substantial number of patients undergoing teleretinal imaging and further conversion to semaglutide; however, due to the low conversion response rate, a more effective method of educating clinicians is warranted. Although the semaglutide cost savings initiative at MEDVAMC resulted in significant savings, a full cost-effective analysis is needed to assess more comprehensive institution savings.

Semaglutide and liraglutide are glucagon-like peptide 1 receptor agonists (GLP-1 RAs) that are approved by the US Food and Drug Administration as subcutaneous injections for patients with type 2 diabetes mellitus (T2DM). Both are recommended by the American Diabetes Association (ADA) as first-line options for patients with concomitant atherosclerotic cardiovascular (CV) disease and exert therapeutic effect via incretin-like mechanisms.¹ These agents lower blood glucose levels by stimulating insulin release, increasing the body’s sensitivity to insulin, and inhibiting inappropriate glucagon secretion.^2,3 They also slow gastric emptying, resulting in decreased appetite and potential weight loss.⁴

The SUSTAIN (1-7) trials concluded that semaglutide presented an equivalent safety profile and greater efficacy compared with other GLP-1 RAs, including exenatide and dulaglutide.² The SUSTAIN-10 open-label, head-to-head trial evaluating 1 mg semaglutide once weekly vs 1.2 mg liraglutide daily concluded that semaglutide was superior in hemoglobin A_1c (HbA_1c) and body weight reduction compared with liraglutide, with slightly increased gastrointestinal (GI) adverse effects (AEs).⁵ Similar to the LEADER trial assessing liraglutide, SUSTAIN-6 evaluated semaglutide in patients at increased CV risk and found that compared with placebo, semaglutide decreased rates of serious CV events, such as CV death, myocardial infarction, and stroke and were similar to the CV outcomes in the LEADER trial.^2,6 Although initial results of the SUSTAIN-6 trial were thought to be nearly equivalent to the LEADER trial, analyses later published comparing both trials noted that semaglutide had more potent HbA_1c lowering and weight loss benefit when compared with liraglutide.^2,6 The cardioprotective outcomes of SUSTAIN-6 qualified semaglutide for inclusion in the current ADA Standards of Medical Care recommendations for CV risk reduction.^6,7 However, despite the CV safety profile and efficacy associated with semaglutide, the SUSTAIN-6 trial noted an increased risk of diabetic retinopathy (DR) complications in 50 of 1648 patients (3%) treated with semaglutide compared with 29 of 1649 (1.8%) who received placebo (P = .02; hazard ratio, 1.76; 95% CI, 1.11-2.78).⁶ Of the 79 total patients who experienced retinopathy complications, 66 had retinopathy at baseline (42 of 50 [84%]) in the semaglutide group; 24 of 29 [83%] in the placebo group).⁶ Worsening of DR became one of the most notable AEs of semaglutide evaluated in clinical trials. This further deemed the effect as a warning in the semaglutide package insert to assist clinicians with treatment decisions.

As part of a US Department of Veterans Affairs (VA) National Lost Opportunity Cost Savings Initiative, which encompasses administrative efforts to promote more cost-effective yet safe and efficacious therapy options for veterans, the Michael E. DeBakey VA Medical Center (MEDVAMC) in Houston, Texas, converted a portion of patients with T2DM established on liraglutide to semaglutide. The 30-day supply cost of the 2-pack liraglutide 6 mg/mL (3 mL) injection pens for the MEDVAMC was $197.64. The 30-day supply cost for the singular multidose semaglutide 0.5 mg/0.375 mL (1.5 mL) injection pen was $115.15. Cost savings for the MEDVAMC facility were initially estimated to reach $642,522.

The subset of patients converted had to have undergone teleretinal imaging and not have a diagnosis of nonproliferative DR (NPDR), proliferative DR (PDR), or PDR with or without diabetic macular edema. These recommendations excluding various forms of retinopathy were implemented per local institution guidance supporting clinical data from the SUSTAIN trials. Patients diagnosed with these conditions were continued on liraglutide due to an increased risk of DR complications associated with semaglutide.

In the fall of 2021, there was also a standing list of patients on liraglutide who were not converted due to a lack of teleretinal imaging. As a result, there was potential for a quality improvement (QI) intervention to target this patient population, which could result in further cost savings for MEDVAMC and improved glycemic control because of increased conversion from liraglutide to semaglutide. The purpose of this project was to perform a QI assessment on this subset of patients both initially converted from liraglutide to semaglutide, and those who were yet to be converted due to a lack of teleretinal imaging to determine the impact on glycemic control and cost savings.

Methods

This QI project was a single-center, prospective cohort study with a retrospective chart review of veterans with T2DM converted from liraglutide to semaglutide at the MEDVAMC. Patient data were collected from the Computerized Patient Record System (CPRS) between March 1, 2021, and November 30, 2021. An initial subset of patients was converted to semaglutide in March and April 2021. Patients initially excluded underwent a second chart review to determine whether they truly met exclusion criteria. Patients who did not have a definitive diagnosis of NPDR or PDR, those due for updated teleretinal imaging, as well as those with updated teleretinal imaging that excluded NPDR or PDR were targeted for clinician education interventions.

Following this intervention, a subset of patients with negative DR findings were converted from liraglutide to semaglutide. Primary care and endocrinology clinicians were notified that patients who met the criteria should be referred for teleretinal imaging if no updated results were present or that patients were eligible for semaglutide conversion based on negative findings. Both patients who were initially converted as well as those converted following education were included for data collection/analysis of glycemic control via HbA_1c and blood glucose levels.

Cost savings were evaluated using outpatient pharmacy procurement pricing data. This project was approved by the MEDVAMC Quality Assurance and Regulatory Affairs Office.

Participants

Patients included in the study were adults aged ≥ 18 years with T2DM, converted from liraglutide 0.6 and 1.2 mg daily to semaglutide 0.25 mg weekly (titrated to 0.5 mg weekly after 4 weeks), and had an active prescription for semaglutide, with or without insulin or other oral antihyperglycemics. Patients with NPDR or PDR, type 1 DM, no HbA_1c data, no filled semaglutide prescriptions, insulin pumps, and those without teleretinal imaging within the postintervention period or who died during the study period were excluded.

Patient baseline characteristics collected included demographic data, CV comorbidities, antihyperglycemic medications, and changes in insulin doses. Parameters analyzed at baseline and 3 to 12 months postconversion included body weight, HbA_1c, and blood glucose levels.

Outcomes

The primary objectives of this QI project were to assess glycemic control (via changes in HbA_1c levels) and cost savings following patient conversion from liraglutide to semaglutide. A second objective was to educate clinicians for referral of T2DM patients without teleretinal imaging in the past 2 years.

The purpose of the latter objective was to encourage conversion from liraglutide to semaglutide in the absence of DR. We predicted that 50% of patients with clinician education would be converted. Secondary objectives included assessing body weight differences, evaluating modifications in diabetes regimen, and documenting AEs. We predicted that glycemic control would either remain stable or improve with conversion to semaglutide.

Statistical Analysis

Patient demographic data were analyzed using descriptive statistics. Quantitative data (HbA_1c, blood glucose, and body weight differences as continuous variables) were analyzed using a paired Student t test, and categorical variables were analyzed using the χ² test.

During the study period, 692 patients were identified with active liraglutide prescriptions (Figure). Of these, 49 patients who were initially excluded due to outdated teleretinal imaging or negative findings met the criteria for clinician education, and 14 of those 49 patients (28.6%) were converted from liraglutide to semaglutide. Thirty-three patients (67.3%) did not schedule teleretinal imaging or did not convert to semaglutide following negative teleretinal findings. Two patients (4.1%) either scheduled or proceeded with teleretinal imaging, without any further action from the clinician.

Including the 14 patients converted posteducational intervention, 425 patients were converted to semaglutide. Excluded from analysis were 121 patients: 57 for incomplete HbA_1c data or no filled semaglutide prescription; 30 for HbA_1c and weight data outside of the study timeframe; 25 died of causes unrelated to the project; 8 had insulin pumps; and 1 was diagnosed with late-onset type 1 DM. The final sample was 304 patients who underwent analysis.

Two hundred seventy-three patients (89.8%) were male, and 180 (59.2%) were White (Table 1). The mean (SD) age of patients was 65.9 (9.6) years, and 236 (77.6%) were established on insulin therapy (either basal, bolus, or a combination). The 3 most common antihyperglycemic agents (other than insulin) that patients used included 185 metformin (60.9%), 104 empagliflozin (34.2%), and 50 glipizide (16.4%) prescriptions.

Most patients had CV disease. Three hundred patients (98.7%) had comorbid hypertension, 298 (98.0%) had hyperlipidemia, and 114 (37.5%) had coronary artery disease (Table 2). Other diseases that patients were concomitantly diagnosed with included peripheral vascular disease, heart failure, history of stroke or transient ischemic attack, and history of myocardial infarction.

Documented AEs included 83 patients (27.3%) with hypoglycemia at any point within 3 to 12 months of conversion and 25 patients (8.2%) with mainly GI-related events, including nausea, vomiting, diarrhea, decreased appetite, and abdominal pain. Six patients (2.0%) had a new diagnosis of DR 3 to 12 months postconversion.

