Pharmacology

HMG-CoA reductase inhibitors (statins) have been shown to effectively reduce low-density lipoprotein cholesterol (LDL-C) as well as morbidity and mortality in patients who have either atherosclerotic cardiovascular disease (ASCVD) or risk factors for ASCVD.^1-12 However, research shows that up to 20% of patients are unable to tolerate statin therapy due to muscle-related adverse events (AEs).¹³ This presents a substantial clinical challenge, as current management strategies for patients with statin-associated muscle symptoms, such as intermittent administration of statins and ezetimibe, seldom achieve the > 50% LDL-C reduction recommended by the 2018 American Heart Association/American College of Cardiology Clinical Practice Guidelines.¹⁴ Additionally, statin-intolerant patients who have antihyperlipidemic medication lowered or discontinued are at an increased risk of future cardiovascular events.¹⁵ Observational data also show that about 70% of adult patients (primarily with genetic lipid disorders such as heterozygous familial hypercholesterolemia) do not achieve an LDL-C level < 100 mg/dL despite treatment with maximum doses of statins with or without ezetimibe.^16,17

PCSK9 inhibitors (PCSK9i) have robust efficacy data to support use in patients who do not meet their LDL-C goal despite maximally tolerated lipid therapy.¹⁴ However, long-term safety data for PCSK9i are not as robust as its efficacy data. Specifically, safety data relating to muscle-related AEs, which are the most widely recognized AE associated with statins, have only been reported in a few clinical trials with varying incidence rates, levels of significance, and relatively small study populations. Furthermore, the real-world prevalence of muscle-related PCSK9i AEs is unknown. Clinical guidance for management strategies for muscle-related AEs associated with PCSK9i is largely lacking. For this study, muscle-related AEs were defined as any new or unusual muscle soreness, weakness, cramping, aches, and stiffness that persists, is generally bilateral, and typically affects the large muscles. It is important to note, that muscle-related AEs associated with statins, ezetimibe, and PCSK9i can be attributed to the nocebo effect.

According to the prescribing information for alirocumab and evolocumab, myalgia, muscle spasms, and musculoskeletal pain each occurred in < 5% of the study populations.^18,19 From these data, muscle-related PCSK9i AEs are thought to be relatively rare, based on the ODYSSEY-OUTCOME and FOURIER trials, which did not enroll statin-intolerant patients.^20,21 However, currently available safety data from 3 small, randomized clinical trials specifically in statin-intolerant patients taking a PCSK9i suggest that muscle-related AEs occur at a rate of 12.2% to 32.5% and discontinuation rates varied from 0% to 15.9%.^22-25 As the incidence rates of muscle-related AEs in the prescribing information and clinical trials varied widely, this study will provide quantitative data on the percentage of patients that developed muscle-related PCSK9i AEs in a veteran population to help shed light on a topic that is not well studied.

Methods

This was a single-center, retrospective chart review of patients prescribed a PCSK9i between December 1, 2017, and September 1, 2021, and were managed in a pharmacy-led patient aligned care team (PACT) clinic at the Wilkes-Barre US Department of Veterans Affairs (VA) Medical Center (WBVAMC) in Pennsylvania. This study was approved by the Coatesville VA Medical Center Institutional Review Board, which oversees research conducted at WBVAMC. Veterans aged ≥ 18 years were included in the study. Patients were excluded if they had a history of serious hypersensitivity reaction to a PCSK9i or rhabdomyolysis or did not meet the VA criteria for use.²⁶

The primary outcome was the percentage of patients who developed a muscle-related AE while on a PCSK9i in a PACT clinic. Data were further analyzed based on patients who (1) tolerated a full PCSK9i dose; (2) tolerated alternative PCSK9i following initial intolerance; (3) required a PCSK9i dose reduction, or (4) discontinued PCSK9i. A secondary outcome was the percentage of statin- and/or ezetimibe-intolerant patients in these 4 groups. Another secondary outcome was the management strategies taken for patients who were on a reduced (monthly) dose of PCSK9i who did not reach their LDL-C goal. Management strategies that were assessed included restarting weekly statin, restarting weekly ezetimibe, increasing the dose of the same PCSK9i administered monthly, and switching to an alternative PCSK9i.

Data were collected using the VA Computerized Patient Record System (CPRS) and stored in a secure, locked spreadsheet. Baseline patient demographic characteristics collected included age (at PCSK9i start); sex; race; and PCSK9i name, dose, and frequency. We recorded when a patient switched PCSK9i, whether or not it was due to a muscle-related AE, and the name of the original PCSK9i. Also collected were lipid therapy intolerances prior to PCSK9i initiation (ie, intolerance to statin, ezetimibe, or both).

Patients were considered statin intolerant due to a muscle-related AE in accordance with the VA PCSK9i Criteria for Use, which requires trial of at least 3 statins, one of which was trialed at the lowest dosage approved by the US Food and Drug Administration (FDA) and resulted in intolerable skeletal muscle AEs that worsened during treatment and resolved when the statin was stopped. For our study purposes, patients taking alternative day dosing of statins due to muscle-related AEs (ie, 2- or 3-times weekly dosing) were not considered statin intolerant; however, patients taking once-weekly statin dosing were considered statin intolerant. Patients were considered ezetimibe intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when ezetimibe was stopped. Patients were considered PCSK9i intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when the PCSK9i was stopped. Patients with non–muscle-related intolerances to statins, ezetimibe, and PCSK9i were not considered statin, ezetimibe, and PCSK9i intolerant.

Alirocumab was initiated at 75 mg subcutaneous (SQ) once every 2 weeks or evolocumab 140 mg SQ once every 2 weeks in our study. The protocol allowed for a dose reduction of alirocumab 75 mg SQ once monthly if a patient experienced AEs, but this dose reduction strategy was not used for any patients on evolocumab in this study. Of note, alirocumab 75 mg SQ once monthly is not an FDA-approved dosing strategy. However, it is similar in concept to the alternative statin dosing (ie, alternate day dosing, once-weekly dosing) and may avoid the need to discontinue PCSK9i therapy altogether.

A review of the CPRS also documented whether a muscle-related AE occurred while the patient was on a PCSK9i (if yes, the specific AE was recorded), the result of PCSK9i therapy (tolerated full dose, required a dose reduction, switched medication, or discontinued), and management strategies taken for patients who did not meet their LDL-C goal while on a reduced (monthly) PCSK9i dose. Prior lipid therapy intolerances, PCSK9i-related AEs, results of PCSK9i therapy, and management strategies for patients who did not meet LDL-C goal while on a reduced PCSK9i dose were obtained by reviewing the PACT pharmacist’s clinic notes and assessment, along with clinic notes and medication history listed within the CPRS.

Statistical Analysis

Descriptive statistics were used for the demographic characteristics of study patients. The primary outcome was calculated as a binary measure (yes/no) of whether the patient developed a muscle-related AE while on a PCSK9i. The secondary outcome of statin, ezetimibe, or statin and ezetimibe intolerances in subgroups also was calculated as a binary measure.

Results

For the study, 156 charts were reviewed and 137 patients were included (Figure).

For the secondary results, 4 patients (2.9%) tolerated an alternate PCSK9i (evolocumab 140 mg SQ every 2 weeks) after initial intolerance to PCSK9i, 16 (11.7%) required a dose reduction, and 6 (4.4%) discontinued PCSK9i due to a muscle-related AE.

Discussion

This retrospective study found 17.5% of patients experienced muscle-related PCSK9i AEs. These occurred at a higher rate than reported in the prescribing information (< 5%) and were similar to the incidence rates reported in the GAUSS-2, GAUSS-3, and ODYSSEY-ALTERNATIVE clinical trials (12.0%-32.5%), which is what we hypothesized.^18,19,22-25 It is important to note that the incidence rates of muscle-related AEs reported in the prescribing information for alirocumab and evolocumab were based on trials that did not include statin- and/or ezetimibe-intolerant patients; whereas many patients in our study and patients in the clinical trials were statin and/or ezetimibe intolerant.

Additionally, a new study by Donald and colleagues found an incidence rate of 32% to 36% for muscle-related PCSK9i AEs.²⁷ Collectively, the data from clinical trials and our study indicate that patients with prior intolerances to statin and/or ezetimibe appear to have a higher likelihood of developing a muscle-related PCSK9i intolerance. In our study, 23 of 24 patients who developed a muscle-related PCSK9i AE had a prior history of statin and/or ezetimibe intolerances. This should alert clinicians prescribing PCSK9i in patients with a history of statin and/or ezetimibe intolerance to counsel their patients on the possibility of muscle-related PCSK9i AEs and management strategies. However, it is important to note that there was a substantial number of patients in our study who were statin and/or ezetimibe intolerant due to a prior muscle-related AE who tolerated the full dose of PCSK9i.

To our knowledge, this was the first trial to evaluate muscle-related PCSK9i AEs in a veteran population. Additionally, our study appears to be the first to use 2 PCSK9i dosing strategies that are not FDA approved: Dose reduction for patients who experienced a muscle-related AE on alirocumab 75 mg SQ every 2 weeks and dose escalation for patients who did not meet their LDL-C goal on alirocumab 75 mg SQ monthly following an initial intolerance to 2-week dosing. The dose-reduction strategy allowed patients who experienced a muscle-related AE to alirocumab 75 mg to reduce administration from every 2 weeks to monthly.

This strategy was only performed with alirocumab, the preferred PCSK9i at WBVAMC, but the same dose-reduction strategy can theoretically be used with evolocumab as well. Reduced monthly dosing of alirocumab allowed patients with a prior intolerance to remain on a lower dosage without discontinuation. This is important because as noted by Myers and colleagues, individuals without access to PCSK9i were found to have a significantly higher incidence ratio of cardiovascular events compared with those taking PCSK9i.¹⁵ Also of note, > 30% of patients on the reduced monthly dose of alirocumab still met their LDL-C goal. Therefore, using this dose-reduction strategy (instead of patients discontinuing therapy altogether due to a muscle-related intolerance) can lessen the risk of major adverse cardiovascular events (MACE) as well as mitigate muscle-related AEs that occurred while on 2-week PCSK9i dosing regimens. While we acknowledge that this reduced monthly dose of either alirocumab or evolocumab is not FDA approved, it is similar to alternative statin dosing that also is not FDA approved but may minimize the need to discontinue PCSK9i therapy. It would be beneficial if these dosing strategies were investigated by future research.

The dose-escalation strategy for patients who did not meet their LDL-C goal while on the reduced, monthly dose of alirocumab also was unique. Alirocumab was increased from 75 mg SQ once monthly to 150 mg SQ once monthly. Interestingly, we found that through the end of the chart review period, all patients tolerated the increase well, despite having an initial muscle-related AE to alirocumab 75 mg every 2 weeks, which is the same total monthly dosage. This approach is similar to that of once-weekly statin dosing or a drug holiday and may be explained by the long half-life of PCSK9i. Regardless of the mechanism, this finding suggests that an increased monthly dose of PCSK9i is a potential alternative for patients who cannot tolerate the FDA-approved dose. However, the ability for patients to achieve goal LDL-C on the monthly dosage requires future study.

Limitations

The results of this study should be considered with the following limitations. First, this was a retrospective chart review performed over a prespecified period. Any muscle-related AEs or LDL-C lowering effects from PCSK9i that occurred outside the review period were not captured. Our study was small and only included 137 patients, though it was similar in size to the GAUSS-2, GAUSS-3, and ODYSSEY-ALTERNATIVE trials.^22-24 Additionally, the study was primarily composed of White men and may not be representative of other populations. Some muscle-related PCSK9i AEs may be attributed to the nocebo. Last, our study did not capture patients on a PCSK9i who were not followed in the PACT clinic.

Conclusions

We found that muscle-related PCSK9i AEs occurred at a similar rate as those reported in previous clinical trials and exceeded the incidence rate reported in the prescribing information for alirocumab and evolocumab. It appears that patients who have a prior muscle-related intolerance to a statin and/or ezetimibe had a higher likelihood of developing a muscle-related PCSK9i AE. In our study, only 1 patient developed a muscle-related PCSK9i AE who did not have a prior history of muscle-related intolerance to either a statin or ezetimibe. However, in our study, a substantial percentage of patients with statin and/or ezetimibe intolerances tolerated the full PCSK9i dose well, proving that PCSK9i are still a reasonable alternative for patients with prior intolerances to statins and/or ezetimibe.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the US Department of Veterans Affairs Medical Center, Wilkes-Barre, Pennsylvania.

HMG-CoA reductase inhibitors (statins) have been shown to effectively reduce low-density lipoprotein cholesterol (LDL-C) as well as morbidity and mortality in patients who have either atherosclerotic cardiovascular disease (ASCVD) or risk factors for ASCVD.^1-12 However, research shows that up to 20% of patients are unable to tolerate statin therapy due to muscle-related adverse events (AEs).¹³ This presents a substantial clinical challenge, as current management strategies for patients with statin-associated muscle symptoms, such as intermittent administration of statins and ezetimibe, seldom achieve the > 50% LDL-C reduction recommended by the 2018 American Heart Association/American College of Cardiology Clinical Practice Guidelines.¹⁴ Additionally, statin-intolerant patients who have antihyperlipidemic medication lowered or discontinued are at an increased risk of future cardiovascular events.¹⁵ Observational data also show that about 70% of adult patients (primarily with genetic lipid disorders such as heterozygous familial hypercholesterolemia) do not achieve an LDL-C level < 100 mg/dL despite treatment with maximum doses of statins with or without ezetimibe.^16,17

PCSK9 inhibitors (PCSK9i) have robust efficacy data to support use in patients who do not meet their LDL-C goal despite maximally tolerated lipid therapy.¹⁴ However, long-term safety data for PCSK9i are not as robust as its efficacy data. Specifically, safety data relating to muscle-related AEs, which are the most widely recognized AE associated with statins, have only been reported in a few clinical trials with varying incidence rates, levels of significance, and relatively small study populations. Furthermore, the real-world prevalence of muscle-related PCSK9i AEs is unknown. Clinical guidance for management strategies for muscle-related AEs associated with PCSK9i is largely lacking. For this study, muscle-related AEs were defined as any new or unusual muscle soreness, weakness, cramping, aches, and stiffness that persists, is generally bilateral, and typically affects the large muscles. It is important to note, that muscle-related AEs associated with statins, ezetimibe, and PCSK9i can be attributed to the nocebo effect.

According to the prescribing information for alirocumab and evolocumab, myalgia, muscle spasms, and musculoskeletal pain each occurred in < 5% of the study populations.^18,19 From these data, muscle-related PCSK9i AEs are thought to be relatively rare, based on the ODYSSEY-OUTCOME and FOURIER trials, which did not enroll statin-intolerant patients.^20,21 However, currently available safety data from 3 small, randomized clinical trials specifically in statin-intolerant patients taking a PCSK9i suggest that muscle-related AEs occur at a rate of 12.2% to 32.5% and discontinuation rates varied from 0% to 15.9%.^22-25 As the incidence rates of muscle-related AEs in the prescribing information and clinical trials varied widely, this study will provide quantitative data on the percentage of patients that developed muscle-related PCSK9i AEs in a veteran population to help shed light on a topic that is not well studied.

Methods

This was a single-center, retrospective chart review of patients prescribed a PCSK9i between December 1, 2017, and September 1, 2021, and were managed in a pharmacy-led patient aligned care team (PACT) clinic at the Wilkes-Barre US Department of Veterans Affairs (VA) Medical Center (WBVAMC) in Pennsylvania. This study was approved by the Coatesville VA Medical Center Institutional Review Board, which oversees research conducted at WBVAMC. Veterans aged ≥ 18 years were included in the study. Patients were excluded if they had a history of serious hypersensitivity reaction to a PCSK9i or rhabdomyolysis or did not meet the VA criteria for use.²⁶

The primary outcome was the percentage of patients who developed a muscle-related AE while on a PCSK9i in a PACT clinic. Data were further analyzed based on patients who (1) tolerated a full PCSK9i dose; (2) tolerated alternative PCSK9i following initial intolerance; (3) required a PCSK9i dose reduction, or (4) discontinued PCSK9i. A secondary outcome was the percentage of statin- and/or ezetimibe-intolerant patients in these 4 groups. Another secondary outcome was the management strategies taken for patients who were on a reduced (monthly) dose of PCSK9i who did not reach their LDL-C goal. Management strategies that were assessed included restarting weekly statin, restarting weekly ezetimibe, increasing the dose of the same PCSK9i administered monthly, and switching to an alternative PCSK9i.

Data were collected using the VA Computerized Patient Record System (CPRS) and stored in a secure, locked spreadsheet. Baseline patient demographic characteristics collected included age (at PCSK9i start); sex; race; and PCSK9i name, dose, and frequency. We recorded when a patient switched PCSK9i, whether or not it was due to a muscle-related AE, and the name of the original PCSK9i. Also collected were lipid therapy intolerances prior to PCSK9i initiation (ie, intolerance to statin, ezetimibe, or both).

Patients were considered statin intolerant due to a muscle-related AE in accordance with the VA PCSK9i Criteria for Use, which requires trial of at least 3 statins, one of which was trialed at the lowest dosage approved by the US Food and Drug Administration (FDA) and resulted in intolerable skeletal muscle AEs that worsened during treatment and resolved when the statin was stopped. For our study purposes, patients taking alternative day dosing of statins due to muscle-related AEs (ie, 2- or 3-times weekly dosing) were not considered statin intolerant; however, patients taking once-weekly statin dosing were considered statin intolerant. Patients were considered ezetimibe intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when ezetimibe was stopped. Patients were considered PCSK9i intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when the PCSK9i was stopped. Patients with non–muscle-related intolerances to statins, ezetimibe, and PCSK9i were not considered statin, ezetimibe, and PCSK9i intolerant.

Alirocumab was initiated at 75 mg subcutaneous (SQ) once every 2 weeks or evolocumab 140 mg SQ once every 2 weeks in our study. The protocol allowed for a dose reduction of alirocumab 75 mg SQ once monthly if a patient experienced AEs, but this dose reduction strategy was not used for any patients on evolocumab in this study. Of note, alirocumab 75 mg SQ once monthly is not an FDA-approved dosing strategy. However, it is similar in concept to the alternative statin dosing (ie, alternate day dosing, once-weekly dosing) and may avoid the need to discontinue PCSK9i therapy altogether.

A review of the CPRS also documented whether a muscle-related AE occurred while the patient was on a PCSK9i (if yes, the specific AE was recorded), the result of PCSK9i therapy (tolerated full dose, required a dose reduction, switched medication, or discontinued), and management strategies taken for patients who did not meet their LDL-C goal while on a reduced (monthly) PCSK9i dose. Prior lipid therapy intolerances, PCSK9i-related AEs, results of PCSK9i therapy, and management strategies for patients who did not meet LDL-C goal while on a reduced PCSK9i dose were obtained by reviewing the PACT pharmacist’s clinic notes and assessment, along with clinic notes and medication history listed within the CPRS.

Statistical Analysis

Descriptive statistics were used for the demographic characteristics of study patients. The primary outcome was calculated as a binary measure (yes/no) of whether the patient developed a muscle-related AE while on a PCSK9i. The secondary outcome of statin, ezetimibe, or statin and ezetimibe intolerances in subgroups also was calculated as a binary measure.

Results

For the study, 156 charts were reviewed and 137 patients were included (Figure).

For the secondary results, 4 patients (2.9%) tolerated an alternate PCSK9i (evolocumab 140 mg SQ every 2 weeks) after initial intolerance to PCSK9i, 16 (11.7%) required a dose reduction, and 6 (4.4%) discontinued PCSK9i due to a muscle-related AE.

Discussion

This retrospective study found 17.5% of patients experienced muscle-related PCSK9i AEs. These occurred at a higher rate than reported in the prescribing information (< 5%) and were similar to the incidence rates reported in the GAUSS-2, GAUSS-3, and ODYSSEY-ALTERNATIVE clinical trials (12.0%-32.5%), which is what we hypothesized.^18,19,22-25 It is important to note that the incidence rates of muscle-related AEs reported in the prescribing information for alirocumab and evolocumab were based on trials that did not include statin- and/or ezetimibe-intolerant patients; whereas many patients in our study and patients in the clinical trials were statin and/or ezetimibe intolerant.

Additionally, a new study by Donald and colleagues found an incidence rate of 32% to 36% for muscle-related PCSK9i AEs.²⁷ Collectively, the data from clinical trials and our study indicate that patients with prior intolerances to statin and/or ezetimibe appear to have a higher likelihood of developing a muscle-related PCSK9i intolerance. In our study, 23 of 24 patients who developed a muscle-related PCSK9i AE had a prior history of statin and/or ezetimibe intolerances. This should alert clinicians prescribing PCSK9i in patients with a history of statin and/or ezetimibe intolerance to counsel their patients on the possibility of muscle-related PCSK9i AEs and management strategies. However, it is important to note that there was a substantial number of patients in our study who were statin and/or ezetimibe intolerant due to a prior muscle-related AE who tolerated the full dose of PCSK9i.

To our knowledge, this was the first trial to evaluate muscle-related PCSK9i AEs in a veteran population. Additionally, our study appears to be the first to use 2 PCSK9i dosing strategies that are not FDA approved: Dose reduction for patients who experienced a muscle-related AE on alirocumab 75 mg SQ every 2 weeks and dose escalation for patients who did not meet their LDL-C goal on alirocumab 75 mg SQ monthly following an initial intolerance to 2-week dosing. The dose-reduction strategy allowed patients who experienced a muscle-related AE to alirocumab 75 mg to reduce administration from every 2 weeks to monthly.

This strategy was only performed with alirocumab, the preferred PCSK9i at WBVAMC, but the same dose-reduction strategy can theoretically be used with evolocumab as well. Reduced monthly dosing of alirocumab allowed patients with a prior intolerance to remain on a lower dosage without discontinuation. This is important because as noted by Myers and colleagues, individuals without access to PCSK9i were found to have a significantly higher incidence ratio of cardiovascular events compared with those taking PCSK9i.¹⁵ Also of note, > 30% of patients on the reduced monthly dose of alirocumab still met their LDL-C goal. Therefore, using this dose-reduction strategy (instead of patients discontinuing therapy altogether due to a muscle-related intolerance) can lessen the risk of major adverse cardiovascular events (MACE) as well as mitigate muscle-related AEs that occurred while on 2-week PCSK9i dosing regimens. While we acknowledge that this reduced monthly dose of either alirocumab or evolocumab is not FDA approved, it is similar to alternative statin dosing that also is not FDA approved but may minimize the need to discontinue PCSK9i therapy. It would be beneficial if these dosing strategies were investigated by future research.

The dose-escalation strategy for patients who did not meet their LDL-C goal while on the reduced, monthly dose of alirocumab also was unique. Alirocumab was increased from 75 mg SQ once monthly to 150 mg SQ once monthly. Interestingly, we found that through the end of the chart review period, all patients tolerated the increase well, despite having an initial muscle-related AE to alirocumab 75 mg every 2 weeks, which is the same total monthly dosage. This approach is similar to that of once-weekly statin dosing or a drug holiday and may be explained by the long half-life of PCSK9i. Regardless of the mechanism, this finding suggests that an increased monthly dose of PCSK9i is a potential alternative for patients who cannot tolerate the FDA-approved dose. However, the ability for patients to achieve goal LDL-C on the monthly dosage requires future study.

Limitations

The results of this study should be considered with the following limitations. First, this was a retrospective chart review performed over a prespecified period. Any muscle-related AEs or LDL-C lowering effects from PCSK9i that occurred outside the review period were not captured. Our study was small and only included 137 patients, though it was similar in size to the GAUSS-2, GAUSS-3, and ODYSSEY-ALTERNATIVE trials.^22-24 Additionally, the study was primarily composed of White men and may not be representative of other populations. Some muscle-related PCSK9i AEs may be attributed to the nocebo. Last, our study did not capture patients on a PCSK9i who were not followed in the PACT clinic.

Conclusions

We found that muscle-related PCSK9i AEs occurred at a similar rate as those reported in previous clinical trials and exceeded the incidence rate reported in the prescribing information for alirocumab and evolocumab. It appears that patients who have a prior muscle-related intolerance to a statin and/or ezetimibe had a higher likelihood of developing a muscle-related PCSK9i AE. In our study, only 1 patient developed a muscle-related PCSK9i AE who did not have a prior history of muscle-related intolerance to either a statin or ezetimibe. However, in our study, a substantial percentage of patients with statin and/or ezetimibe intolerances tolerated the full PCSK9i dose well, proving that PCSK9i are still a reasonable alternative for patients with prior intolerances to statins and/or ezetimibe.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the US Department of Veterans Affairs Medical Center, Wilkes-Barre, Pennsylvania.

HMG-CoA reductase inhibitors (statins) have been shown to effectively reduce low-density lipoprotein cholesterol (LDL-C) as well as morbidity and mortality in patients who have either atherosclerotic cardiovascular disease (ASCVD) or risk factors for ASCVD.^1-12 However, research shows that up to 20% of patients are unable to tolerate statin therapy due to muscle-related adverse events (AEs).¹³ This presents a substantial clinical challenge, as current management strategies for patients with statin-associated muscle symptoms, such as intermittent administration of statins and ezetimibe, seldom achieve the > 50% LDL-C reduction recommended by the 2018 American Heart Association/American College of Cardiology Clinical Practice Guidelines.¹⁴ Additionally, statin-intolerant patients who have antihyperlipidemic medication lowered or discontinued are at an increased risk of future cardiovascular events.¹⁵ Observational data also show that about 70% of adult patients (primarily with genetic lipid disorders such as heterozygous familial hypercholesterolemia) do not achieve an LDL-C level < 100 mg/dL despite treatment with maximum doses of statins with or without ezetimibe.^16,17

PCSK9 inhibitors (PCSK9i) have robust efficacy data to support use in patients who do not meet their LDL-C goal despite maximally tolerated lipid therapy.¹⁴ However, long-term safety data for PCSK9i are not as robust as its efficacy data. Specifically, safety data relating to muscle-related AEs, which are the most widely recognized AE associated with statins, have only been reported in a few clinical trials with varying incidence rates, levels of significance, and relatively small study populations. Furthermore, the real-world prevalence of muscle-related PCSK9i AEs is unknown. Clinical guidance for management strategies for muscle-related AEs associated with PCSK9i is largely lacking. For this study, muscle-related AEs were defined as any new or unusual muscle soreness, weakness, cramping, aches, and stiffness that persists, is generally bilateral, and typically affects the large muscles. It is important to note, that muscle-related AEs associated with statins, ezetimibe, and PCSK9i can be attributed to the nocebo effect.

According to the prescribing information for alirocumab and evolocumab, myalgia, muscle spasms, and musculoskeletal pain each occurred in < 5% of the study populations.^18,19 From these data, muscle-related PCSK9i AEs are thought to be relatively rare, based on the ODYSSEY-OUTCOME and FOURIER trials, which did not enroll statin-intolerant patients.^20,21 However, currently available safety data from 3 small, randomized clinical trials specifically in statin-intolerant patients taking a PCSK9i suggest that muscle-related AEs occur at a rate of 12.2% to 32.5% and discontinuation rates varied from 0% to 15.9%.^22-25 As the incidence rates of muscle-related AEs in the prescribing information and clinical trials varied widely, this study will provide quantitative data on the percentage of patients that developed muscle-related PCSK9i AEs in a veteran population to help shed light on a topic that is not well studied.