Glycemic Control and Weight Changes

At baseline, mean (SD) HbA_1c was 8.1% (1.5), blood glucose was 187.4 (44.2) mg/dL, and body weight was 112.9 (23.0) kg (Table 3). In the timeframe evaluated (3 to 12 months postconversion), patients’ mean (SD) HbA_1c was found to have significantly decreased to 7.6% (1.4) (P < .001; 95% CI, -0.7 to -0.3), blood glucose decreased to 172.6 (39.0) mg/dL (P < .001; 95% CI, -19.3 to -10.2), and body weight decreased to 105.2 (32.3) kg (P < .001; 95% CI, -10.6 to -4.8). All parameters evaluated were deemed statistically significant.

Further analyses evaluating specific changes in HbA_1c observed postconversion are as follows: 199 patients (65.5%) experienced a decrease, 92 (30.3%) experienced an increase, and 13 (4.3%) experienced no change in their HbA_1c.

As the timeframe was fairly broad to assess HbA_1c changes, a prespecified subgroup analysis was conducted to determine specific changes in HbA_1c within 3 to 6, 6 to 9, and 9 to 12 months postconversion (Table 4). At 3 to 6 months postconversion, patient mean (SD) HbA_1c levels significantly decreased from 8.2% (1.5) at baseline to 7.6% (1.3) postconversion (P = .002; 95% CI, -1.0 to -0.2). At 6 to 9 months postconversion, the mean (SD) HbA_1c significantly decreased from 8.1% (1.5) at baseline to 7.6% (1.4) postconversion (P = .002; 95% CI, -0.8 to -0.2).

Glucose-Lowering Agent Adjustments

One hundred thirteen patients (37.2%) required no changes to their antihyperglycemic regimen with the conversion, 85 (28.0%) required increased insulin doses, and 77 (25.3%) required decreased insulin doses (Table 5). Forty-five (14.8%) patients underwent discontinuation of either insulin or other antihyperglycemic agents; 44 (14.5%) had other antihyperglycemic agents dose increased, 39 (12.8%) required adding other glucose-lowering agents, 28 (9.2%) discontinued semaglutide, and 10 (3.3%) had other glucose-lowering medication doses decreased.

Cost Savings

Cost savings were evaluated using the MEDVAMC outpatient pharmacy procurement service. The total cost savings per patient per month was $82.49. For the 411 preclinician education patients converted to semaglutide, this resulted in a prospective annual cost savings of $406,840.68. An additional $13,858.32 was saved due to the intervention/clinician education for 14 patients converted to semaglutide. The total annual cost savings was $420,699.00.

Discussion

Overall, glycemic control significantly improved with veterans’ conversion from liraglutide to semaglutide. Not only were significant changes noted with HbA_1c levels and weight, but consistencies were noted with mean HbA_1c decrease and weight loss expected of GLP-1 RAs noted in clinical trials. The typical range for HbA_1c changes expected is -1% to -2% and weight loss of 1 to 6 kg.^4,7 Data from the LEAD-5 and SUSTAIN-4 trials, evaluating glycemic control in liraglutide and semaglutide, respectively, have noted comparable yet slightly more potent HbA_1c decreases (-1.33% for liraglutide 1.8 mg daily vs -1.2% and -1.6% for semaglutide 0.5 mg and 1 mg weekly, respectively).^8,9 However, more robust weight loss has been noted with semaglutide vs liraglutide (-4.62 kg for semaglutide 0.5 mg weekly and -6.33 kg for semaglutide 1 mg weekly vs -3.43 kg for liraglutide 1.8 mg daily).^8,9 Results from the SUSTAIN-10 trial also noted mean changes in HbA_1c of -1.7% for semaglutide 1 mg weekly vs -1.0% for liraglutide 1.2 mg daily; mean body weight differences were -5.8 kg for semaglutide and -1.9 kg for liraglutide at their respective doses.⁵ The mean weight loss noted with this QI project is consistent with prior trials of semaglutide.

Of note, 44 patients (14.5%) required the dosage increase of either one or multiple additional glucose-lowering agents at any time point within the 3- to 12-month period. Of those patients, 38 (86.4%) underwent further semaglutide dose titration to 1 mg weekly. Common reasons for a further dose increase to 1 mg weekly were an indication for more robust HbA_1c lowering, a desire to decrease patients’ either basal or bolus insulin requirements, or a treatment goal of completely titrating patients off insulin.

It is uncertain why 30.3% of patients experienced an increase in HbA_1c and 4.3% experienced no change. However, possibilities for the divergence in HbA_1c outcomes in these subsets of patients may include suboptimal adherence to semaglutide or other antihyperglycemic agents as indicated by clinicians or nonadherence to dietary and lifestyle modifications.

Most patients (65.5%) experienced a decrease in HbA_1c because of conversion to semaglutide, and AEs appeared as follows: 27.3% experienced hypoglycemia, and 8.2% experienced GI intolerance. The semaglutide discontinuation rate neared 10%, a majority due to intolerable AEs as previously described. Overall, patients seemed to tolerate the medication well as their glycemic control and weight loss improved. Adherence was not objectively assessed for this QI project but could be an area of improvement for future studies.

At the MEDVAMC, liraglutide is a nonformulary agent and semaglutide is now the formulary-preferred option. For patients with uncontrolled T2DM, if a GLP-1 RA is desired for therapy, clinicians are to place a prior authorization drug request (PADR) consultation for semaglutide for further evaluation and review of VA Criteria for Use (CFU) by clinical pharmacist practitioners. Liraglutide is the alternative option if patients do not meet the CFU for semaglutide (ie, have a diagnosis of DR among other exclusions). However, the semaglutide CFU was updated in April 2022 to exclude those specifically diagnosed with PDR, severe NPDR, and macular edema unless an ophthalmologist deems semaglutide acceptable. This indicates that patients with mild-to-moderate NPDR (who were originally excluded from this QI project) are now eligible to receive semaglutide. The incidence of new DR diagnoses (2%) observed in this study could indicate an unclear relationship between semaglutide and increased rates of DR; however, no definitive correlation can be established due to the retrospective nature of this project. The implications of the results of this QI project in relation to the updated CFU remain undetermined.

Due to the comparable improvements in HbA_1c and more robust weight loss noted with semaglutide vs liraglutide, we deem it appropriate to select semaglutide as the more cost-efficient GLP-1 RA and formulary preferred option. The data of this QI project supports the overall safety and treatment utility of this option. Although significant cost savings were achieved (> $400,000), the long-term benefit of the liraglutide to semaglutide conversion remains unknown.

Strengths and Limitations

Strengths of this project include the large sample size, its setting in a large VA medical center, and the evaluation of multiple outcomes beyond HbA_1c for assessment of glycemic control (ie, mean blood glucose, insulin titration, and dose adjustment of other glucose-lowering agents).

Limitations of this study include the retrospective chart review used for data collection, limited accuracy of objective data due to the COVID-19 pandemic, and inconsistencies with documentation in patients’ electronic health records. As a protective measure in the height of the pandemic between March 2021 and November 2021, the VA promoted using telephone and virtual-visit clinics to minimize exposure for patients with nonurgent follow-up needs. Patient hesitance to present to the clinic in person due to COVID-19 was also a significant factor in obtaining objective follow-up data. As a result, less accurate and timely baseline and postconversion weight and HbA_1c data resulted, leading to our decision to extend the timeframe evaluated postconversion to 3 to 12 months. We also noted inconsistencies with documentation in CPRS. Unless veterans were closely followed by clinical pharmacist practitioners or endocrine consultation service clinicians, it was more difficult to follow and document trends of insulin titration to assess the impact of semaglutide conversion. The number of AEs, including hypoglycemia and GI intolerance, were also not consistently documented within the CPRS, and the frequency of AEs may be underestimated.

Another possible limitation regarding the interpretation of the results includes the portion of patients titrated up to semaglutide 1 mg weekly. As the focal point of this project was to review changes in glycemic control in the conversion to semaglutide 0.5 mg, this population of patients converted to 1 mg could potentially overestimate the HbA_1c and weight changes described, as it is consistent with the SUSTAIN trials that show more robust decreases in those parameters described earlier.

Conclusions

A subset of patients with T2DM converted from liraglutide to semaglutide experienced significant changes in glycemic control and body weight. Significant differences were noted for a decreased HbA_1c, decreased mean blood glucose, and weight loss. A fair portion of patients’ antihyperglycemic regimens required no changes on conversion to semaglutide. Although the semaglutide discontinuation rate neared 10%, AEs that may have contributed to this discontinuation rate included hypoglycemia and GI intolerance. Clinician education resulted in a substantial number of patients undergoing teleretinal imaging and further conversion to semaglutide; however, due to the low conversion response rate, a more effective method of educating clinicians is warranted. Although the semaglutide cost savings initiative at MEDVAMC resulted in significant savings, a full cost-effective analysis is needed to assess more comprehensive institution savings.