Methods

This was a single-center, retrospective chart review of patients prescribed a PCSK9i between December 1, 2017, and September 1, 2021, and were managed in a pharmacy-led patient aligned care team (PACT) clinic at the Wilkes-Barre US Department of Veterans Affairs (VA) Medical Center (WBVAMC) in Pennsylvania. This study was approved by the Coatesville VA Medical Center Institutional Review Board, which oversees research conducted at WBVAMC. Veterans aged ≥ 18 years were included in the study. Patients were excluded if they had a history of serious hypersensitivity reaction to a PCSK9i or rhabdomyolysis or did not meet the VA criteria for use.²⁶

The primary outcome was the percentage of patients who developed a muscle-related AE while on a PCSK9i in a PACT clinic. Data were further analyzed based on patients who (1) tolerated a full PCSK9i dose; (2) tolerated alternative PCSK9i following initial intolerance; (3) required a PCSK9i dose reduction, or (4) discontinued PCSK9i. A secondary outcome was the percentage of statin- and/or ezetimibe-intolerant patients in these 4 groups. Another secondary outcome was the management strategies taken for patients who were on a reduced (monthly) dose of PCSK9i who did not reach their LDL-C goal. Management strategies that were assessed included restarting weekly statin, restarting weekly ezetimibe, increasing the dose of the same PCSK9i administered monthly, and switching to an alternative PCSK9i.

Data were collected using the VA Computerized Patient Record System (CPRS) and stored in a secure, locked spreadsheet. Baseline patient demographic characteristics collected included age (at PCSK9i start); sex; race; and PCSK9i name, dose, and frequency. We recorded when a patient switched PCSK9i, whether or not it was due to a muscle-related AE, and the name of the original PCSK9i. Also collected were lipid therapy intolerances prior to PCSK9i initiation (ie, intolerance to statin, ezetimibe, or both).

Patients were considered statin intolerant due to a muscle-related AE in accordance with the VA PCSK9i Criteria for Use, which requires trial of at least 3 statins, one of which was trialed at the lowest dosage approved by the US Food and Drug Administration (FDA) and resulted in intolerable skeletal muscle AEs that worsened during treatment and resolved when the statin was stopped. For our study purposes, patients taking alternative day dosing of statins due to muscle-related AEs (ie, 2- or 3-times weekly dosing) were not considered statin intolerant; however, patients taking once-weekly statin dosing were considered statin intolerant. Patients were considered ezetimibe intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when ezetimibe was stopped. Patients were considered PCSK9i intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when the PCSK9i was stopped. Patients with non–muscle-related intolerances to statins, ezetimibe, and PCSK9i were not considered statin, ezetimibe, and PCSK9i intolerant.

Alirocumab was initiated at 75 mg subcutaneous (SQ) once every 2 weeks or evolocumab 140 mg SQ once every 2 weeks in our study. The protocol allowed for a dose reduction of alirocumab 75 mg SQ once monthly if a patient experienced AEs, but this dose reduction strategy was not used for any patients on evolocumab in this study. Of note, alirocumab 75 mg SQ once monthly is not an FDA-approved dosing strategy. However, it is similar in concept to the alternative statin dosing (ie, alternate day dosing, once-weekly dosing) and may avoid the need to discontinue PCSK9i therapy altogether.

A review of the CPRS also documented whether a muscle-related AE occurred while the patient was on a PCSK9i (if yes, the specific AE was recorded), the result of PCSK9i therapy (tolerated full dose, required a dose reduction, switched medication, or discontinued), and management strategies taken for patients who did not meet their LDL-C goal while on a reduced (monthly) PCSK9i dose. Prior lipid therapy intolerances, PCSK9i-related AEs, results of PCSK9i therapy, and management strategies for patients who did not meet LDL-C goal while on a reduced PCSK9i dose were obtained by reviewing the PACT pharmacist’s clinic notes and assessment, along with clinic notes and medication history listed within the CPRS.

Statistical Analysis

Descriptive statistics were used for the demographic characteristics of study patients. The primary outcome was calculated as a binary measure (yes/no) of whether the patient developed a muscle-related AE while on a PCSK9i. The secondary outcome of statin, ezetimibe, or statin and ezetimibe intolerances in subgroups also was calculated as a binary measure.

Results

For the study, 156 charts were reviewed and 137 patients were included (Figure).

For the secondary results, 4 patients (2.9%) tolerated an alternate PCSK9i (evolocumab 140 mg SQ every 2 weeks) after initial intolerance to PCSK9i, 16 (11.7%) required a dose reduction, and 6 (4.4%) discontinued PCSK9i due to a muscle-related AE.

Discussion

This retrospective study found 17.5% of patients experienced muscle-related PCSK9i AEs. These occurred at a higher rate than reported in the prescribing information (< 5%) and were similar to the incidence rates reported in the GAUSS-2, GAUSS-3, and ODYSSEY-ALTERNATIVE clinical trials (12.0%-32.5%), which is what we hypothesized.^18,19,22-25 It is important to note that the incidence rates of muscle-related AEs reported in the prescribing information for alirocumab and evolocumab were based on trials that did not include statin- and/or ezetimibe-intolerant patients; whereas many patients in our study and patients in the clinical trials were statin and/or ezetimibe intolerant.

Additionally, a new study by Donald and colleagues found an incidence rate of 32% to 36% for muscle-related PCSK9i AEs.²⁷ Collectively, the data from clinical trials and our study indicate that patients with prior intolerances to statin and/or ezetimibe appear to have a higher likelihood of developing a muscle-related PCSK9i intolerance. In our study, 23 of 24 patients who developed a muscle-related PCSK9i AE had a prior history of statin and/or ezetimibe intolerances. This should alert clinicians prescribing PCSK9i in patients with a history of statin and/or ezetimibe intolerance to counsel their patients on the possibility of muscle-related PCSK9i AEs and management strategies. However, it is important to note that there was a substantial number of patients in our study who were statin and/or ezetimibe intolerant due to a prior muscle-related AE who tolerated the full dose of PCSK9i.

To our knowledge, this was the first trial to evaluate muscle-related PCSK9i AEs in a veteran population. Additionally, our study appears to be the first to use 2 PCSK9i dosing strategies that are not FDA approved: Dose reduction for patients who experienced a muscle-related AE on alirocumab 75 mg SQ every 2 weeks and dose escalation for patients who did not meet their LDL-C goal on alirocumab 75 mg SQ monthly following an initial intolerance to 2-week dosing. The dose-reduction strategy allowed patients who experienced a muscle-related AE to alirocumab 75 mg to reduce administration from every 2 weeks to monthly.

This strategy was only performed with alirocumab, the preferred PCSK9i at WBVAMC, but the same dose-reduction strategy can theoretically be used with evolocumab as well. Reduced monthly dosing of alirocumab allowed patients with a prior intolerance to remain on a lower dosage without discontinuation. This is important because as noted by Myers and colleagues, individuals without access to PCSK9i were found to have a significantly higher incidence ratio of cardiovascular events compared with those taking PCSK9i.¹⁵ Also of note, > 30% of patients on the reduced monthly dose of alirocumab still met their LDL-C goal. Therefore, using this dose-reduction strategy (instead of patients discontinuing therapy altogether due to a muscle-related intolerance) can lessen the risk of major adverse cardiovascular events (MACE) as well as mitigate muscle-related AEs that occurred while on 2-week PCSK9i dosing regimens. While we acknowledge that this reduced monthly dose of either alirocumab or evolocumab is not FDA approved, it is similar to alternative statin dosing that also is not FDA approved but may minimize the need to discontinue PCSK9i therapy. It would be beneficial if these dosing strategies were investigated by future research.

The dose-escalation strategy for patients who did not meet their LDL-C goal while on the reduced, monthly dose of alirocumab also was unique. Alirocumab was increased from 75 mg SQ once monthly to 150 mg SQ once monthly. Interestingly, we found that through the end of the chart review period, all patients tolerated the increase well, despite having an initial muscle-related AE to alirocumab 75 mg every 2 weeks, which is the same total monthly dosage. This approach is similar to that of once-weekly statin dosing or a drug holiday and may be explained by the long half-life of PCSK9i. Regardless of the mechanism, this finding suggests that an increased monthly dose of PCSK9i is a potential alternative for patients who cannot tolerate the FDA-approved dose. However, the ability for patients to achieve goal LDL-C on the monthly dosage requires future study.

Limitations

The results of this study should be considered with the following limitations. First, this was a retrospective chart review performed over a prespecified period. Any muscle-related AEs or LDL-C lowering effects from PCSK9i that occurred outside the review period were not captured. Our study was small and only included 137 patients, though it was similar in size to the GAUSS-2, GAUSS-3, and ODYSSEY-ALTERNATIVE trials.^22-24 Additionally, the study was primarily composed of White men and may not be representative of other populations. Some muscle-related PCSK9i AEs may be attributed to the nocebo. Last, our study did not capture patients on a PCSK9i who were not followed in the PACT clinic.

Conclusions

We found that muscle-related PCSK9i AEs occurred at a similar rate as those reported in previous clinical trials and exceeded the incidence rate reported in the prescribing information for alirocumab and evolocumab. It appears that patients who have a prior muscle-related intolerance to a statin and/or ezetimibe had a higher likelihood of developing a muscle-related PCSK9i AE. In our study, only 1 patient developed a muscle-related PCSK9i AE who did not have a prior history of muscle-related intolerance to either a statin or ezetimibe. However, in our study, a substantial percentage of patients with statin and/or ezetimibe intolerances tolerated the full PCSK9i dose well, proving that PCSK9i are still a reasonable alternative for patients with prior intolerances to statins and/or ezetimibe.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the US Department of Veterans Affairs Medical Center, Wilkes-Barre, Pennsylvania.

Measures enacted in the early days of the COVID-19 pandemic to increase access to buprenorphine did not lead to an increase in the proportion of overdose deaths involving the drug, new research suggests.

Researchers say the data add weight to the argument for permanently adopting the pandemic-era prescribing regulations for buprenorphine, a treatment for opioid use disorder.

“We saw no evidence that increased availability of buprenorphine through the loosening of rules around prescribing and dispensing of buprenorphine during the pandemic increased overdose deaths,” investigator Wilson Compton, MD, deputy director of the National Institute on Drug Abuse, told this news organization.

“This is reassuring that, even when we opened up the doors to easier access to buprenorphine, we didn’t see that most serious consequence,” Dr. Compton said.

The findings were published online in JAMA Network Open .
 

Cause and effect

Federal agencies relaxed prescribing regulations for buprenorphine in March 2020 to make it easier for clinicians to prescribe the drug via telemedicine and for patients to take the medication at home.

The number of buprenorphine prescriptions has increased since that change, with more than 1 million people receiving the medication in 2021 from retail pharmacies in the United States.

However, questions remained about whether increased access would lead to an increase in buprenorphine-involved overdose.

Researchers with NIDA and the Centers for Disease Control and Prevention analyzed data from the State Unintentional Drug Overdose Reporting System, a CDC database that combines medical examiner and coroner reports and postmortem toxicology testing.

The study included information about overdose deaths from July 2019 to June 2021 in 46 states and the District of Columbia.

Between July 2019 and June 2021, there were 1,955 buprenorphine-involved overdose deaths, which accounted for 2.2% of all drug overdose deaths and 2.6% of opioid-involved overdose deaths.

However, researchers went beyond overall numbers and evaluated details from coroner’s and medical examiner reports, something they had not done before.

“For the first time we looked at the characteristics of decedents from buprenorphine because this has not been studied in this type of detail with a near-national sample,” Dr. Compton said.

“That allowed us to look at patterns of use of other substances as well as the circumstances that are recorded at the death scene that are in the data set,” he added.
 

Important insights

Reports from nearly all buprenorphine-involved deaths included the presence of at least one other drug, compared with opioid overdose deaths that typically involved only one drug.

“This is consistent with the pharmacology of buprenorphine being a partial agonist, so it may not be as fatal all by itself as some of the other opioids,” Dr. Compton said.

Deaths involving buprenorphine were less likely to include illicitly manufactured fentanyls, and other prescription medications were more often found on the scene, such as antidepressants.

Compared with opioid decedents, buprenorphine decedents were more likely to be women, age 35-44, White, and receiving treatment for mental health conditions, including for substance use disorder (SUD).

These kinds of characteristics provide important insights about potential ways to improve safety and clinical outcomes, Dr. Compton noted.

“When we see things like a little higher rate of SUD treatment and this evidence of other prescription drugs on the scene, and some higher rates of antidepressants in these decedents than I might have expected, I’m very curious about their use of other medical services outside of substance use treatment, because that might be a place where some interventions could be implemented,” he said.

A similar study showed pandemic-era policy changes that allowed methadone to be taken at home was followed by a decrease in methadone-related overdose deaths.

The new findings are consistent with those results, Dr. Compton said.
 

‘Chipping away’ at stigma

Commenting on the study, O. Trent Hall, DO, assistant professor of addiction medicine, Department of Psychiatry and Behavioral Health, Ohio State University Wexner Medical Center, Columbus, said that, although he welcomed the findings, they aren’t unexpected.

“Buprenorphine is well established as a safe and effective medication for opioid use disorder and as a physician who routinely cares for patients in the hospital after opioid overdose, I am not at all surprised by these results,” said Dr. Hall, who was not involved with the research.

“When my patients leave the hospital with a buprenorphine prescription, they are much less likely to return with another overdose or serious opioid-related medical problem,” he added.

U.S. drug overdose deaths topped 100,000 for the first time in 2021, and most were opioid-related. Although the latest data from the CDC shows drug overdose deaths have been declining slowly since early 2022, the numbers remain high.

Buprenorphine is one of only two drugs known to reduce the risk of opioid overdose. While prescriptions have increased since 2020, the medication remains underutilized, despite its known effectiveness in treating opioid use disorder.

Dr. Hall noted that research such as the new study could help increase buprenorphine’s use.

“Studies like this one chip away at the stigma that has been misapplied to buprenorphine,” he said. “I hope this article will encourage more providers to offer buprenorphine to patients with opioid use disorder.”

The study was funded internally by NIDA and the CDC. Dr. Compton reported owning stock in General Electric, 3M, and Pfizer outside the submitted work. Dr. Hall has disclosed no relevant financial relationships.

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

Measures enacted in the early days of the COVID-19 pandemic to increase access to buprenorphine did not lead to an increase in the proportion of overdose deaths involving the drug, new research suggests.

Researchers say the data add weight to the argument for permanently adopting the pandemic-era prescribing regulations for buprenorphine, a treatment for opioid use disorder.

“We saw no evidence that increased availability of buprenorphine through the loosening of rules around prescribing and dispensing of buprenorphine during the pandemic increased overdose deaths,” investigator Wilson Compton, MD, deputy director of the National Institute on Drug Abuse, told this news organization.

“This is reassuring that, even when we opened up the doors to easier access to buprenorphine, we didn’t see that most serious consequence,” Dr. Compton said.

The findings were published online in JAMA Network Open .
 

Cause and effect

Federal agencies relaxed prescribing regulations for buprenorphine in March 2020 to make it easier for clinicians to prescribe the drug via telemedicine and for patients to take the medication at home.

The number of buprenorphine prescriptions has increased since that change, with more than 1 million people receiving the medication in 2021 from retail pharmacies in the United States.

However, questions remained about whether increased access would lead to an increase in buprenorphine-involved overdose.

Researchers with NIDA and the Centers for Disease Control and Prevention analyzed data from the State Unintentional Drug Overdose Reporting System, a CDC database that combines medical examiner and coroner reports and postmortem toxicology testing.

The study included information about overdose deaths from July 2019 to June 2021 in 46 states and the District of Columbia.

Between July 2019 and June 2021, there were 1,955 buprenorphine-involved overdose deaths, which accounted for 2.2% of all drug overdose deaths and 2.6% of opioid-involved overdose deaths.

However, researchers went beyond overall numbers and evaluated details from coroner’s and medical examiner reports, something they had not done before.

“For the first time we looked at the characteristics of decedents from buprenorphine because this has not been studied in this type of detail with a near-national sample,” Dr. Compton said.

“That allowed us to look at patterns of use of other substances as well as the circumstances that are recorded at the death scene that are in the data set,” he added.
 

Important insights

Reports from nearly all buprenorphine-involved deaths included the presence of at least one other drug, compared with opioid overdose deaths that typically involved only one drug.

“This is consistent with the pharmacology of buprenorphine being a partial agonist, so it may not be as fatal all by itself as some of the other opioids,” Dr. Compton said.

Deaths involving buprenorphine were less likely to include illicitly manufactured fentanyls, and other prescription medications were more often found on the scene, such as antidepressants.

Compared with opioid decedents, buprenorphine decedents were more likely to be women, age 35-44, White, and receiving treatment for mental health conditions, including for substance use disorder (SUD).

These kinds of characteristics provide important insights about potential ways to improve safety and clinical outcomes, Dr. Compton noted.

“When we see things like a little higher rate of SUD treatment and this evidence of other prescription drugs on the scene, and some higher rates of antidepressants in these decedents than I might have expected, I’m very curious about their use of other medical services outside of substance use treatment, because that might be a place where some interventions could be implemented,” he said.

A similar study showed pandemic-era policy changes that allowed methadone to be taken at home was followed by a decrease in methadone-related overdose deaths.

The new findings are consistent with those results, Dr. Compton said.
 

‘Chipping away’ at stigma

Commenting on the study, O. Trent Hall, DO, assistant professor of addiction medicine, Department of Psychiatry and Behavioral Health, Ohio State University Wexner Medical Center, Columbus, said that, although he welcomed the findings, they aren’t unexpected.

“Buprenorphine is well established as a safe and effective medication for opioid use disorder and as a physician who routinely cares for patients in the hospital after opioid overdose, I am not at all surprised by these results,” said Dr. Hall, who was not involved with the research.

“When my patients leave the hospital with a buprenorphine prescription, they are much less likely to return with another overdose or serious opioid-related medical problem,” he added.

U.S. drug overdose deaths topped 100,000 for the first time in 2021, and most were opioid-related. Although the latest data from the CDC shows drug overdose deaths have been declining slowly since early 2022, the numbers remain high.

Buprenorphine is one of only two drugs known to reduce the risk of opioid overdose. While prescriptions have increased since 2020, the medication remains underutilized, despite its known effectiveness in treating opioid use disorder.

Dr. Hall noted that research such as the new study could help increase buprenorphine’s use.

“Studies like this one chip away at the stigma that has been misapplied to buprenorphine,” he said. “I hope this article will encourage more providers to offer buprenorphine to patients with opioid use disorder.”

The study was funded internally by NIDA and the CDC. Dr. Compton reported owning stock in General Electric, 3M, and Pfizer outside the submitted work. Dr. Hall has disclosed no relevant financial relationships.

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

Measures enacted in the early days of the COVID-19 pandemic to increase access to buprenorphine did not lead to an increase in the proportion of overdose deaths involving the drug, new research suggests.

Researchers say the data add weight to the argument for permanently adopting the pandemic-era prescribing regulations for buprenorphine, a treatment for opioid use disorder.

“We saw no evidence that increased availability of buprenorphine through the loosening of rules around prescribing and dispensing of buprenorphine during the pandemic increased overdose deaths,” investigator Wilson Compton, MD, deputy director of the National Institute on Drug Abuse, told this news organization.

“This is reassuring that, even when we opened up the doors to easier access to buprenorphine, we didn’t see that most serious consequence,” Dr. Compton said.

The findings were published online in JAMA Network Open .
 

Cause and effect

Federal agencies relaxed prescribing regulations for buprenorphine in March 2020 to make it easier for clinicians to prescribe the drug via telemedicine and for patients to take the medication at home.

The number of buprenorphine prescriptions has increased since that change, with more than 1 million people receiving the medication in 2021 from retail pharmacies in the United States.

However, questions remained about whether increased access would lead to an increase in buprenorphine-involved overdose.

Researchers with NIDA and the Centers for Disease Control and Prevention analyzed data from the State Unintentional Drug Overdose Reporting System, a CDC database that combines medical examiner and coroner reports and postmortem toxicology testing.

The study included information about overdose deaths from July 2019 to June 2021 in 46 states and the District of Columbia.

Between July 2019 and June 2021, there were 1,955 buprenorphine-involved overdose deaths, which accounted for 2.2% of all drug overdose deaths and 2.6% of opioid-involved overdose deaths.

However, researchers went beyond overall numbers and evaluated details from coroner’s and medical examiner reports, something they had not done before.

“For the first time we looked at the characteristics of decedents from buprenorphine because this has not been studied in this type of detail with a near-national sample,” Dr. Compton said.

“That allowed us to look at patterns of use of other substances as well as the circumstances that are recorded at the death scene that are in the data set,” he added.
 

Important insights

Reports from nearly all buprenorphine-involved deaths included the presence of at least one other drug, compared with opioid overdose deaths that typically involved only one drug.

“This is consistent with the pharmacology of buprenorphine being a partial agonist, so it may not be as fatal all by itself as some of the other opioids,” Dr. Compton said.

Deaths involving buprenorphine were less likely to include illicitly manufactured fentanyls, and other prescription medications were more often found on the scene, such as antidepressants.

Compared with opioid decedents, buprenorphine decedents were more likely to be women, age 35-44, White, and receiving treatment for mental health conditions, including for substance use disorder (SUD).

These kinds of characteristics provide important insights about potential ways to improve safety and clinical outcomes, Dr. Compton noted.

“When we see things like a little higher rate of SUD treatment and this evidence of other prescription drugs on the scene, and some higher rates of antidepressants in these decedents than I might have expected, I’m very curious about their use of other medical services outside of substance use treatment, because that might be a place where some interventions could be implemented,” he said.

A similar study showed pandemic-era policy changes that allowed methadone to be taken at home was followed by a decrease in methadone-related overdose deaths.

The new findings are consistent with those results, Dr. Compton said.
 

‘Chipping away’ at stigma

Commenting on the study, O. Trent Hall, DO, assistant professor of addiction medicine, Department of Psychiatry and Behavioral Health, Ohio State University Wexner Medical Center, Columbus, said that, although he welcomed the findings, they aren’t unexpected.

“Buprenorphine is well established as a safe and effective medication for opioid use disorder and as a physician who routinely cares for patients in the hospital after opioid overdose, I am not at all surprised by these results,” said Dr. Hall, who was not involved with the research.

“When my patients leave the hospital with a buprenorphine prescription, they are much less likely to return with another overdose or serious opioid-related medical problem,” he added.

U.S. drug overdose deaths topped 100,000 for the first time in 2021, and most were opioid-related. Although the latest data from the CDC shows drug overdose deaths have been declining slowly since early 2022, the numbers remain high.

Buprenorphine is one of only two drugs known to reduce the risk of opioid overdose. While prescriptions have increased since 2020, the medication remains underutilized, despite its known effectiveness in treating opioid use disorder.

Dr. Hall noted that research such as the new study could help increase buprenorphine’s use.

“Studies like this one chip away at the stigma that has been misapplied to buprenorphine,” he said. “I hope this article will encourage more providers to offer buprenorphine to patients with opioid use disorder.”

The study was funded internally by NIDA and the CDC. Dr. Compton reported owning stock in General Electric, 3M, and Pfizer outside the submitted work. Dr. Hall has disclosed no relevant financial relationships.

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

A 27-gene immuno-oncology assay appears to provide useful information about whether patients with advanced non–small cell lung cancer (NSCLC) could benefit from immune checkpoint inhibitor (ICI) therapy despite their poor status, researchers reported.

Positive findings on the test, known as DetermaIO, were “associated with efficacy of response to ICI therapy in advanced NSCLC patients,” Matthew G. Varga, PhD, manager of scientific affairs at Oncocyte, said in an interview. “These data suggest that DetermaIO warrants further study in poor performance status patients as it has the potential to identify likely responders to ICI therapy.”

Oncocyte, which is developing the test, presented the findings in a poster at the annual meeting of the Society for Immunotherapy of Cancer.

According to Dr. Varga, “DetermaIO is an RT-qPCR test that can be applied to FFPE [formalin-fixed, paraffin-embedded] tissue specimens to quantify the relative gene expression of 27 genes and subsequently applies our proprietary algorithm to generate an IO score based on the gene expression profile. The DetermaIO score is a binary IO+ or IO– score, representing likely responder or nonresponder, respectively.”

The test was originally developed for triple negative breast cancer, Dr. Varga said, and it’s been validated in non–small cell lung cancer, metastatic urothelial carcinoma, and metastatic colorectal carcinoma.

For the study, the researchers retrospectively tracked associations between DetermaIO score and either progression-free survival (PFS) or overall survival (OS) in 147 patients in Canada with NSCLC who were treated with ICI monotherapy. All had programmed death-ligand 1 (PD-L1) ≥ 50%.

Overall, outcomes were poor: The median survival was 12.7 months, and median PFS was 7.0 months. These outcomes were even worse in those who underwent therapy as a second- line treatment: The median survival was 9.7 months, and median PFS was 4.4 months.

“DetermaIO was significantly associated with PFS at hazard ratio [HR] = 0.55, 95% [confidence interval] CI, 0.32-0.94, P = .028. In our analyses, a hazard ratio less than 1 suggests lower risk – i.e, that DetermaIO+ patients have lower risk of an event – death or progression – compared to a DetermaIO– patient,” Dr. Varga said. “The association for overall survival was not statistically significant, but it was suggestive of clinically meaningful benefit.”

He added that “we could identify likely responders from nonresponders, suggesting that the DetermaIO score adds both independent and incremental data to the existing gold standard biomarker. The objective response rate for all first-line patients – n = 78 – was 44.9%. Twenty-two DetermaIO– tumors had a 23% response rate (5 partial responses) whereas of the 56 DetermaIO+ patients, the response rate was 54% (2 complete response and 28 partial responses).”

A score on the test, he said, was not associated with OS or PFS in patients who received second-line or later treatment.

The study was not designed to evaluate the predictive power of the test. “For a biomarker to be defined as predictive requires a formal test of interaction between a treatment group (ICI monotherapy, for example) vs. a control group (chemo-only or other regimen),” Dr. Varga explained. “In our analysis, there was no group of patients who did not receive ICI monotherapy. Thus a test for interaction and a predictive claim cannot be made.”

The test is available for at no cost via an early access program, Dr. Varga said, and Oncocyte is getting ready to seek Medicare coverage. The ultimate cost of the test, he said, is unknown.

Oncocyte funded this study. Dr. Varga and several other study authors are Oncocyte employees, and another author is a paid consultant to the company.

A 27-gene immuno-oncology assay appears to provide useful information about whether patients with advanced non–small cell lung cancer (NSCLC) could benefit from immune checkpoint inhibitor (ICI) therapy despite their poor status, researchers reported.

Positive findings on the test, known as DetermaIO, were “associated with efficacy of response to ICI therapy in advanced NSCLC patients,” Matthew G. Varga, PhD, manager of scientific affairs at Oncocyte, said in an interview. “These data suggest that DetermaIO warrants further study in poor performance status patients as it has the potential to identify likely responders to ICI therapy.”

Oncocyte, which is developing the test, presented the findings in a poster at the annual meeting of the Society for Immunotherapy of Cancer.

According to Dr. Varga, “DetermaIO is an RT-qPCR test that can be applied to FFPE [formalin-fixed, paraffin-embedded] tissue specimens to quantify the relative gene expression of 27 genes and subsequently applies our proprietary algorithm to generate an IO score based on the gene expression profile. The DetermaIO score is a binary IO+ or IO– score, representing likely responder or nonresponder, respectively.”

The test was originally developed for triple negative breast cancer, Dr. Varga said, and it’s been validated in non–small cell lung cancer, metastatic urothelial carcinoma, and metastatic colorectal carcinoma.