Semaglutide and liraglutide are glucagon-like peptide 1 receptor agonists (GLP-1 RAs) that are approved by the US Food and Drug Administration as subcutaneous injections for patients with type 2 diabetes mellitus (T2DM). Both are recommended by the American Diabetes Association (ADA) as first-line options for patients with concomitant atherosclerotic cardiovascular (CV) disease and exert therapeutic effect via incretin-like mechanisms.¹ These agents lower blood glucose levels by stimulating insulin release, increasing the body’s sensitivity to insulin, and inhibiting inappropriate glucagon secretion.^2,3 They also slow gastric emptying, resulting in decreased appetite and potential weight loss.⁴

The SUSTAIN (1-7) trials concluded that semaglutide presented an equivalent safety profile and greater efficacy compared with other GLP-1 RAs, including exenatide and dulaglutide.² The SUSTAIN-10 open-label, head-to-head trial evaluating 1 mg semaglutide once weekly vs 1.2 mg liraglutide daily concluded that semaglutide was superior in hemoglobin A_1c (HbA_1c) and body weight reduction compared with liraglutide, with slightly increased gastrointestinal (GI) adverse effects (AEs).⁵ Similar to the LEADER trial assessing liraglutide, SUSTAIN-6 evaluated semaglutide in patients at increased CV risk and found that compared with placebo, semaglutide decreased rates of serious CV events, such as CV death, myocardial infarction, and stroke and were similar to the CV outcomes in the LEADER trial.^2,6 Although initial results of the SUSTAIN-6 trial were thought to be nearly equivalent to the LEADER trial, analyses later published comparing both trials noted that semaglutide had more potent HbA_1c lowering and weight loss benefit when compared with liraglutide.^2,6 The cardioprotective outcomes of SUSTAIN-6 qualified semaglutide for inclusion in the current ADA Standards of Medical Care recommendations for CV risk reduction.^6,7 However, despite the CV safety profile and efficacy associated with semaglutide, the SUSTAIN-6 trial noted an increased risk of diabetic retinopathy (DR) complications in 50 of 1648 patients (3%) treated with semaglutide compared with 29 of 1649 (1.8%) who received placebo (P = .02; hazard ratio, 1.76; 95% CI, 1.11-2.78).⁶ Of the 79 total patients who experienced retinopathy complications, 66 had retinopathy at baseline (42 of 50 [84%]) in the semaglutide group; 24 of 29 [83%] in the placebo group).⁶ Worsening of DR became one of the most notable AEs of semaglutide evaluated in clinical trials. This further deemed the effect as a warning in the semaglutide package insert to assist clinicians with treatment decisions.

As part of a US Department of Veterans Affairs (VA) National Lost Opportunity Cost Savings Initiative, which encompasses administrative efforts to promote more cost-effective yet safe and efficacious therapy options for veterans, the Michael E. DeBakey VA Medical Center (MEDVAMC) in Houston, Texas, converted a portion of patients with T2DM established on liraglutide to semaglutide. The 30-day supply cost of the 2-pack liraglutide 6 mg/mL (3 mL) injection pens for the MEDVAMC was $197.64. The 30-day supply cost for the singular multidose semaglutide 0.5 mg/0.375 mL (1.5 mL) injection pen was $115.15. Cost savings for the MEDVAMC facility were initially estimated to reach $642,522.

The subset of patients converted had to have undergone teleretinal imaging and not have a diagnosis of nonproliferative DR (NPDR), proliferative DR (PDR), or PDR with or without diabetic macular edema. These recommendations excluding various forms of retinopathy were implemented per local institution guidance supporting clinical data from the SUSTAIN trials. Patients diagnosed with these conditions were continued on liraglutide due to an increased risk of DR complications associated with semaglutide.

In the fall of 2021, there was also a standing list of patients on liraglutide who were not converted due to a lack of teleretinal imaging. As a result, there was potential for a quality improvement (QI) intervention to target this patient population, which could result in further cost savings for MEDVAMC and improved glycemic control because of increased conversion from liraglutide to semaglutide. The purpose of this project was to perform a QI assessment on this subset of patients both initially converted from liraglutide to semaglutide, and those who were yet to be converted due to a lack of teleretinal imaging to determine the impact on glycemic control and cost savings.

Methods

This QI project was a single-center, prospective cohort study with a retrospective chart review of veterans with T2DM converted from liraglutide to semaglutide at the MEDVAMC. Patient data were collected from the Computerized Patient Record System (CPRS) between March 1, 2021, and November 30, 2021. An initial subset of patients was converted to semaglutide in March and April 2021. Patients initially excluded underwent a second chart review to determine whether they truly met exclusion criteria. Patients who did not have a definitive diagnosis of NPDR or PDR, those due for updated teleretinal imaging, as well as those with updated teleretinal imaging that excluded NPDR or PDR were targeted for clinician education interventions.

Following this intervention, a subset of patients with negative DR findings were converted from liraglutide to semaglutide. Primary care and endocrinology clinicians were notified that patients who met the criteria should be referred for teleretinal imaging if no updated results were present or that patients were eligible for semaglutide conversion based on negative findings. Both patients who were initially converted as well as those converted following education were included for data collection/analysis of glycemic control via HbA_1c and blood glucose levels.

Cost savings were evaluated using outpatient pharmacy procurement pricing data. This project was approved by the MEDVAMC Quality Assurance and Regulatory Affairs Office.

Participants

Patients included in the study were adults aged ≥ 18 years with T2DM, converted from liraglutide 0.6 and 1.2 mg daily to semaglutide 0.25 mg weekly (titrated to 0.5 mg weekly after 4 weeks), and had an active prescription for semaglutide, with or without insulin or other oral antihyperglycemics. Patients with NPDR or PDR, type 1 DM, no HbA_1c data, no filled semaglutide prescriptions, insulin pumps, and those without teleretinal imaging within the postintervention period or who died during the study period were excluded.

Patient baseline characteristics collected included demographic data, CV comorbidities, antihyperglycemic medications, and changes in insulin doses. Parameters analyzed at baseline and 3 to 12 months postconversion included body weight, HbA_1c, and blood glucose levels.

Outcomes

The primary objectives of this QI project were to assess glycemic control (via changes in HbA_1c levels) and cost savings following patient conversion from liraglutide to semaglutide. A second objective was to educate clinicians for referral of T2DM patients without teleretinal imaging in the past 2 years.

The purpose of the latter objective was to encourage conversion from liraglutide to semaglutide in the absence of DR. We predicted that 50% of patients with clinician education would be converted. Secondary objectives included assessing body weight differences, evaluating modifications in diabetes regimen, and documenting AEs. We predicted that glycemic control would either remain stable or improve with conversion to semaglutide.

Statistical Analysis

Patient demographic data were analyzed using descriptive statistics. Quantitative data (HbA_1c, blood glucose, and body weight differences as continuous variables) were analyzed using a paired Student t test, and categorical variables were analyzed using the χ² test.

During the study period, 692 patients were identified with active liraglutide prescriptions (Figure). Of these, 49 patients who were initially excluded due to outdated teleretinal imaging or negative findings met the criteria for clinician education, and 14 of those 49 patients (28.6%) were converted from liraglutide to semaglutide. Thirty-three patients (67.3%) did not schedule teleretinal imaging or did not convert to semaglutide following negative teleretinal findings. Two patients (4.1%) either scheduled or proceeded with teleretinal imaging, without any further action from the clinician.

Including the 14 patients converted posteducational intervention, 425 patients were converted to semaglutide. Excluded from analysis were 121 patients: 57 for incomplete HbA_1c data or no filled semaglutide prescription; 30 for HbA_1c and weight data outside of the study timeframe; 25 died of causes unrelated to the project; 8 had insulin pumps; and 1 was diagnosed with late-onset type 1 DM. The final sample was 304 patients who underwent analysis.

Two hundred seventy-three patients (89.8%) were male, and 180 (59.2%) were White (Table 1). The mean (SD) age of patients was 65.9 (9.6) years, and 236 (77.6%) were established on insulin therapy (either basal, bolus, or a combination). The 3 most common antihyperglycemic agents (other than insulin) that patients used included 185 metformin (60.9%), 104 empagliflozin (34.2%), and 50 glipizide (16.4%) prescriptions.

Most patients had CV disease. Three hundred patients (98.7%) had comorbid hypertension, 298 (98.0%) had hyperlipidemia, and 114 (37.5%) had coronary artery disease (Table 2). Other diseases that patients were concomitantly diagnosed with included peripheral vascular disease, heart failure, history of stroke or transient ischemic attack, and history of myocardial infarction.

Documented AEs included 83 patients (27.3%) with hypoglycemia at any point within 3 to 12 months of conversion and 25 patients (8.2%) with mainly GI-related events, including nausea, vomiting, diarrhea, decreased appetite, and abdominal pain. Six patients (2.0%) had a new diagnosis of DR 3 to 12 months postconversion.

Glycemic Control and Weight Changes

At baseline, mean (SD) HbA_1c was 8.1% (1.5), blood glucose was 187.4 (44.2) mg/dL, and body weight was 112.9 (23.0) kg (Table 3). In the timeframe evaluated (3 to 12 months postconversion), patients’ mean (SD) HbA_1c was found to have significantly decreased to 7.6% (1.4) (P < .001; 95% CI, -0.7 to -0.3), blood glucose decreased to 172.6 (39.0) mg/dL (P < .001; 95% CI, -19.3 to -10.2), and body weight decreased to 105.2 (32.3) kg (P < .001; 95% CI, -10.6 to -4.8). All parameters evaluated were deemed statistically significant.