For the study, the researchers retrospectively tracked associations between DetermaIO score and either progression-free survival (PFS) or overall survival (OS) in 147 patients in Canada with NSCLC who were treated with ICI monotherapy. All had programmed death-ligand 1 (PD-L1) ≥ 50%.

Overall, outcomes were poor: The median survival was 12.7 months, and median PFS was 7.0 months. These outcomes were even worse in those who underwent therapy as a second- line treatment: The median survival was 9.7 months, and median PFS was 4.4 months.

“DetermaIO was significantly associated with PFS at hazard ratio [HR] = 0.55, 95% [confidence interval] CI, 0.32-0.94, P = .028. In our analyses, a hazard ratio less than 1 suggests lower risk – i.e, that DetermaIO+ patients have lower risk of an event – death or progression – compared to a DetermaIO– patient,” Dr. Varga said. “The association for overall survival was not statistically significant, but it was suggestive of clinically meaningful benefit.”

He added that “we could identify likely responders from nonresponders, suggesting that the DetermaIO score adds both independent and incremental data to the existing gold standard biomarker. The objective response rate for all first-line patients – n = 78 – was 44.9%. Twenty-two DetermaIO– tumors had a 23% response rate (5 partial responses) whereas of the 56 DetermaIO+ patients, the response rate was 54% (2 complete response and 28 partial responses).”

A score on the test, he said, was not associated with OS or PFS in patients who received second-line or later treatment.

The study was not designed to evaluate the predictive power of the test. “For a biomarker to be defined as predictive requires a formal test of interaction between a treatment group (ICI monotherapy, for example) vs. a control group (chemo-only or other regimen),” Dr. Varga explained. “In our analysis, there was no group of patients who did not receive ICI monotherapy. Thus a test for interaction and a predictive claim cannot be made.”

The test is available for at no cost via an early access program, Dr. Varga said, and Oncocyte is getting ready to seek Medicare coverage. The ultimate cost of the test, he said, is unknown.

Oncocyte funded this study. Dr. Varga and several other study authors are Oncocyte employees, and another author is a paid consultant to the company.

A 27-gene immuno-oncology assay appears to provide useful information about whether patients with advanced non–small cell lung cancer (NSCLC) could benefit from immune checkpoint inhibitor (ICI) therapy despite their poor status, researchers reported.

Positive findings on the test, known as DetermaIO, were “associated with efficacy of response to ICI therapy in advanced NSCLC patients,” Matthew G. Varga, PhD, manager of scientific affairs at Oncocyte, said in an interview. “These data suggest that DetermaIO warrants further study in poor performance status patients as it has the potential to identify likely responders to ICI therapy.”

Oncocyte, which is developing the test, presented the findings in a poster at the annual meeting of the Society for Immunotherapy of Cancer.

According to Dr. Varga, “DetermaIO is an RT-qPCR test that can be applied to FFPE [formalin-fixed, paraffin-embedded] tissue specimens to quantify the relative gene expression of 27 genes and subsequently applies our proprietary algorithm to generate an IO score based on the gene expression profile. The DetermaIO score is a binary IO+ or IO– score, representing likely responder or nonresponder, respectively.”

The test was originally developed for triple negative breast cancer, Dr. Varga said, and it’s been validated in non–small cell lung cancer, metastatic urothelial carcinoma, and metastatic colorectal carcinoma.

For the study, the researchers retrospectively tracked associations between DetermaIO score and either progression-free survival (PFS) or overall survival (OS) in 147 patients in Canada with NSCLC who were treated with ICI monotherapy. All had programmed death-ligand 1 (PD-L1) ≥ 50%.

Overall, outcomes were poor: The median survival was 12.7 months, and median PFS was 7.0 months. These outcomes were even worse in those who underwent therapy as a second- line treatment: The median survival was 9.7 months, and median PFS was 4.4 months.

“DetermaIO was significantly associated with PFS at hazard ratio [HR] = 0.55, 95% [confidence interval] CI, 0.32-0.94, P = .028. In our analyses, a hazard ratio less than 1 suggests lower risk – i.e, that DetermaIO+ patients have lower risk of an event – death or progression – compared to a DetermaIO– patient,” Dr. Varga said. “The association for overall survival was not statistically significant, but it was suggestive of clinically meaningful benefit.”

He added that “we could identify likely responders from nonresponders, suggesting that the DetermaIO score adds both independent and incremental data to the existing gold standard biomarker. The objective response rate for all first-line patients – n = 78 – was 44.9%. Twenty-two DetermaIO– tumors had a 23% response rate (5 partial responses) whereas of the 56 DetermaIO+ patients, the response rate was 54% (2 complete response and 28 partial responses).”

A score on the test, he said, was not associated with OS or PFS in patients who received second-line or later treatment.

The study was not designed to evaluate the predictive power of the test. “For a biomarker to be defined as predictive requires a formal test of interaction between a treatment group (ICI monotherapy, for example) vs. a control group (chemo-only or other regimen),” Dr. Varga explained. “In our analysis, there was no group of patients who did not receive ICI monotherapy. Thus a test for interaction and a predictive claim cannot be made.”

The test is available for at no cost via an early access program, Dr. Varga said, and Oncocyte is getting ready to seek Medicare coverage. The ultimate cost of the test, he said, is unknown.

Oncocyte funded this study. Dr. Varga and several other study authors are Oncocyte employees, and another author is a paid consultant to the company.

In adults with prediabetes, vitamin D helped decrease the risk that these individuals would develop diabetes, suggests a meta-analysis of three trials.

Results of the analysis, led by Anastassios G. Pittas, MD, MS, with the division of endocrinology, diabetes, and metabolism at Tufts Medical Center, in Boston, were published online in Annals of Internal Medicine (2023 Feb 7. doi: 10.7326/M22-3018).

All three eligible trials included in the analysis were randomized, double blinded, and placebo controlled. The three eligible trials tested three oral formulations of Vitamin D: cholecalciferol, 20,000 IU (500 mcg) weekly; cholecalciferol, 4,000 IU (100 mcg) daily; or eldecalcitol, 0.75 mcg daily, against placebos.

The authors of the new paper found that vitamin D reduced the risk for diabetes in people with prediabetes by a statistically significant 15% in adjusted analyses. The 3-year absolute risk reduction was 3.3%.

They found no difference in the rate ratios for adverse events (kidney stones, 1.17, 95% confidence interval, 0.69-1.99; hypercalcemia, 2.34; 95% CI, 0.83-6.66]; hypercalciuria, 1.65; 95% CI, 0.83-3.28]; death, 0.85; 95% CI, 0.31-2.36]) when study participants got vitamin D instead of placebo.

Differences from previous analyses

The relationship between vitamin D levels and risk for type 2 diabetes has been studied in previous trials and results have been mixed.

The authors note that two previous meta-analyses included trials “that had relatively short durations for assessment of diabetes risk (for example, ≤ 1 year), had high risk of bias (for example, open-label trials), or were not specifically designed and conducted for primary prevention of type 2 diabetes, potentially undermining the validity of the results.”

Each of the trials in this meta-analysis had a low risk of bias as determined by the Cochrane risk-of-bias tool, Dr. Pittas and colleagues said.

“The present study does not reach an opposite conclusion from the D2d study,” said Dr. Pittas, who coauthored that paper as well. “Rather, it confirms the results of the D2d study. In D2d and two other similar vitamin D and diabetes prevention trials (one in Norway and one in Japan), vitamin D reduced the rate of progression to diabetes in adults with prediabetes, but the observed differences were not statistically significant because the reported relative risk reductions (10%-13%) were smaller than each trial was powered to detect (25%-36%).”

“Individual participant data meta-analyses increase the statistical power to detect an effect. After combining data, we found that vitamin D reduced the risk of progression from prediabetes to diabetes by 15% and this result was statistically significant. So, the conclusion of the meta-analysis is essentially the same conclusion as in D2d and the other two trials. The difference is that the result is now statistically significant,” Dr. Pittas added.

Small reduction but large population

The authors acknowledged that the absolute risk reduction number is small, especially when compared with the risk reduction seen with intensive lifestyle changes (58%) and metformin (31%), as reported in an article published in the New England of Journal of Medicine (2002 Feb 7;346:393-403). But “extrapolating to the more than 374 million adults worldwide who have prediabetes suggests that inexpensive vitamin D supplementation could delay the development of diabetes in more than 10 million people,” they said.

As for how high vitamin D levels need to be, the authors write that their research indicates that the optimal level of vitamin D in the blood needed to reduce diabetes risk may be higher than an Institute of Medicine committee recommendation in 2011.

“The blood 25-hydroxy vitamin D level needed to optimally reduce diabetes risk may be near and possibly above the range of 125-150 nmol/L (50-60 ng/mL) that the 2011 Institute of Medicine Committee to Review Dietary Reference Intakes for Calcium and Vitamin D provided as the range corresponding to the tolerable upper intake level (UL) of 4,000 IU/d for vitamin D,” the authors of the new paper said.

Editorialists urge caution

In an accompanying editorial also published in the Annals of Internal Medicine, Malachi J. McKenna, MD, with the department of clinical chemistry, at St. Vincent’s University Hospital, and Mary A.T. Flynn, PhD, RD, with the Food Safety Authority of Ireland in Dublin, urge caution regarding vitamin D dosing.

They write that there are important distinctions between vitamin D supplements and vitamin D therapy, and the potential harms of high-dose vitamin D are still unclear.

“Vitamin D supplementation of 10 to 20 mcg (400 to 800 IU) daily can be applied safely at the population level to prevent skeletal and possibly nonskeletal disease. Very-high-dose vitamin D therapy might prevent type 2 diabetes in some patients but may also cause harm,” they note.

Dr. Pittas said in an interview that there have been some studies with high-dose vitamin D (up to 500,000 IU a year in one study) that reported an increased fall risk in older adults who had high fall risk. “However, these findings are not generalizable to other populations that are younger and at low or average fall risk, such as the prediabetes population to which the results of this meta-analysis apply,” he noted.

“The benefit-to-risk ratio for vitamin D depends on the target population and medical condition,” Dr. Pittas said. “The editorial refers to the NAM (National Academy of Medicine) vitamin D guidelines for the general, healthy population to promote bone health. The guidelines should not be extrapolated to specific populations, for example [patients with] prediabetes,” where the vitamin D benefit-to-risk ratio would be different from that in the general population.

Dr. Pittas and colleagues caution that the people studied in this meta-analysis were at high risk for type 2 diabetes, so these results do not apply to the general healthy population. The results also should not be extrapolated to people at average risk for any type of diabetes, they add.

Several physicians either declined to comment or did not respond to requests for comment on this research.

Dr. Pittas reports the National Institutes of Health and the American Diabetes Association made payments to his institution to conduct Vitamin D-related research. He is an unpaid cochair of the Endocrine Society’s Evaluation, Treatment and Prevention of Vitamin D Deficiency Clinical Practice Guideline team.

Coauthor Dr. Jorde reports grants from Novo Nordisk Foundation, North Norwegian Regional Health Authorities, and the Research Council of Norway.

Dr. Dawson-Hughes reports she is on the DSMB for AgNovos Healthcare. AgNovos is developing a bone implant to reduce hip fracture risk and she gets a stipend from the company. She reports Helsinn Therapeutics provided anamorelin and matching placebo for an NIH-funded clinical trial.

Dr. Trikalinos was supported by the D2d study. He is a technical methodological consultant to Latham and Watkins, who is retained by Pacira Pharmaceuticals.

Dr. Angellotti has been employed by Takeda and owns stock in the company.

The editorialists report no relevant financial relationships.

In adults with prediabetes, vitamin D helped decrease the risk that these individuals would develop diabetes, suggests a meta-analysis of three trials.

Results of the analysis, led by Anastassios G. Pittas, MD, MS, with the division of endocrinology, diabetes, and metabolism at Tufts Medical Center, in Boston, were published online in Annals of Internal Medicine (2023 Feb 7. doi: 10.7326/M22-3018).

All three eligible trials included in the analysis were randomized, double blinded, and placebo controlled. The three eligible trials tested three oral formulations of Vitamin D: cholecalciferol, 20,000 IU (500 mcg) weekly; cholecalciferol, 4,000 IU (100 mcg) daily; or eldecalcitol, 0.75 mcg daily, against placebos.

The authors of the new paper found that vitamin D reduced the risk for diabetes in people with prediabetes by a statistically significant 15% in adjusted analyses. The 3-year absolute risk reduction was 3.3%.

They found no difference in the rate ratios for adverse events (kidney stones, 1.17, 95% confidence interval, 0.69-1.99; hypercalcemia, 2.34; 95% CI, 0.83-6.66]; hypercalciuria, 1.65; 95% CI, 0.83-3.28]; death, 0.85; 95% CI, 0.31-2.36]) when study participants got vitamin D instead of placebo.

Differences from previous analyses

The relationship between vitamin D levels and risk for type 2 diabetes has been studied in previous trials and results have been mixed.

The authors note that two previous meta-analyses included trials “that had relatively short durations for assessment of diabetes risk (for example, ≤ 1 year), had high risk of bias (for example, open-label trials), or were not specifically designed and conducted for primary prevention of type 2 diabetes, potentially undermining the validity of the results.”

Each of the trials in this meta-analysis had a low risk of bias as determined by the Cochrane risk-of-bias tool, Dr. Pittas and colleagues said.

“The present study does not reach an opposite conclusion from the D2d study,” said Dr. Pittas, who coauthored that paper as well. “Rather, it confirms the results of the D2d study. In D2d and two other similar vitamin D and diabetes prevention trials (one in Norway and one in Japan), vitamin D reduced the rate of progression to diabetes in adults with prediabetes, but the observed differences were not statistically significant because the reported relative risk reductions (10%-13%) were smaller than each trial was powered to detect (25%-36%).”