Further analyses evaluating specific changes in HbA_1c observed postconversion are as follows: 199 patients (65.5%) experienced a decrease, 92 (30.3%) experienced an increase, and 13 (4.3%) experienced no change in their HbA_1c.

As the timeframe was fairly broad to assess HbA_1c changes, a prespecified subgroup analysis was conducted to determine specific changes in HbA_1c within 3 to 6, 6 to 9, and 9 to 12 months postconversion (Table 4). At 3 to 6 months postconversion, patient mean (SD) HbA_1c levels significantly decreased from 8.2% (1.5) at baseline to 7.6% (1.3) postconversion (P = .002; 95% CI, -1.0 to -0.2). At 6 to 9 months postconversion, the mean (SD) HbA_1c significantly decreased from 8.1% (1.5) at baseline to 7.6% (1.4) postconversion (P = .002; 95% CI, -0.8 to -0.2).

Glucose-Lowering Agent Adjustments

One hundred thirteen patients (37.2%) required no changes to their antihyperglycemic regimen with the conversion, 85 (28.0%) required increased insulin doses, and 77 (25.3%) required decreased insulin doses (Table 5). Forty-five (14.8%) patients underwent discontinuation of either insulin or other antihyperglycemic agents; 44 (14.5%) had other antihyperglycemic agents dose increased, 39 (12.8%) required adding other glucose-lowering agents, 28 (9.2%) discontinued semaglutide, and 10 (3.3%) had other glucose-lowering medication doses decreased.

Cost Savings

Cost savings were evaluated using the MEDVAMC outpatient pharmacy procurement service. The total cost savings per patient per month was $82.49. For the 411 preclinician education patients converted to semaglutide, this resulted in a prospective annual cost savings of $406,840.68. An additional $13,858.32 was saved due to the intervention/clinician education for 14 patients converted to semaglutide. The total annual cost savings was $420,699.00.

Discussion

Overall, glycemic control significantly improved with veterans’ conversion from liraglutide to semaglutide. Not only were significant changes noted with HbA_1c levels and weight, but consistencies were noted with mean HbA_1c decrease and weight loss expected of GLP-1 RAs noted in clinical trials. The typical range for HbA_1c changes expected is -1% to -2% and weight loss of 1 to 6 kg.^4,7 Data from the LEAD-5 and SUSTAIN-4 trials, evaluating glycemic control in liraglutide and semaglutide, respectively, have noted comparable yet slightly more potent HbA_1c decreases (-1.33% for liraglutide 1.8 mg daily vs -1.2% and -1.6% for semaglutide 0.5 mg and 1 mg weekly, respectively).^8,9 However, more robust weight loss has been noted with semaglutide vs liraglutide (-4.62 kg for semaglutide 0.5 mg weekly and -6.33 kg for semaglutide 1 mg weekly vs -3.43 kg for liraglutide 1.8 mg daily).^8,9 Results from the SUSTAIN-10 trial also noted mean changes in HbA_1c of -1.7% for semaglutide 1 mg weekly vs -1.0% for liraglutide 1.2 mg daily; mean body weight differences were -5.8 kg for semaglutide and -1.9 kg for liraglutide at their respective doses.⁵ The mean weight loss noted with this QI project is consistent with prior trials of semaglutide.

Of note, 44 patients (14.5%) required the dosage increase of either one or multiple additional glucose-lowering agents at any time point within the 3- to 12-month period. Of those patients, 38 (86.4%) underwent further semaglutide dose titration to 1 mg weekly. Common reasons for a further dose increase to 1 mg weekly were an indication for more robust HbA_1c lowering, a desire to decrease patients’ either basal or bolus insulin requirements, or a treatment goal of completely titrating patients off insulin.

It is uncertain why 30.3% of patients experienced an increase in HbA_1c and 4.3% experienced no change. However, possibilities for the divergence in HbA_1c outcomes in these subsets of patients may include suboptimal adherence to semaglutide or other antihyperglycemic agents as indicated by clinicians or nonadherence to dietary and lifestyle modifications.

Most patients (65.5%) experienced a decrease in HbA_1c because of conversion to semaglutide, and AEs appeared as follows: 27.3% experienced hypoglycemia, and 8.2% experienced GI intolerance. The semaglutide discontinuation rate neared 10%, a majority due to intolerable AEs as previously described. Overall, patients seemed to tolerate the medication well as their glycemic control and weight loss improved. Adherence was not objectively assessed for this QI project but could be an area of improvement for future studies.

At the MEDVAMC, liraglutide is a nonformulary agent and semaglutide is now the formulary-preferred option. For patients with uncontrolled T2DM, if a GLP-1 RA is desired for therapy, clinicians are to place a prior authorization drug request (PADR) consultation for semaglutide for further evaluation and review of VA Criteria for Use (CFU) by clinical pharmacist practitioners. Liraglutide is the alternative option if patients do not meet the CFU for semaglutide (ie, have a diagnosis of DR among other exclusions). However, the semaglutide CFU was updated in April 2022 to exclude those specifically diagnosed with PDR, severe NPDR, and macular edema unless an ophthalmologist deems semaglutide acceptable. This indicates that patients with mild-to-moderate NPDR (who were originally excluded from this QI project) are now eligible to receive semaglutide. The incidence of new DR diagnoses (2%) observed in this study could indicate an unclear relationship between semaglutide and increased rates of DR; however, no definitive correlation can be established due to the retrospective nature of this project. The implications of the results of this QI project in relation to the updated CFU remain undetermined.

Due to the comparable improvements in HbA_1c and more robust weight loss noted with semaglutide vs liraglutide, we deem it appropriate to select semaglutide as the more cost-efficient GLP-1 RA and formulary preferred option. The data of this QI project supports the overall safety and treatment utility of this option. Although significant cost savings were achieved (> $400,000), the long-term benefit of the liraglutide to semaglutide conversion remains unknown.

Strengths and Limitations

Strengths of this project include the large sample size, its setting in a large VA medical center, and the evaluation of multiple outcomes beyond HbA_1c for assessment of glycemic control (ie, mean blood glucose, insulin titration, and dose adjustment of other glucose-lowering agents).

Limitations of this study include the retrospective chart review used for data collection, limited accuracy of objective data due to the COVID-19 pandemic, and inconsistencies with documentation in patients’ electronic health records. As a protective measure in the height of the pandemic between March 2021 and November 2021, the VA promoted using telephone and virtual-visit clinics to minimize exposure for patients with nonurgent follow-up needs. Patient hesitance to present to the clinic in person due to COVID-19 was also a significant factor in obtaining objective follow-up data. As a result, less accurate and timely baseline and postconversion weight and HbA_1c data resulted, leading to our decision to extend the timeframe evaluated postconversion to 3 to 12 months. We also noted inconsistencies with documentation in CPRS. Unless veterans were closely followed by clinical pharmacist practitioners or endocrine consultation service clinicians, it was more difficult to follow and document trends of insulin titration to assess the impact of semaglutide conversion. The number of AEs, including hypoglycemia and GI intolerance, were also not consistently documented within the CPRS, and the frequency of AEs may be underestimated.

Another possible limitation regarding the interpretation of the results includes the portion of patients titrated up to semaglutide 1 mg weekly. As the focal point of this project was to review changes in glycemic control in the conversion to semaglutide 0.5 mg, this population of patients converted to 1 mg could potentially overestimate the HbA_1c and weight changes described, as it is consistent with the SUSTAIN trials that show more robust decreases in those parameters described earlier.

Conclusions

A subset of patients with T2DM converted from liraglutide to semaglutide experienced significant changes in glycemic control and body weight. Significant differences were noted for a decreased HbA_1c, decreased mean blood glucose, and weight loss. A fair portion of patients’ antihyperglycemic regimens required no changes on conversion to semaglutide. Although the semaglutide discontinuation rate neared 10%, AEs that may have contributed to this discontinuation rate included hypoglycemia and GI intolerance. Clinician education resulted in a substantial number of patients undergoing teleretinal imaging and further conversion to semaglutide; however, due to the low conversion response rate, a more effective method of educating clinicians is warranted. Although the semaglutide cost savings initiative at MEDVAMC resulted in significant savings, a full cost-effective analysis is needed to assess more comprehensive institution savings.

Click to read more from Federal Health Care Data Trends 2023.

Click to read more from Federal Health Care Data Trends 2023.

Click to read more from Federal Health Care Data Trends 2023.

I have written before about the COSMOS study and its finding that multivitamins (and chocolate) did not improve brain or cardiovascular health. So I was surprised to read that a “new” study found that vitamins can forestall dementia and age-related cognitive decline.

Upon closer look, the new data are neither new nor convincing, at least to me.

©Graça Victoria/iStockphoto.com

Chocolate and multivitamins for CVD and cancer prevention

The large randomized COSMOS trial was supposed to be the definitive study on chocolate that would establish its heart-health benefits without a doubt. Or, rather, the benefits of a cocoa bean extract in pill form given to healthy, older volunteers. The COSMOS study was negative. Chocolate, or the cocoa bean extract they used, did not reduce cardiovascular events.

And yet for all the prepublication importance attached to COSMOS, it is scarcely mentioned. Had it been positive, rest assured that Mars, the candy bar company that cofunded the research, and other interested parties would have been shouting it from the rooftops. As it is, they’re already spinning it.

Which brings us to the multivitamin component. COSMOS actually had a 2 × 2 design. In other words, there were four groups in this study: chocolate plus multivitamin, chocolate plus placebo, placebo plus multivitamin, and placebo plus placebo. This type of study design allows you to study two different interventions simultaneously, provided that they are independent and do not interact with each other. In addition to the primary cardiovascular endpoint, they also studied a cancer endpoint.

The multivitamin supplement didn’t reduce cardiovascular events either. Nor did it affect cancer outcomes. The main COSMOS study was negative and reinforced what countless other studies have proven: Taking a daily multivitamin does not reduce your risk of having a heart attack or developing cancer.
 

But wait, there’s more: COSMOS-Mind

But no researcher worth his salt studies just one or two endpoints in a study. The participants also underwent neurologic and memory testing. These results were reported separately in the COSMOS-Mind study.

COSMOS-Mind is often described as a separate (or “new”) study. In reality, it included the same participants from the original COSMOS trial and measured yet another primary outcome of cognitive performance on a series of tests administered by telephone. Although there is nothing inherently wrong with studying multiple outcomes in your patient population (after all, that salami isn’t going to slice itself), they cannot all be primary outcomes. Some, by necessity, must be secondary hypothesis–generating outcomes. If you test enough endpoints, multiple hypothesis testing dictates that eventually you will get a positive result simply by chance.

There was a time when the neurocognitive outcomes of COSMOS would have been reported in the same paper as the cardiovascular outcomes, but that time seems to have passed us by. Researchers live or die by the number of their publications, and there is an inherent advantage to squeezing as many publications as possible from the same dataset. Though, to be fair, the journal would probably have asked them to split up the paper as well.

In brief, the cocoa extract again fell short in COSMOS-Mind, but the multivitamin arm did better on the composite cognitive outcome. It was a fairly small difference – a 0.07-point improvement on the z-score at the 3-year mark (the z-score is the mean divided by the standard deviation). Much was also made of the fact that the improvement seemed to vary by prior history of cardiovascular disease (CVD). Those with a history of CVD had a 0.11-point improvement, whereas those without had a 0.06-point improvement. The authors couldn’t offer a definitive explanation for these findings. Any argument that multivitamins improve cardiovascular health and therefore prevent vascular dementia has to contend with the fact that the main COSMOS study didn’t show a cardiovascular benefit for vitamins. Speculation that you are treating nutritional deficiencies is exactly that: speculation.

A more salient question is: What does a 0.07-point improvement on the z-score mean clinically? This study didn’t assess whether a multivitamin supplement prevented dementia or allowed people to live independently for longer. In fairness, that would have been exceptionally difficult to do and would have required a much longer study.

Their one attempt to quantify the cognitive benefit clinically was a calculation about normal age-related decline. Test scores were 0.045 points lower for every 1-year increase in age among participants (their mean age was 73 years). So the authors contend that a 0.07-point increase, or the 0.083-point increase that they found at year 3, corresponds to 1.8 years of age-related decline forestalled. Whether this is an appropriate assumption, I leave for the reader to decide.
 

COSMOS-Web and replication

The results of COSMOS-Mind were seemingly bolstered by the recent publication of COSMOS-Web. Although I’ve seen this study described as having replicated the results of COSMOS-Mind, that description is a bit misleading. This was yet another ancillary COSMOS study; more than half of the 2,262 participants in COSMOS-Mind were also included in COSMOS-Web. Replicating results in the same people isn’t true replication.

The main difference between COSMOS-Mind and COSMOS-Web is that the former used a telephone interview to administer the cognitive tests and the latter used the Internet. They also had different endpoints, with COSMOS-Web looking at immediate recall rather than a global test composite.

COSMOS-Web was a positive study in that patients getting the multivitamin supplement did better on the test for immediate memory recall (remembering a list of 20 words), though they didn’t improve on tests of memory retention, executive function, or novel object recognition (basically a test where subjects have to identify matching geometric patterns and then recall them later). They were able to remember an additional 0.71 word on average, compared with 0.44 word in the placebo group. (For the record, it found no benefit for the cocoa extract).

Everybody does better on memory tests the second time around because practice makes perfect, hence the improvement in the placebo group. This benefit at 1 year did not survive to the end of follow-up at 3 years, in contrast to COSMOS-Mind, where the benefit was not apparent at 1 year and seen only at year 3. A history of cardiovascular disease didn’t seem to affect the results in COSMOS-Web as it did in COSMOS-Mind. As far as replications go, COSMOS-Web has some very non-negligible differences, compared with COSMOS-Mind. This incongruity, especially given the overlap in the patient populations is hard to reconcile. If COSMOS-Web was supposed to assuage any doubts that persisted after COSMOS-Mind, it hasn’t for me.
 

One of these studies is not like the others

Finally, although the COSMOS trial and all its ancillary study analyses suggest a neurocognitive benefit to multivitamin supplementation, it’s not the first study to test the matter. The Age-Related Eye Disease Study looked at vitamin C, vitamin E, beta-carotene, zinc, and copper. There was no benefit on any of the six cognitive tests administered to patients. The Women’s Health Study, the Women’s Antioxidant Cardiovascular Study and PREADViSE have all failed to show any benefit to the various vitamins and minerals they studied. A meta-analysis of 11 trials found no benefit to B vitamins in slowing cognitive aging.

The claim that COSMOS is the “first” study to test the hypothesis hinges on some careful wordplay. Prior studies tested specific vitamins, not a multivitamin. In the discussion of the paper, these other studies are critiqued for being short term. But the Physicians’ Health Study II did in fact study a multivitamin and assessed cognitive performance on average 2.5 years after randomization. It found no benefit. The authors of COSMOS-Web critiqued the 2.5-year wait to perform cognitive testing, saying it would have missed any short-term benefits. Although, given that they simultaneously praised their 3 years of follow-up, the criticism is hard to fully accept or even understand.

Whether follow-up is short or long, uses individual vitamins or a multivitamin, the results excluding COSMOS are uniformly negative. I for one am skeptical that a multivitamin or any individual vitamin can prevent dementia. Same goes for chocolate.

Do enough tests in the same population, and something will rise above the noise just by chance. When you get a positive result in your research, it’s always exciting. But when a slew of studies that came before you are negative, you aren’t groundbreaking. You’re an outlier.

Dr. Labos is a cardiologist at Hôpital Notre-Dame, Montreal. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

I have written before about the COSMOS study and its finding that multivitamins (and chocolate) did not improve brain or cardiovascular health. So I was surprised to read that a “new” study found that vitamins can forestall dementia and age-related cognitive decline.

Upon closer look, the new data are neither new nor convincing, at least to me.

©Graça Victoria/iStockphoto.com

Chocolate and multivitamins for CVD and cancer prevention

The large randomized COSMOS trial was supposed to be the definitive study on chocolate that would establish its heart-health benefits without a doubt. Or, rather, the benefits of a cocoa bean extract in pill form given to healthy, older volunteers. The COSMOS study was negative. Chocolate, or the cocoa bean extract they used, did not reduce cardiovascular events.

And yet for all the prepublication importance attached to COSMOS, it is scarcely mentioned. Had it been positive, rest assured that Mars, the candy bar company that cofunded the research, and other interested parties would have been shouting it from the rooftops. As it is, they’re already spinning it.

Which brings us to the multivitamin component. COSMOS actually had a 2 × 2 design. In other words, there were four groups in this study: chocolate plus multivitamin, chocolate plus placebo, placebo plus multivitamin, and placebo plus placebo. This type of study design allows you to study two different interventions simultaneously, provided that they are independent and do not interact with each other. In addition to the primary cardiovascular endpoint, they also studied a cancer endpoint.

The multivitamin supplement didn’t reduce cardiovascular events either. Nor did it affect cancer outcomes. The main COSMOS study was negative and reinforced what countless other studies have proven: Taking a daily multivitamin does not reduce your risk of having a heart attack or developing cancer.
 

But wait, there’s more: COSMOS-Mind

But no researcher worth his salt studies just one or two endpoints in a study. The participants also underwent neurologic and memory testing. These results were reported separately in the COSMOS-Mind study.

COSMOS-Mind is often described as a separate (or “new”) study. In reality, it included the same participants from the original COSMOS trial and measured yet another primary outcome of cognitive performance on a series of tests administered by telephone. Although there is nothing inherently wrong with studying multiple outcomes in your patient population (after all, that salami isn’t going to slice itself), they cannot all be primary outcomes. Some, by necessity, must be secondary hypothesis–generating outcomes. If you test enough endpoints, multiple hypothesis testing dictates that eventually you will get a positive result simply by chance.