“Individual participant data meta-analyses increase the statistical power to detect an effect. After combining data, we found that vitamin D reduced the risk of progression from prediabetes to diabetes by 15% and this result was statistically significant. So, the conclusion of the meta-analysis is essentially the same conclusion as in D2d and the other two trials. The difference is that the result is now statistically significant,” Dr. Pittas added.

Small reduction but large population

The authors acknowledged that the absolute risk reduction number is small, especially when compared with the risk reduction seen with intensive lifestyle changes (58%) and metformin (31%), as reported in an article published in the New England of Journal of Medicine (2002 Feb 7;346:393-403). But “extrapolating to the more than 374 million adults worldwide who have prediabetes suggests that inexpensive vitamin D supplementation could delay the development of diabetes in more than 10 million people,” they said.

As for how high vitamin D levels need to be, the authors write that their research indicates that the optimal level of vitamin D in the blood needed to reduce diabetes risk may be higher than an Institute of Medicine committee recommendation in 2011.

“The blood 25-hydroxy vitamin D level needed to optimally reduce diabetes risk may be near and possibly above the range of 125-150 nmol/L (50-60 ng/mL) that the 2011 Institute of Medicine Committee to Review Dietary Reference Intakes for Calcium and Vitamin D provided as the range corresponding to the tolerable upper intake level (UL) of 4,000 IU/d for vitamin D,” the authors of the new paper said.

Editorialists urge caution

In an accompanying editorial also published in the Annals of Internal Medicine, Malachi J. McKenna, MD, with the department of clinical chemistry, at St. Vincent’s University Hospital, and Mary A.T. Flynn, PhD, RD, with the Food Safety Authority of Ireland in Dublin, urge caution regarding vitamin D dosing.

They write that there are important distinctions between vitamin D supplements and vitamin D therapy, and the potential harms of high-dose vitamin D are still unclear.

“Vitamin D supplementation of 10 to 20 mcg (400 to 800 IU) daily can be applied safely at the population level to prevent skeletal and possibly nonskeletal disease. Very-high-dose vitamin D therapy might prevent type 2 diabetes in some patients but may also cause harm,” they note.

Dr. Pittas said in an interview that there have been some studies with high-dose vitamin D (up to 500,000 IU a year in one study) that reported an increased fall risk in older adults who had high fall risk. “However, these findings are not generalizable to other populations that are younger and at low or average fall risk, such as the prediabetes population to which the results of this meta-analysis apply,” he noted.

“The benefit-to-risk ratio for vitamin D depends on the target population and medical condition,” Dr. Pittas said. “The editorial refers to the NAM (National Academy of Medicine) vitamin D guidelines for the general, healthy population to promote bone health. The guidelines should not be extrapolated to specific populations, for example [patients with] prediabetes,” where the vitamin D benefit-to-risk ratio would be different from that in the general population.

Dr. Pittas and colleagues caution that the people studied in this meta-analysis were at high risk for type 2 diabetes, so these results do not apply to the general healthy population. The results also should not be extrapolated to people at average risk for any type of diabetes, they add.

Several physicians either declined to comment or did not respond to requests for comment on this research.

Dr. Pittas reports the National Institutes of Health and the American Diabetes Association made payments to his institution to conduct Vitamin D-related research. He is an unpaid cochair of the Endocrine Society’s Evaluation, Treatment and Prevention of Vitamin D Deficiency Clinical Practice Guideline team.

Coauthor Dr. Jorde reports grants from Novo Nordisk Foundation, North Norwegian Regional Health Authorities, and the Research Council of Norway.

Dr. Dawson-Hughes reports she is on the DSMB for AgNovos Healthcare. AgNovos is developing a bone implant to reduce hip fracture risk and she gets a stipend from the company. She reports Helsinn Therapeutics provided anamorelin and matching placebo for an NIH-funded clinical trial.

Dr. Trikalinos was supported by the D2d study. He is a technical methodological consultant to Latham and Watkins, who is retained by Pacira Pharmaceuticals.

Dr. Angellotti has been employed by Takeda and owns stock in the company.

The editorialists report no relevant financial relationships.

In adults with prediabetes, vitamin D helped decrease the risk that these individuals would develop diabetes, suggests a meta-analysis of three trials.

Results of the analysis, led by Anastassios G. Pittas, MD, MS, with the division of endocrinology, diabetes, and metabolism at Tufts Medical Center, in Boston, were published online in Annals of Internal Medicine (2023 Feb 7. doi: 10.7326/M22-3018).

All three eligible trials included in the analysis were randomized, double blinded, and placebo controlled. The three eligible trials tested three oral formulations of Vitamin D: cholecalciferol, 20,000 IU (500 mcg) weekly; cholecalciferol, 4,000 IU (100 mcg) daily; or eldecalcitol, 0.75 mcg daily, against placebos.

The authors of the new paper found that vitamin D reduced the risk for diabetes in people with prediabetes by a statistically significant 15% in adjusted analyses. The 3-year absolute risk reduction was 3.3%.

They found no difference in the rate ratios for adverse events (kidney stones, 1.17, 95% confidence interval, 0.69-1.99; hypercalcemia, 2.34; 95% CI, 0.83-6.66]; hypercalciuria, 1.65; 95% CI, 0.83-3.28]; death, 0.85; 95% CI, 0.31-2.36]) when study participants got vitamin D instead of placebo.

Differences from previous analyses

The relationship between vitamin D levels and risk for type 2 diabetes has been studied in previous trials and results have been mixed.

The authors note that two previous meta-analyses included trials “that had relatively short durations for assessment of diabetes risk (for example, ≤ 1 year), had high risk of bias (for example, open-label trials), or were not specifically designed and conducted for primary prevention of type 2 diabetes, potentially undermining the validity of the results.”

Each of the trials in this meta-analysis had a low risk of bias as determined by the Cochrane risk-of-bias tool, Dr. Pittas and colleagues said.

“The present study does not reach an opposite conclusion from the D2d study,” said Dr. Pittas, who coauthored that paper as well. “Rather, it confirms the results of the D2d study. In D2d and two other similar vitamin D and diabetes prevention trials (one in Norway and one in Japan), vitamin D reduced the rate of progression to diabetes in adults with prediabetes, but the observed differences were not statistically significant because the reported relative risk reductions (10%-13%) were smaller than each trial was powered to detect (25%-36%).”

“Individual participant data meta-analyses increase the statistical power to detect an effect. After combining data, we found that vitamin D reduced the risk of progression from prediabetes to diabetes by 15% and this result was statistically significant. So, the conclusion of the meta-analysis is essentially the same conclusion as in D2d and the other two trials. The difference is that the result is now statistically significant,” Dr. Pittas added.

Small reduction but large population

The authors acknowledged that the absolute risk reduction number is small, especially when compared with the risk reduction seen with intensive lifestyle changes (58%) and metformin (31%), as reported in an article published in the New England of Journal of Medicine (2002 Feb 7;346:393-403). But “extrapolating to the more than 374 million adults worldwide who have prediabetes suggests that inexpensive vitamin D supplementation could delay the development of diabetes in more than 10 million people,” they said.

As for how high vitamin D levels need to be, the authors write that their research indicates that the optimal level of vitamin D in the blood needed to reduce diabetes risk may be higher than an Institute of Medicine committee recommendation in 2011.

“The blood 25-hydroxy vitamin D level needed to optimally reduce diabetes risk may be near and possibly above the range of 125-150 nmol/L (50-60 ng/mL) that the 2011 Institute of Medicine Committee to Review Dietary Reference Intakes for Calcium and Vitamin D provided as the range corresponding to the tolerable upper intake level (UL) of 4,000 IU/d for vitamin D,” the authors of the new paper said.

Editorialists urge caution

In an accompanying editorial also published in the Annals of Internal Medicine, Malachi J. McKenna, MD, with the department of clinical chemistry, at St. Vincent’s University Hospital, and Mary A.T. Flynn, PhD, RD, with the Food Safety Authority of Ireland in Dublin, urge caution regarding vitamin D dosing.

They write that there are important distinctions between vitamin D supplements and vitamin D therapy, and the potential harms of high-dose vitamin D are still unclear.

“Vitamin D supplementation of 10 to 20 mcg (400 to 800 IU) daily can be applied safely at the population level to prevent skeletal and possibly nonskeletal disease. Very-high-dose vitamin D therapy might prevent type 2 diabetes in some patients but may also cause harm,” they note.

Dr. Pittas said in an interview that there have been some studies with high-dose vitamin D (up to 500,000 IU a year in one study) that reported an increased fall risk in older adults who had high fall risk. “However, these findings are not generalizable to other populations that are younger and at low or average fall risk, such as the prediabetes population to which the results of this meta-analysis apply,” he noted.

“The benefit-to-risk ratio for vitamin D depends on the target population and medical condition,” Dr. Pittas said. “The editorial refers to the NAM (National Academy of Medicine) vitamin D guidelines for the general, healthy population to promote bone health. The guidelines should not be extrapolated to specific populations, for example [patients with] prediabetes,” where the vitamin D benefit-to-risk ratio would be different from that in the general population.

Dr. Pittas and colleagues caution that the people studied in this meta-analysis were at high risk for type 2 diabetes, so these results do not apply to the general healthy population. The results also should not be extrapolated to people at average risk for any type of diabetes, they add.

Several physicians either declined to comment or did not respond to requests for comment on this research.

Dr. Pittas reports the National Institutes of Health and the American Diabetes Association made payments to his institution to conduct Vitamin D-related research. He is an unpaid cochair of the Endocrine Society’s Evaluation, Treatment and Prevention of Vitamin D Deficiency Clinical Practice Guideline team.

Coauthor Dr. Jorde reports grants from Novo Nordisk Foundation, North Norwegian Regional Health Authorities, and the Research Council of Norway.

Dr. Dawson-Hughes reports she is on the DSMB for AgNovos Healthcare. AgNovos is developing a bone implant to reduce hip fracture risk and she gets a stipend from the company. She reports Helsinn Therapeutics provided anamorelin and matching placebo for an NIH-funded clinical trial.

Dr. Trikalinos was supported by the D2d study. He is a technical methodological consultant to Latham and Watkins, who is retained by Pacira Pharmaceuticals.

Dr. Angellotti has been employed by Takeda and owns stock in the company.

The editorialists report no relevant financial relationships.

The Food and Drug Administration approved a new indication for sacituzumab govitecan (Trodelvy, Gilead Sciences) on Feb. 3 for patients with unresectable, locally advanced or metastatic hormone receptor (HR)–positive, HER2-negative breast cancer after endocrine-based therapy and at least two additional systemic therapies for metastatic disease.

Label expansion for the Trop-2–directed antibody-drug conjugate was based on the TROPICS-02 trial, which randomized 543 adults 1:1 to either sacituzumab govitecan 10 mg/kg IV on days 1 and 8 of a 21-day cycle or single agent chemotherapy, most often eribulin but also vinorelbine, gemcitabine, or capecitabine.

Median progression free survival was 5.5 months with sacituzumab govitecan versus 4 months with single agent chemotherapy (hazard ratio, 0.66; P = .0003). Median overall survival was 14.4 months in the sacituzumab govitecan group versus 11.2 months with chemotherapy (HR, 0.79), according to an FDA press release announcing the approval.

In a Gilead press release, Hope Rugo, MD, a breast cancer specialist at the University of California, San Francisco, and principal investigator for TROPICS-02, said the approval “is significant for the breast cancer community. We have had limited options to offer patients after endocrine-based therapy and chemotherapy, and to see a clinically meaningful survival benefit of more than 3 months with a quality-of-life benefit for these women is exceptional.”

The most common adverse events associated with sacituzumab govitecan in the trial, occurring in a quarter or more of participants, were decreased leukocyte count, decreased neutrophil count, decreased hemoglobin, decreased lymphocyte count, diarrhea, fatigue, nausea, alopecia, glucose elevation, constipation, and decreased albumin.

Labeling for the agent carries a boxedwarning of severe or life-threatening neutropenia and severe diarrhea.

The recommended dose is the trial dose: 10 mg/kg IV on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity.

Sacituzumab govitecan was previously approved for unresectable, locally advanced or metastatic triple-negative breast cancer after two or more prior systemic therapies and locally advanced or metastatic urothelial cancer after platinum-based chemotherapy and either a PD-1 or PD-L1 inhibitor.

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

The Food and Drug Administration approved a new indication for sacituzumab govitecan (Trodelvy, Gilead Sciences) on Feb. 3 for patients with unresectable, locally advanced or metastatic hormone receptor (HR)–positive, HER2-negative breast cancer after endocrine-based therapy and at least two additional systemic therapies for metastatic disease.

Label expansion for the Trop-2–directed antibody-drug conjugate was based on the TROPICS-02 trial, which randomized 543 adults 1:1 to either sacituzumab govitecan 10 mg/kg IV on days 1 and 8 of a 21-day cycle or single agent chemotherapy, most often eribulin but also vinorelbine, gemcitabine, or capecitabine.

Median progression free survival was 5.5 months with sacituzumab govitecan versus 4 months with single agent chemotherapy (hazard ratio, 0.66; P = .0003). Median overall survival was 14.4 months in the sacituzumab govitecan group versus 11.2 months with chemotherapy (HR, 0.79), according to an FDA press release announcing the approval.

In a Gilead press release, Hope Rugo, MD, a breast cancer specialist at the University of California, San Francisco, and principal investigator for TROPICS-02, said the approval “is significant for the breast cancer community. We have had limited options to offer patients after endocrine-based therapy and chemotherapy, and to see a clinically meaningful survival benefit of more than 3 months with a quality-of-life benefit for these women is exceptional.”

The most common adverse events associated with sacituzumab govitecan in the trial, occurring in a quarter or more of participants, were decreased leukocyte count, decreased neutrophil count, decreased hemoglobin, decreased lymphocyte count, diarrhea, fatigue, nausea, alopecia, glucose elevation, constipation, and decreased albumin.