There was a time when the neurocognitive outcomes of COSMOS would have been reported in the same paper as the cardiovascular outcomes, but that time seems to have passed us by. Researchers live or die by the number of their publications, and there is an inherent advantage to squeezing as many publications as possible from the same dataset. Though, to be fair, the journal would probably have asked them to split up the paper as well.

In brief, the cocoa extract again fell short in COSMOS-Mind, but the multivitamin arm did better on the composite cognitive outcome. It was a fairly small difference – a 0.07-point improvement on the z-score at the 3-year mark (the z-score is the mean divided by the standard deviation). Much was also made of the fact that the improvement seemed to vary by prior history of cardiovascular disease (CVD). Those with a history of CVD had a 0.11-point improvement, whereas those without had a 0.06-point improvement. The authors couldn’t offer a definitive explanation for these findings. Any argument that multivitamins improve cardiovascular health and therefore prevent vascular dementia has to contend with the fact that the main COSMOS study didn’t show a cardiovascular benefit for vitamins. Speculation that you are treating nutritional deficiencies is exactly that: speculation.

A more salient question is: What does a 0.07-point improvement on the z-score mean clinically? This study didn’t assess whether a multivitamin supplement prevented dementia or allowed people to live independently for longer. In fairness, that would have been exceptionally difficult to do and would have required a much longer study.

Their one attempt to quantify the cognitive benefit clinically was a calculation about normal age-related decline. Test scores were 0.045 points lower for every 1-year increase in age among participants (their mean age was 73 years). So the authors contend that a 0.07-point increase, or the 0.083-point increase that they found at year 3, corresponds to 1.8 years of age-related decline forestalled. Whether this is an appropriate assumption, I leave for the reader to decide.
 

COSMOS-Web and replication

The results of COSMOS-Mind were seemingly bolstered by the recent publication of COSMOS-Web. Although I’ve seen this study described as having replicated the results of COSMOS-Mind, that description is a bit misleading. This was yet another ancillary COSMOS study; more than half of the 2,262 participants in COSMOS-Mind were also included in COSMOS-Web. Replicating results in the same people isn’t true replication.

The main difference between COSMOS-Mind and COSMOS-Web is that the former used a telephone interview to administer the cognitive tests and the latter used the Internet. They also had different endpoints, with COSMOS-Web looking at immediate recall rather than a global test composite.

COSMOS-Web was a positive study in that patients getting the multivitamin supplement did better on the test for immediate memory recall (remembering a list of 20 words), though they didn’t improve on tests of memory retention, executive function, or novel object recognition (basically a test where subjects have to identify matching geometric patterns and then recall them later). They were able to remember an additional 0.71 word on average, compared with 0.44 word in the placebo group. (For the record, it found no benefit for the cocoa extract).

Everybody does better on memory tests the second time around because practice makes perfect, hence the improvement in the placebo group. This benefit at 1 year did not survive to the end of follow-up at 3 years, in contrast to COSMOS-Mind, where the benefit was not apparent at 1 year and seen only at year 3. A history of cardiovascular disease didn’t seem to affect the results in COSMOS-Web as it did in COSMOS-Mind. As far as replications go, COSMOS-Web has some very non-negligible differences, compared with COSMOS-Mind. This incongruity, especially given the overlap in the patient populations is hard to reconcile. If COSMOS-Web was supposed to assuage any doubts that persisted after COSMOS-Mind, it hasn’t for me.
 

One of these studies is not like the others

Finally, although the COSMOS trial and all its ancillary study analyses suggest a neurocognitive benefit to multivitamin supplementation, it’s not the first study to test the matter. The Age-Related Eye Disease Study looked at vitamin C, vitamin E, beta-carotene, zinc, and copper. There was no benefit on any of the six cognitive tests administered to patients. The Women’s Health Study, the Women’s Antioxidant Cardiovascular Study and PREADViSE have all failed to show any benefit to the various vitamins and minerals they studied. A meta-analysis of 11 trials found no benefit to B vitamins in slowing cognitive aging.

The claim that COSMOS is the “first” study to test the hypothesis hinges on some careful wordplay. Prior studies tested specific vitamins, not a multivitamin. In the discussion of the paper, these other studies are critiqued for being short term. But the Physicians’ Health Study II did in fact study a multivitamin and assessed cognitive performance on average 2.5 years after randomization. It found no benefit. The authors of COSMOS-Web critiqued the 2.5-year wait to perform cognitive testing, saying it would have missed any short-term benefits. Although, given that they simultaneously praised their 3 years of follow-up, the criticism is hard to fully accept or even understand.

Whether follow-up is short or long, uses individual vitamins or a multivitamin, the results excluding COSMOS are uniformly negative. I for one am skeptical that a multivitamin or any individual vitamin can prevent dementia. Same goes for chocolate.

Do enough tests in the same population, and something will rise above the noise just by chance. When you get a positive result in your research, it’s always exciting. But when a slew of studies that came before you are negative, you aren’t groundbreaking. You’re an outlier.

Dr. Labos is a cardiologist at Hôpital Notre-Dame, Montreal. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

I have written before about the COSMOS study and its finding that multivitamins (and chocolate) did not improve brain or cardiovascular health. So I was surprised to read that a “new” study found that vitamins can forestall dementia and age-related cognitive decline.

Upon closer look, the new data are neither new nor convincing, at least to me.

©Graça Victoria/iStockphoto.com

Chocolate and multivitamins for CVD and cancer prevention

The large randomized COSMOS trial was supposed to be the definitive study on chocolate that would establish its heart-health benefits without a doubt. Or, rather, the benefits of a cocoa bean extract in pill form given to healthy, older volunteers. The COSMOS study was negative. Chocolate, or the cocoa bean extract they used, did not reduce cardiovascular events.

And yet for all the prepublication importance attached to COSMOS, it is scarcely mentioned. Had it been positive, rest assured that Mars, the candy bar company that cofunded the research, and other interested parties would have been shouting it from the rooftops. As it is, they’re already spinning it.

Which brings us to the multivitamin component. COSMOS actually had a 2 × 2 design. In other words, there were four groups in this study: chocolate plus multivitamin, chocolate plus placebo, placebo plus multivitamin, and placebo plus placebo. This type of study design allows you to study two different interventions simultaneously, provided that they are independent and do not interact with each other. In addition to the primary cardiovascular endpoint, they also studied a cancer endpoint.

The multivitamin supplement didn’t reduce cardiovascular events either. Nor did it affect cancer outcomes. The main COSMOS study was negative and reinforced what countless other studies have proven: Taking a daily multivitamin does not reduce your risk of having a heart attack or developing cancer.
 

But wait, there’s more: COSMOS-Mind

But no researcher worth his salt studies just one or two endpoints in a study. The participants also underwent neurologic and memory testing. These results were reported separately in the COSMOS-Mind study.

COSMOS-Mind is often described as a separate (or “new”) study. In reality, it included the same participants from the original COSMOS trial and measured yet another primary outcome of cognitive performance on a series of tests administered by telephone. Although there is nothing inherently wrong with studying multiple outcomes in your patient population (after all, that salami isn’t going to slice itself), they cannot all be primary outcomes. Some, by necessity, must be secondary hypothesis–generating outcomes. If you test enough endpoints, multiple hypothesis testing dictates that eventually you will get a positive result simply by chance.

There was a time when the neurocognitive outcomes of COSMOS would have been reported in the same paper as the cardiovascular outcomes, but that time seems to have passed us by. Researchers live or die by the number of their publications, and there is an inherent advantage to squeezing as many publications as possible from the same dataset. Though, to be fair, the journal would probably have asked them to split up the paper as well.

In brief, the cocoa extract again fell short in COSMOS-Mind, but the multivitamin arm did better on the composite cognitive outcome. It was a fairly small difference – a 0.07-point improvement on the z-score at the 3-year mark (the z-score is the mean divided by the standard deviation). Much was also made of the fact that the improvement seemed to vary by prior history of cardiovascular disease (CVD). Those with a history of CVD had a 0.11-point improvement, whereas those without had a 0.06-point improvement. The authors couldn’t offer a definitive explanation for these findings. Any argument that multivitamins improve cardiovascular health and therefore prevent vascular dementia has to contend with the fact that the main COSMOS study didn’t show a cardiovascular benefit for vitamins. Speculation that you are treating nutritional deficiencies is exactly that: speculation.

A more salient question is: What does a 0.07-point improvement on the z-score mean clinically? This study didn’t assess whether a multivitamin supplement prevented dementia or allowed people to live independently for longer. In fairness, that would have been exceptionally difficult to do and would have required a much longer study.

Their one attempt to quantify the cognitive benefit clinically was a calculation about normal age-related decline. Test scores were 0.045 points lower for every 1-year increase in age among participants (their mean age was 73 years). So the authors contend that a 0.07-point increase, or the 0.083-point increase that they found at year 3, corresponds to 1.8 years of age-related decline forestalled. Whether this is an appropriate assumption, I leave for the reader to decide.
 

COSMOS-Web and replication

The results of COSMOS-Mind were seemingly bolstered by the recent publication of COSMOS-Web. Although I’ve seen this study described as having replicated the results of COSMOS-Mind, that description is a bit misleading. This was yet another ancillary COSMOS study; more than half of the 2,262 participants in COSMOS-Mind were also included in COSMOS-Web. Replicating results in the same people isn’t true replication.

The main difference between COSMOS-Mind and COSMOS-Web is that the former used a telephone interview to administer the cognitive tests and the latter used the Internet. They also had different endpoints, with COSMOS-Web looking at immediate recall rather than a global test composite.

COSMOS-Web was a positive study in that patients getting the multivitamin supplement did better on the test for immediate memory recall (remembering a list of 20 words), though they didn’t improve on tests of memory retention, executive function, or novel object recognition (basically a test where subjects have to identify matching geometric patterns and then recall them later). They were able to remember an additional 0.71 word on average, compared with 0.44 word in the placebo group. (For the record, it found no benefit for the cocoa extract).

Everybody does better on memory tests the second time around because practice makes perfect, hence the improvement in the placebo group. This benefit at 1 year did not survive to the end of follow-up at 3 years, in contrast to COSMOS-Mind, where the benefit was not apparent at 1 year and seen only at year 3. A history of cardiovascular disease didn’t seem to affect the results in COSMOS-Web as it did in COSMOS-Mind. As far as replications go, COSMOS-Web has some very non-negligible differences, compared with COSMOS-Mind. This incongruity, especially given the overlap in the patient populations is hard to reconcile. If COSMOS-Web was supposed to assuage any doubts that persisted after COSMOS-Mind, it hasn’t for me.
 

One of these studies is not like the others

Finally, although the COSMOS trial and all its ancillary study analyses suggest a neurocognitive benefit to multivitamin supplementation, it’s not the first study to test the matter. The Age-Related Eye Disease Study looked at vitamin C, vitamin E, beta-carotene, zinc, and copper. There was no benefit on any of the six cognitive tests administered to patients. The Women’s Health Study, the Women’s Antioxidant Cardiovascular Study and PREADViSE have all failed to show any benefit to the various vitamins and minerals they studied. A meta-analysis of 11 trials found no benefit to B vitamins in slowing cognitive aging.

The claim that COSMOS is the “first” study to test the hypothesis hinges on some careful wordplay. Prior studies tested specific vitamins, not a multivitamin. In the discussion of the paper, these other studies are critiqued for being short term. But the Physicians’ Health Study II did in fact study a multivitamin and assessed cognitive performance on average 2.5 years after randomization. It found no benefit. The authors of COSMOS-Web critiqued the 2.5-year wait to perform cognitive testing, saying it would have missed any short-term benefits. Although, given that they simultaneously praised their 3 years of follow-up, the criticism is hard to fully accept or even understand.

Whether follow-up is short or long, uses individual vitamins or a multivitamin, the results excluding COSMOS are uniformly negative. I for one am skeptical that a multivitamin or any individual vitamin can prevent dementia. Same goes for chocolate.

Do enough tests in the same population, and something will rise above the noise just by chance. When you get a positive result in your research, it’s always exciting. But when a slew of studies that came before you are negative, you aren’t groundbreaking. You’re an outlier.

Dr. Labos is a cardiologist at Hôpital Notre-Dame, Montreal. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

The American Heart Association has released a focused update on managing patients with cardiac arrest or life-threatening toxicity due to poisoning.

The update reflects treatment advances and new knowledge, including the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) for patients whose condition is refractory to poison antidotes and other therapies.

The new guidelines are designed primarily for North American health care professionals who treat adults and children who are critically ill because of poisoning, including intentional and unintentional drug overdose, chemical exposure, and drug-drug interactions, the authors note.

Published online in Circulation, the update was endorsed by the American Academy of Pediatrics.
 

‘Nearly miraculous’

“It’s been 13 years since the poisoning treatment guidelines had a comprehensive update,” lead author Eric J. Lavonas, MD, professor of emergency medicine at Denver Health and the Rocky Mountain Poison and Drug Center, Colo., told this news organization. “In that time, we’ve learned a lot about how to best use antidotes and other treatments to save the most critically poisoned patients.”

Highlighting a few key points from the update, he said, “For those rare situations when antidotes aren’t enough, the new guidelines include the use of heart-lung machines (VA-ECMO) for patients with beta-blocker, calcium channel blocker, or sodium channel blocker poisoning causing cardiogenic shock.”

Furthermore, he said, “High-dose insulin treatment for patients with beta-blocker and calcium channel blocker poisoning [also recommended in the update] has really become mainstream. The doses are up to 10 times higher than the amount used to treat diabetic emergencies.

“Some excellent science has shown that giving IV lipid emulsion can save the life of someone with an accidental overdose of local anesthetic medications, particularly bupivacaine,” he added. “The result is sometimes nearly miraculous.

“But when this treatment is extended to poisoning from other medications, it often doesn’t work as well, and in some situations may make things worse,” he said. “The issue may be that giving lipids increases absorption of drug from the stomach and intestines, which can be dangerous when the patient took an overdose of pills.”
 

Low level of evidence

The guidelines were compiled by the Critical Poisoning Writing Group, which includes experts from emergency medicine, pediatrics, medical toxicology, pharmacology, critical care, emergency medical services, education, research, and nursing. Group members were appointed by the AHA Emergency Cardiovascular Care Science Subcommittee and were approved by the AHA Manuscript Oversight Committee.

First and foremost, the group recommends timely consultation with a medical toxicologist, a clinical toxicologist, or a regional poison center to facilitate rapid, effective therapy, because treatment of cardiac arrest and toxicity from poisoning often requires treatments that most clinicians don’t use frequently.

Other key points include the following:

• Naloxone administration may reverse respiratory arrest due to opioid overdose, preventing progression to cardiac arrest.
• Give high-dose insulin therapy early in the treatment of patients with beta-blocker and calcium channel blocker poisoning, Dr. Lavonas noted.
• Standard advanced life support plus sodium bicarbonate is appropriate for life-threatening dysrhythmias caused by cocaine or other sodium channel blockers.
• If cyanide poisoning is suspected, clinicians should not wait for confirmatory testing; treatment should begin immediately with hydroxocobalamin (preferred) or sodium nitrite plus sodium thiosulfate.
• Digoxin-specific immune antibody fragments can reverse life-threatening dysrhythmias from digoxin poisoning.
• Use of 20% intravenous lipid emulsion can be efficacious in the resuscitation of life-threatening local anesthetic toxicity, especially from bupivacaine, Dr. Lavonas indicated.
• Sedation is recommended for patients with severe agitation from sympathomimetic poisoning to manage hyperthermia and acidosis, prevent rhabdomyolysis and injury, and allow evaluation for other life-threatening conditions.
• Although flumazenil reverses central nervous system and respiratory depression from benzodiazepine poisoning, risks and contraindications, provided in the guidelines, limit its use.
• VA-ECMO can be lifesaving for patients with cardiogenic shock or dysrhythmias that are refractory to other treatments.

“Unfortunately, despite improvements in the design and funding support for resuscitation research, the overall certainty of the evidence base for resuscitation science and management of critical poisoning is low,” the group acknowledges.

Of the 73 guideline recommendations, only 2 are supported by level A evidence; 3 are supported by level B-randomized evidence, 12 by level B-nonrandomized evidence, and the rest by level C evidence.

“Accordingly, the strength of recommendations is weaker than optimal,” they write. “Clinical trials in resuscitation and the management of critical poisoning are sorely needed.”
 

‘Don’t go it alone!’

“Most critical poisonings are pretty uncommon, and each patient is different,” Dr. Lavonas said. “Even in the emergency department or ICU, most physicians will treat a patient who is critically ill with any given poison less than once a year. The antidotes and medication doses needed to effectively treat these patients are often very different than everyday medical practice.

“Don’t try to go it alone!” he urges. “Poisoning cases are complex, and the treatments work best when they are implemented quickly and assertively. A toxicologist can help sort through complex situations and get effective treatment started without delay.”

Every certified poison center has a medical toxicologist or clinical toxicologist on call 24/7 to give advice to physicians and hospitals about patients who are critically ill after being poisoned, he added. “Everyone in the U.S. has access to a poison center by calling one number: 1-800-222-1222.”

Dr. Lavonas has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

The American Heart Association has released a focused update on managing patients with cardiac arrest or life-threatening toxicity due to poisoning.

The update reflects treatment advances and new knowledge, including the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) for patients whose condition is refractory to poison antidotes and other therapies.

The new guidelines are designed primarily for North American health care professionals who treat adults and children who are critically ill because of poisoning, including intentional and unintentional drug overdose, chemical exposure, and drug-drug interactions, the authors note.

Published online in Circulation, the update was endorsed by the American Academy of Pediatrics.
 

‘Nearly miraculous’

“It’s been 13 years since the poisoning treatment guidelines had a comprehensive update,” lead author Eric J. Lavonas, MD, professor of emergency medicine at Denver Health and the Rocky Mountain Poison and Drug Center, Colo., told this news organization. “In that time, we’ve learned a lot about how to best use antidotes and other treatments to save the most critically poisoned patients.”

Highlighting a few key points from the update, he said, “For those rare situations when antidotes aren’t enough, the new guidelines include the use of heart-lung machines (VA-ECMO) for patients with beta-blocker, calcium channel blocker, or sodium channel blocker poisoning causing cardiogenic shock.”