Labeling for the agent carries a boxedwarning of severe or life-threatening neutropenia and severe diarrhea.

The recommended dose is the trial dose: 10 mg/kg IV on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity.

Sacituzumab govitecan was previously approved for unresectable, locally advanced or metastatic triple-negative breast cancer after two or more prior systemic therapies and locally advanced or metastatic urothelial cancer after platinum-based chemotherapy and either a PD-1 or PD-L1 inhibitor.

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

The Food and Drug Administration approved a new indication for sacituzumab govitecan (Trodelvy, Gilead Sciences) on Feb. 3 for patients with unresectable, locally advanced or metastatic hormone receptor (HR)–positive, HER2-negative breast cancer after endocrine-based therapy and at least two additional systemic therapies for metastatic disease.

Label expansion for the Trop-2–directed antibody-drug conjugate was based on the TROPICS-02 trial, which randomized 543 adults 1:1 to either sacituzumab govitecan 10 mg/kg IV on days 1 and 8 of a 21-day cycle or single agent chemotherapy, most often eribulin but also vinorelbine, gemcitabine, or capecitabine.

Median progression free survival was 5.5 months with sacituzumab govitecan versus 4 months with single agent chemotherapy (hazard ratio, 0.66; P = .0003). Median overall survival was 14.4 months in the sacituzumab govitecan group versus 11.2 months with chemotherapy (HR, 0.79), according to an FDA press release announcing the approval.

In a Gilead press release, Hope Rugo, MD, a breast cancer specialist at the University of California, San Francisco, and principal investigator for TROPICS-02, said the approval “is significant for the breast cancer community. We have had limited options to offer patients after endocrine-based therapy and chemotherapy, and to see a clinically meaningful survival benefit of more than 3 months with a quality-of-life benefit for these women is exceptional.”

The most common adverse events associated with sacituzumab govitecan in the trial, occurring in a quarter or more of participants, were decreased leukocyte count, decreased neutrophil count, decreased hemoglobin, decreased lymphocyte count, diarrhea, fatigue, nausea, alopecia, glucose elevation, constipation, and decreased albumin.

Labeling for the agent carries a boxedwarning of severe or life-threatening neutropenia and severe diarrhea.

The recommended dose is the trial dose: 10 mg/kg IV on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity.

Sacituzumab govitecan was previously approved for unresectable, locally advanced or metastatic triple-negative breast cancer after two or more prior systemic therapies and locally advanced or metastatic urothelial cancer after platinum-based chemotherapy and either a PD-1 or PD-L1 inhibitor.

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

While it’s well known that COVID-19 vaccines are less effective in patients with chronic lymphocytic leukemia (CLL) who take immunity-lowering drugs, a new study offers fresh insight into what’s happening inside the body. In these patients, the vaccines often don’t boost B cells, which produce antibodies, but they do strengthen T cells, potentially providing crucial protection against severe illness and death.

These findings don’t reveal whether the T-cell boost actually provides extra protection against COVID-19. Still, the study suggests that patients with CLL should be vaccinated no matter which medications they’re taking, coauthor and hematologist/oncologist Clemens-Martin Wendtner, MD, of the Munich (Germany) Clinic, said in an interview.

“Do not defer or pause treatment,” said Dr. Wendtner, whose study was published in Blood Advances.

Patients with CLL appear to have among the weakest responses to the COVID-19 vaccine among people with various types of blood cancer. A meta-analysis published in 2022 found that seropositivity rates following vaccination were just 51% in patients with CLL, compared with 80%-90% in those with acute leukemia and 76%-80% of those with myeloma.

“Usually, the response rate to vaccination among the nonimmunocompromised would be 95%,” Dr. Wendtner said.

Research has also suggested that patients treated with B-cell pathway inhibitors and anti-CD20 antibodies are especially likely to have poorer responses to COVID-19 vaccines, no surprise considering that their job is to dampen the immune system. But there’s an unanswered question, according to Dr. Wendtner: Does “just measuring B-cell response tell us everything about the immune response?”

The new prospective, single-institution study aims to answer that question in patients who each received two types of vaccines. Researchers compared peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates in 15 patients with CLL/small lymphocytic lymphoma following vaccination with both the Pfizer-BioNTech and AstraZeneca vaccines.

The average antibody response was limited. “Overall, 7/15 of patients failed to mount a humoral response even after three-dose vaccination,” the researchers reported. All of the patients were “heavily pretreated” with CLL medications such as venetoclax, an anti-CD20 monoclonal antibody.

By contrast, the T-cell response was much stronger: 80% of patients (12/15) had a robust response, a number that grew to 90% (14/15) after a booster. This response is “almost ideal” considering that the response in a nonimmunocompromised person would be about 99%, Dr. Wendtner said.

The study also revealed that vaccine responses were weaker in patients who took a combination of a Bruton tyrosine kinase inhibitor and venetoclax within a year.

Four patients developed COVID-19 infections with the Omicron variant about 6 months after vaccination. All had mild symptoms. A lone patient had a history of COVID-19 infection prior to vaccination.

The researchers noted that the study had several limitations, including its small size, its reliance on a single institution, and the differences in treatments and vaccination protocols among the patient population.

Broadly speaking, the study showed that “a vaccine is not in vain” in patients with CLL, “although the doctor might not detect an antibody response,” Dr. Wendtner said. He added that mixing vaccine types should provide more protection. Start with a viral vector vaccine followed by an mRNA vaccine or vice versa, he suggested.

In an interview, infectious disease physician Joshua A. Hill, MD, from Fred Hutchinson Cancer Center, Seattle, who wasn’t involved with the study, said it makes “important and interesting observations to reinforce other studies with similar findings.”

Specifically, Dr. Hill said, “despite the absence of a robust antibody response some of these patients who are on active treatment, patients can still generate robust cellular immune responses in the form of T-cell immunity. Our understanding is that having T cell immunity will provide important additional protection for developing severe disease, although is less easily tested.”

As for the best vaccination strategies, Dr. Hill said “patients should get vaccinated as soon as they are eligible, according to standard guidelines. If patients have not yet started therapy, they should get their indicated vaccines before starting treatment whenever possible.”

The German study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Bavarian State Ministry of Science and Art. Dr. Wendtner disclosed consultant fees from AstraZeneca and BioNTech, and another author disclosed consultant fees from AstraZeneca. The other authors reported no disclosures. Dr. Hill disclosed consultant fees from Moderna, Pfizer, and Gilead.

While it’s well known that COVID-19 vaccines are less effective in patients with chronic lymphocytic leukemia (CLL) who take immunity-lowering drugs, a new study offers fresh insight into what’s happening inside the body. In these patients, the vaccines often don’t boost B cells, which produce antibodies, but they do strengthen T cells, potentially providing crucial protection against severe illness and death.

These findings don’t reveal whether the T-cell boost actually provides extra protection against COVID-19. Still, the study suggests that patients with CLL should be vaccinated no matter which medications they’re taking, coauthor and hematologist/oncologist Clemens-Martin Wendtner, MD, of the Munich (Germany) Clinic, said in an interview.

“Do not defer or pause treatment,” said Dr. Wendtner, whose study was published in Blood Advances.

Patients with CLL appear to have among the weakest responses to the COVID-19 vaccine among people with various types of blood cancer. A meta-analysis published in 2022 found that seropositivity rates following vaccination were just 51% in patients with CLL, compared with 80%-90% in those with acute leukemia and 76%-80% of those with myeloma.

“Usually, the response rate to vaccination among the nonimmunocompromised would be 95%,” Dr. Wendtner said.

Research has also suggested that patients treated with B-cell pathway inhibitors and anti-CD20 antibodies are especially likely to have poorer responses to COVID-19 vaccines, no surprise considering that their job is to dampen the immune system. But there’s an unanswered question, according to Dr. Wendtner: Does “just measuring B-cell response tell us everything about the immune response?”

The new prospective, single-institution study aims to answer that question in patients who each received two types of vaccines. Researchers compared peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates in 15 patients with CLL/small lymphocytic lymphoma following vaccination with both the Pfizer-BioNTech and AstraZeneca vaccines.

The average antibody response was limited. “Overall, 7/15 of patients failed to mount a humoral response even after three-dose vaccination,” the researchers reported. All of the patients were “heavily pretreated” with CLL medications such as venetoclax, an anti-CD20 monoclonal antibody.

By contrast, the T-cell response was much stronger: 80% of patients (12/15) had a robust response, a number that grew to 90% (14/15) after a booster. This response is “almost ideal” considering that the response in a nonimmunocompromised person would be about 99%, Dr. Wendtner said.

The study also revealed that vaccine responses were weaker in patients who took a combination of a Bruton tyrosine kinase inhibitor and venetoclax within a year.

Four patients developed COVID-19 infections with the Omicron variant about 6 months after vaccination. All had mild symptoms. A lone patient had a history of COVID-19 infection prior to vaccination.

The researchers noted that the study had several limitations, including its small size, its reliance on a single institution, and the differences in treatments and vaccination protocols among the patient population.

Broadly speaking, the study showed that “a vaccine is not in vain” in patients with CLL, “although the doctor might not detect an antibody response,” Dr. Wendtner said. He added that mixing vaccine types should provide more protection. Start with a viral vector vaccine followed by an mRNA vaccine or vice versa, he suggested.

In an interview, infectious disease physician Joshua A. Hill, MD, from Fred Hutchinson Cancer Center, Seattle, who wasn’t involved with the study, said it makes “important and interesting observations to reinforce other studies with similar findings.”

Specifically, Dr. Hill said, “despite the absence of a robust antibody response some of these patients who are on active treatment, patients can still generate robust cellular immune responses in the form of T-cell immunity. Our understanding is that having T cell immunity will provide important additional protection for developing severe disease, although is less easily tested.”

As for the best vaccination strategies, Dr. Hill said “patients should get vaccinated as soon as they are eligible, according to standard guidelines. If patients have not yet started therapy, they should get their indicated vaccines before starting treatment whenever possible.”

The German study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Bavarian State Ministry of Science and Art. Dr. Wendtner disclosed consultant fees from AstraZeneca and BioNTech, and another author disclosed consultant fees from AstraZeneca. The other authors reported no disclosures. Dr. Hill disclosed consultant fees from Moderna, Pfizer, and Gilead.

While it’s well known that COVID-19 vaccines are less effective in patients with chronic lymphocytic leukemia (CLL) who take immunity-lowering drugs, a new study offers fresh insight into what’s happening inside the body. In these patients, the vaccines often don’t boost B cells, which produce antibodies, but they do strengthen T cells, potentially providing crucial protection against severe illness and death.

These findings don’t reveal whether the T-cell boost actually provides extra protection against COVID-19. Still, the study suggests that patients with CLL should be vaccinated no matter which medications they’re taking, coauthor and hematologist/oncologist Clemens-Martin Wendtner, MD, of the Munich (Germany) Clinic, said in an interview.

“Do not defer or pause treatment,” said Dr. Wendtner, whose study was published in Blood Advances.

Patients with CLL appear to have among the weakest responses to the COVID-19 vaccine among people with various types of blood cancer. A meta-analysis published in 2022 found that seropositivity rates following vaccination were just 51% in patients with CLL, compared with 80%-90% in those with acute leukemia and 76%-80% of those with myeloma.

“Usually, the response rate to vaccination among the nonimmunocompromised would be 95%,” Dr. Wendtner said.

Research has also suggested that patients treated with B-cell pathway inhibitors and anti-CD20 antibodies are especially likely to have poorer responses to COVID-19 vaccines, no surprise considering that their job is to dampen the immune system. But there’s an unanswered question, according to Dr. Wendtner: Does “just measuring B-cell response tell us everything about the immune response?”

The new prospective, single-institution study aims to answer that question in patients who each received two types of vaccines. Researchers compared peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates in 15 patients with CLL/small lymphocytic lymphoma following vaccination with both the Pfizer-BioNTech and AstraZeneca vaccines.

The average antibody response was limited. “Overall, 7/15 of patients failed to mount a humoral response even after three-dose vaccination,” the researchers reported. All of the patients were “heavily pretreated” with CLL medications such as venetoclax, an anti-CD20 monoclonal antibody.

By contrast, the T-cell response was much stronger: 80% of patients (12/15) had a robust response, a number that grew to 90% (14/15) after a booster. This response is “almost ideal” considering that the response in a nonimmunocompromised person would be about 99%, Dr. Wendtner said.

The study also revealed that vaccine responses were weaker in patients who took a combination of a Bruton tyrosine kinase inhibitor and venetoclax within a year.

Four patients developed COVID-19 infections with the Omicron variant about 6 months after vaccination. All had mild symptoms. A lone patient had a history of COVID-19 infection prior to vaccination.

The researchers noted that the study had several limitations, including its small size, its reliance on a single institution, and the differences in treatments and vaccination protocols among the patient population.

Broadly speaking, the study showed that “a vaccine is not in vain” in patients with CLL, “although the doctor might not detect an antibody response,” Dr. Wendtner said. He added that mixing vaccine types should provide more protection. Start with a viral vector vaccine followed by an mRNA vaccine or vice versa, he suggested.

In an interview, infectious disease physician Joshua A. Hill, MD, from Fred Hutchinson Cancer Center, Seattle, who wasn’t involved with the study, said it makes “important and interesting observations to reinforce other studies with similar findings.”

Specifically, Dr. Hill said, “despite the absence of a robust antibody response some of these patients who are on active treatment, patients can still generate robust cellular immune responses in the form of T-cell immunity. Our understanding is that having T cell immunity will provide important additional protection for developing severe disease, although is less easily tested.”

As for the best vaccination strategies, Dr. Hill said “patients should get vaccinated as soon as they are eligible, according to standard guidelines. If patients have not yet started therapy, they should get their indicated vaccines before starting treatment whenever possible.”