Furthermore, he said, “High-dose insulin treatment for patients with beta-blocker and calcium channel blocker poisoning [also recommended in the update] has really become mainstream. The doses are up to 10 times higher than the amount used to treat diabetic emergencies.

“Some excellent science has shown that giving IV lipid emulsion can save the life of someone with an accidental overdose of local anesthetic medications, particularly bupivacaine,” he added. “The result is sometimes nearly miraculous.

“But when this treatment is extended to poisoning from other medications, it often doesn’t work as well, and in some situations may make things worse,” he said. “The issue may be that giving lipids increases absorption of drug from the stomach and intestines, which can be dangerous when the patient took an overdose of pills.”
 

Low level of evidence

The guidelines were compiled by the Critical Poisoning Writing Group, which includes experts from emergency medicine, pediatrics, medical toxicology, pharmacology, critical care, emergency medical services, education, research, and nursing. Group members were appointed by the AHA Emergency Cardiovascular Care Science Subcommittee and were approved by the AHA Manuscript Oversight Committee.

First and foremost, the group recommends timely consultation with a medical toxicologist, a clinical toxicologist, or a regional poison center to facilitate rapid, effective therapy, because treatment of cardiac arrest and toxicity from poisoning often requires treatments that most clinicians don’t use frequently.

Other key points include the following:

• Naloxone administration may reverse respiratory arrest due to opioid overdose, preventing progression to cardiac arrest.
• Give high-dose insulin therapy early in the treatment of patients with beta-blocker and calcium channel blocker poisoning, Dr. Lavonas noted.
• Standard advanced life support plus sodium bicarbonate is appropriate for life-threatening dysrhythmias caused by cocaine or other sodium channel blockers.
• If cyanide poisoning is suspected, clinicians should not wait for confirmatory testing; treatment should begin immediately with hydroxocobalamin (preferred) or sodium nitrite plus sodium thiosulfate.
• Digoxin-specific immune antibody fragments can reverse life-threatening dysrhythmias from digoxin poisoning.
• Use of 20% intravenous lipid emulsion can be efficacious in the resuscitation of life-threatening local anesthetic toxicity, especially from bupivacaine, Dr. Lavonas indicated.
• Sedation is recommended for patients with severe agitation from sympathomimetic poisoning to manage hyperthermia and acidosis, prevent rhabdomyolysis and injury, and allow evaluation for other life-threatening conditions.
• Although flumazenil reverses central nervous system and respiratory depression from benzodiazepine poisoning, risks and contraindications, provided in the guidelines, limit its use.
• VA-ECMO can be lifesaving for patients with cardiogenic shock or dysrhythmias that are refractory to other treatments.

“Unfortunately, despite improvements in the design and funding support for resuscitation research, the overall certainty of the evidence base for resuscitation science and management of critical poisoning is low,” the group acknowledges.

Of the 73 guideline recommendations, only 2 are supported by level A evidence; 3 are supported by level B-randomized evidence, 12 by level B-nonrandomized evidence, and the rest by level C evidence.

“Accordingly, the strength of recommendations is weaker than optimal,” they write. “Clinical trials in resuscitation and the management of critical poisoning are sorely needed.”
 

‘Don’t go it alone!’

“Most critical poisonings are pretty uncommon, and each patient is different,” Dr. Lavonas said. “Even in the emergency department or ICU, most physicians will treat a patient who is critically ill with any given poison less than once a year. The antidotes and medication doses needed to effectively treat these patients are often very different than everyday medical practice.

“Don’t try to go it alone!” he urges. “Poisoning cases are complex, and the treatments work best when they are implemented quickly and assertively. A toxicologist can help sort through complex situations and get effective treatment started without delay.”

Every certified poison center has a medical toxicologist or clinical toxicologist on call 24/7 to give advice to physicians and hospitals about patients who are critically ill after being poisoned, he added. “Everyone in the U.S. has access to a poison center by calling one number: 1-800-222-1222.”

Dr. Lavonas has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

The American Heart Association has released a focused update on managing patients with cardiac arrest or life-threatening toxicity due to poisoning.

The update reflects treatment advances and new knowledge, including the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) for patients whose condition is refractory to poison antidotes and other therapies.

The new guidelines are designed primarily for North American health care professionals who treat adults and children who are critically ill because of poisoning, including intentional and unintentional drug overdose, chemical exposure, and drug-drug interactions, the authors note.

Published online in Circulation, the update was endorsed by the American Academy of Pediatrics.
 

‘Nearly miraculous’

“It’s been 13 years since the poisoning treatment guidelines had a comprehensive update,” lead author Eric J. Lavonas, MD, professor of emergency medicine at Denver Health and the Rocky Mountain Poison and Drug Center, Colo., told this news organization. “In that time, we’ve learned a lot about how to best use antidotes and other treatments to save the most critically poisoned patients.”

Highlighting a few key points from the update, he said, “For those rare situations when antidotes aren’t enough, the new guidelines include the use of heart-lung machines (VA-ECMO) for patients with beta-blocker, calcium channel blocker, or sodium channel blocker poisoning causing cardiogenic shock.”

Furthermore, he said, “High-dose insulin treatment for patients with beta-blocker and calcium channel blocker poisoning [also recommended in the update] has really become mainstream. The doses are up to 10 times higher than the amount used to treat diabetic emergencies.

“Some excellent science has shown that giving IV lipid emulsion can save the life of someone with an accidental overdose of local anesthetic medications, particularly bupivacaine,” he added. “The result is sometimes nearly miraculous.

“But when this treatment is extended to poisoning from other medications, it often doesn’t work as well, and in some situations may make things worse,” he said. “The issue may be that giving lipids increases absorption of drug from the stomach and intestines, which can be dangerous when the patient took an overdose of pills.”
 

Low level of evidence

The guidelines were compiled by the Critical Poisoning Writing Group, which includes experts from emergency medicine, pediatrics, medical toxicology, pharmacology, critical care, emergency medical services, education, research, and nursing. Group members were appointed by the AHA Emergency Cardiovascular Care Science Subcommittee and were approved by the AHA Manuscript Oversight Committee.

First and foremost, the group recommends timely consultation with a medical toxicologist, a clinical toxicologist, or a regional poison center to facilitate rapid, effective therapy, because treatment of cardiac arrest and toxicity from poisoning often requires treatments that most clinicians don’t use frequently.

Other key points include the following:

• Naloxone administration may reverse respiratory arrest due to opioid overdose, preventing progression to cardiac arrest.
• Give high-dose insulin therapy early in the treatment of patients with beta-blocker and calcium channel blocker poisoning, Dr. Lavonas noted.
• Standard advanced life support plus sodium bicarbonate is appropriate for life-threatening dysrhythmias caused by cocaine or other sodium channel blockers.
• If cyanide poisoning is suspected, clinicians should not wait for confirmatory testing; treatment should begin immediately with hydroxocobalamin (preferred) or sodium nitrite plus sodium thiosulfate.
• Digoxin-specific immune antibody fragments can reverse life-threatening dysrhythmias from digoxin poisoning.
• Use of 20% intravenous lipid emulsion can be efficacious in the resuscitation of life-threatening local anesthetic toxicity, especially from bupivacaine, Dr. Lavonas indicated.
• Sedation is recommended for patients with severe agitation from sympathomimetic poisoning to manage hyperthermia and acidosis, prevent rhabdomyolysis and injury, and allow evaluation for other life-threatening conditions.
• Although flumazenil reverses central nervous system and respiratory depression from benzodiazepine poisoning, risks and contraindications, provided in the guidelines, limit its use.
• VA-ECMO can be lifesaving for patients with cardiogenic shock or dysrhythmias that are refractory to other treatments.

“Unfortunately, despite improvements in the design and funding support for resuscitation research, the overall certainty of the evidence base for resuscitation science and management of critical poisoning is low,” the group acknowledges.

Of the 73 guideline recommendations, only 2 are supported by level A evidence; 3 are supported by level B-randomized evidence, 12 by level B-nonrandomized evidence, and the rest by level C evidence.

“Accordingly, the strength of recommendations is weaker than optimal,” they write. “Clinical trials in resuscitation and the management of critical poisoning are sorely needed.”
 

‘Don’t go it alone!’

“Most critical poisonings are pretty uncommon, and each patient is different,” Dr. Lavonas said. “Even in the emergency department or ICU, most physicians will treat a patient who is critically ill with any given poison less than once a year. The antidotes and medication doses needed to effectively treat these patients are often very different than everyday medical practice.

“Don’t try to go it alone!” he urges. “Poisoning cases are complex, and the treatments work best when they are implemented quickly and assertively. A toxicologist can help sort through complex situations and get effective treatment started without delay.”

Every certified poison center has a medical toxicologist or clinical toxicologist on call 24/7 to give advice to physicians and hospitals about patients who are critically ill after being poisoned, he added. “Everyone in the U.S. has access to a poison center by calling one number: 1-800-222-1222.”

Dr. Lavonas has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Click to read more from Federal Health Care Data Trends 2023.

Click to read more from Federal Health Care Data Trends 2023.

Click to read more from Federal Health Care Data Trends 2023.