The German study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Bavarian State Ministry of Science and Art. Dr. Wendtner disclosed consultant fees from AstraZeneca and BioNTech, and another author disclosed consultant fees from AstraZeneca. The other authors reported no disclosures. Dr. Hill disclosed consultant fees from Moderna, Pfizer, and Gilead.

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

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

*This story was updated 2/1/2023.

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

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

*This story was updated 2/1/2023.

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

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

*This story was updated 2/1/2023.

New renin-angiotensin-system (RAS) inhibitor therapy using sacubitril-valsartan (Entresto) is no more likely to cause angioedema than starting out with an ACE inhibitor or angiotensin receptor blocker (ARB).

But the risk climbs when such patients start on an ACE inhibitor or ARB and then switch to sacubitril-valsartan, compared with those prescribed the newer drug, the only available angiotensin receptor-neprilysin inhibitor (ARNI), in the first place.

Those findings and others from a large database analysis, by researchers at the Food and Drug Administration and Harvard Medical School, may clarify and help alleviate a residual safety concern about the ARNI – that it might promote angioedema – that persists after the drug’s major HF trials.  

The angioedema risk increased the most right after the switch to the ARNI from one of the older RAS inhibitors. For example, the overall risk doubled for patients who started with an ARB then switched to sacubitril-valsartan, compared with those who started on the newer drug. But it went up about 2.5 times during the first 14 days after the switch.

A similar pattern emerged for ACE inhibitors, but the increased angioedema risk reached significance only within 2 weeks of the switch from an ACE inhibitor to sacubitril-valsartan compared to starting on the latter.

The analysis, based on data from the FDA’s Sentinel adverse event reporting system, was published in the Journal of the American College of Cardiology.
 

A rare complication, but ...

Angioedema was rare overall in the study, with an unadjusted rate of about 6.75 per 1,000 person-years for users of ACE inhibitors, less than half that rate for ARB users, and only one-fifth that rate for sacubitril-valsartan recipients.

But even a rare complication can be a worry for drugs as widely used as RAS inhibitors. And it’s not unusual for patients cautiously started on an ACE inhibitor or ARB to be switched to sacubitril-valsartan, which is only recently a core guideline–recommended therapy for HF with reduced ejection fraction.

Such patients transitioning to the ARNI, the current study suggests, should probably be watched closely for signs of angioedema for 2 weeks but especially during the first few days. Indeed, the study’s event curves show most of the extra risk “popping up” right after the switch to sacubitril-valsartan, lead author Efe Eworuke, PhD, told this news organization.

The ARNI’s labeling, which states the drug should follow ACE inhibitors only after 36-hour washout period, “has done justice to this issue,” she said. But “whether clinicians are adhering to that, we can’t tell.”

Potentially, patients who miss the 36-hour washout between ACE inhibitors or ARBs and sacubitril-valsartan may account for the excess angioedema risk seen in the analysis, said Dr. Eworuke, with the FDA’s Center for Drug Evaluation and Research, Silver Spring, Md.

But the analysis doesn’t nail down the window of excess risk to only 36 hours. It suggests that patients switching to the ARNI – even those pausing for 36 hours in between drugs – should probably be monitored “2 weeks or longer,” she said. “They could still have angioedema after the washout period.”

Indeed, the “timing of the switch may be critical,” according to an editorial accompanying the report. “Perhaps a longer initial exposure period of ACE inhibitor or ARB,” beyond 2 weeks, “should be considered before switching to an ARNI,” contended Robert L. Page II, PharmD, MSPH, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora.

American Heart Association

Moreover, he wrote, the study suggests that “initiation of an ARNI de novo may be safer compared with trialing an ACE inhibitor or ARB then switching to an ARNI,” and “should be a consideration when beginning guideline-directed medical therapy for patients with HF.”
 

New RAS inhibition with ARNI ‘protective’

Compared with ARNI “new users” who had not received any RAS inhibitor in the prior 6 months, patients in the study who switched from an ACE inhibitor to ARNI (41,548 matched pairs) showed a hazard ratio (HR) for angioedema of 1.62 (95% confidence interval [CI], 0.91-2.89), that is, only a “trend,” the report states.

But that trend became significant when the analysis considered only angioedema cases in the first 14 days after the drug switch: HR, 1.98 (95% CI, 1.11-3.53).

Those switching from an ARB to ARNI, compared with ARNI new users (37,893 matched pairs), showed a significant HR for angioedema of 2.03 (95% CI, 1.16-3.54). The effect was more pronounced when considering only angioedema arising in the first 2 weeks: HR, 2.45 (95% CI, 1.36-4.43).

Compared with new use of ACE inhibitors, new ARNI use (41,998 matched pairs) was “protective,” the report states, with an HR for angioedema of 0.18 (95% CI, 0.11-0.29). So was a switch from ACE inhibitors to the ARNI (69,639 matched pairs), with an HR of 0.31 (95% CI, 0.23-0.43).

But compared with starting with an ARB, ARNI new use (43,755 matched pairs) had a null effect on angioedema risk, HR, 0.59 (95% CI, 0.35-1.01); as did switching from an ARB to ARNI (49,137 matched pairs), HR, 0.85 (95% CI, 0.58-1.26).

The analysis has limitations, Dr. Eworuke acknowledged. The comparator groups probably differed in unknown ways given the limits of propensity matching, for example, and because the FDA’s Sentinel system data can reflect only cases that are reported, the study probably underestimates the true prevalence of angioedema.

For example, a patient may see a clinician for a milder case that resolves without a significant intervention, she noted. But “those types of angioedema would not have been captured by our study.”

Dr. Eworuke disclosed that her comments reflect her views and are not those of the Food and Drug Administration; she and the other authors, as well as editorialist Dr. Page, report no relevant financial relationships.

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

New renin-angiotensin-system (RAS) inhibitor therapy using sacubitril-valsartan (Entresto) is no more likely to cause angioedema than starting out with an ACE inhibitor or angiotensin receptor blocker (ARB).

But the risk climbs when such patients start on an ACE inhibitor or ARB and then switch to sacubitril-valsartan, compared with those prescribed the newer drug, the only available angiotensin receptor-neprilysin inhibitor (ARNI), in the first place.

Those findings and others from a large database analysis, by researchers at the Food and Drug Administration and Harvard Medical School, may clarify and help alleviate a residual safety concern about the ARNI – that it might promote angioedema – that persists after the drug’s major HF trials.  

The angioedema risk increased the most right after the switch to the ARNI from one of the older RAS inhibitors. For example, the overall risk doubled for patients who started with an ARB then switched to sacubitril-valsartan, compared with those who started on the newer drug. But it went up about 2.5 times during the first 14 days after the switch.

A similar pattern emerged for ACE inhibitors, but the increased angioedema risk reached significance only within 2 weeks of the switch from an ACE inhibitor to sacubitril-valsartan compared to starting on the latter.

The analysis, based on data from the FDA’s Sentinel adverse event reporting system, was published in the Journal of the American College of Cardiology.
 

A rare complication, but ...

Angioedema was rare overall in the study, with an unadjusted rate of about 6.75 per 1,000 person-years for users of ACE inhibitors, less than half that rate for ARB users, and only one-fifth that rate for sacubitril-valsartan recipients.

But even a rare complication can be a worry for drugs as widely used as RAS inhibitors. And it’s not unusual for patients cautiously started on an ACE inhibitor or ARB to be switched to sacubitril-valsartan, which is only recently a core guideline–recommended therapy for HF with reduced ejection fraction.

Such patients transitioning to the ARNI, the current study suggests, should probably be watched closely for signs of angioedema for 2 weeks but especially during the first few days. Indeed, the study’s event curves show most of the extra risk “popping up” right after the switch to sacubitril-valsartan, lead author Efe Eworuke, PhD, told this news organization.

The ARNI’s labeling, which states the drug should follow ACE inhibitors only after 36-hour washout period, “has done justice to this issue,” she said. But “whether clinicians are adhering to that, we can’t tell.”

Potentially, patients who miss the 36-hour washout between ACE inhibitors or ARBs and sacubitril-valsartan may account for the excess angioedema risk seen in the analysis, said Dr. Eworuke, with the FDA’s Center for Drug Evaluation and Research, Silver Spring, Md.

But the analysis doesn’t nail down the window of excess risk to only 36 hours. It suggests that patients switching to the ARNI – even those pausing for 36 hours in between drugs – should probably be monitored “2 weeks or longer,” she said. “They could still have angioedema after the washout period.”

Indeed, the “timing of the switch may be critical,” according to an editorial accompanying the report. “Perhaps a longer initial exposure period of ACE inhibitor or ARB,” beyond 2 weeks, “should be considered before switching to an ARNI,” contended Robert L. Page II, PharmD, MSPH, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora.

American Heart Association

Moreover, he wrote, the study suggests that “initiation of an ARNI de novo may be safer compared with trialing an ACE inhibitor or ARB then switching to an ARNI,” and “should be a consideration when beginning guideline-directed medical therapy for patients with HF.”
 

New RAS inhibition with ARNI ‘protective’

Compared with ARNI “new users” who had not received any RAS inhibitor in the prior 6 months, patients in the study who switched from an ACE inhibitor to ARNI (41,548 matched pairs) showed a hazard ratio (HR) for angioedema of 1.62 (95% confidence interval [CI], 0.91-2.89), that is, only a “trend,” the report states.

But that trend became significant when the analysis considered only angioedema cases in the first 14 days after the drug switch: HR, 1.98 (95% CI, 1.11-3.53).

Those switching from an ARB to ARNI, compared with ARNI new users (37,893 matched pairs), showed a significant HR for angioedema of 2.03 (95% CI, 1.16-3.54). The effect was more pronounced when considering only angioedema arising in the first 2 weeks: HR, 2.45 (95% CI, 1.36-4.43).

Compared with new use of ACE inhibitors, new ARNI use (41,998 matched pairs) was “protective,” the report states, with an HR for angioedema of 0.18 (95% CI, 0.11-0.29). So was a switch from ACE inhibitors to the ARNI (69,639 matched pairs), with an HR of 0.31 (95% CI, 0.23-0.43).

But compared with starting with an ARB, ARNI new use (43,755 matched pairs) had a null effect on angioedema risk, HR, 0.59 (95% CI, 0.35-1.01); as did switching from an ARB to ARNI (49,137 matched pairs), HR, 0.85 (95% CI, 0.58-1.26).

The analysis has limitations, Dr. Eworuke acknowledged. The comparator groups probably differed in unknown ways given the limits of propensity matching, for example, and because the FDA’s Sentinel system data can reflect only cases that are reported, the study probably underestimates the true prevalence of angioedema.

For example, a patient may see a clinician for a milder case that resolves without a significant intervention, she noted. But “those types of angioedema would not have been captured by our study.”

Dr. Eworuke disclosed that her comments reflect her views and are not those of the Food and Drug Administration; she and the other authors, as well as editorialist Dr. Page, report no relevant financial relationships.

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

New renin-angiotensin-system (RAS) inhibitor therapy using sacubitril-valsartan (Entresto) is no more likely to cause angioedema than starting out with an ACE inhibitor or angiotensin receptor blocker (ARB).

But the risk climbs when such patients start on an ACE inhibitor or ARB and then switch to sacubitril-valsartan, compared with those prescribed the newer drug, the only available angiotensin receptor-neprilysin inhibitor (ARNI), in the first place.

Those findings and others from a large database analysis, by researchers at the Food and Drug Administration and Harvard Medical School, may clarify and help alleviate a residual safety concern about the ARNI – that it might promote angioedema – that persists after the drug’s major HF trials.  

The angioedema risk increased the most right after the switch to the ARNI from one of the older RAS inhibitors. For example, the overall risk doubled for patients who started with an ARB then switched to sacubitril-valsartan, compared with those who started on the newer drug. But it went up about 2.5 times during the first 14 days after the switch.

A similar pattern emerged for ACE inhibitors, but the increased angioedema risk reached significance only within 2 weeks of the switch from an ACE inhibitor to sacubitril-valsartan compared to starting on the latter.

The analysis, based on data from the FDA’s Sentinel adverse event reporting system, was published in the Journal of the American College of Cardiology.
 

A rare complication, but ...

Angioedema was rare overall in the study, with an unadjusted rate of about 6.75 per 1,000 person-years for users of ACE inhibitors, less than half that rate for ARB users, and only one-fifth that rate for sacubitril-valsartan recipients.

But even a rare complication can be a worry for drugs as widely used as RAS inhibitors. And it’s not unusual for patients cautiously started on an ACE inhibitor or ARB to be switched to sacubitril-valsartan, which is only recently a core guideline–recommended therapy for HF with reduced ejection fraction.

Such patients transitioning to the ARNI, the current study suggests, should probably be watched closely for signs of angioedema for 2 weeks but especially during the first few days. Indeed, the study’s event curves show most of the extra risk “popping up” right after the switch to sacubitril-valsartan, lead author Efe Eworuke, PhD, told this news organization.

The ARNI’s labeling, which states the drug should follow ACE inhibitors only after 36-hour washout period, “has done justice to this issue,” she said. But “whether clinicians are adhering to that, we can’t tell.”

Potentially, patients who miss the 36-hour washout between ACE inhibitors or ARBs and sacubitril-valsartan may account for the excess angioedema risk seen in the analysis, said Dr. Eworuke, with the FDA’s Center for Drug Evaluation and Research, Silver Spring, Md.

But the analysis doesn’t nail down the window of excess risk to only 36 hours. It suggests that patients switching to the ARNI – even those pausing for 36 hours in between drugs – should probably be monitored “2 weeks or longer,” she said. “They could still have angioedema after the washout period.”

Indeed, the “timing of the switch may be critical,” according to an editorial accompanying the report. “Perhaps a longer initial exposure period of ACE inhibitor or ARB,” beyond 2 weeks, “should be considered before switching to an ARNI,” contended Robert L. Page II, PharmD, MSPH, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora.

American Heart Association

Moreover, he wrote, the study suggests that “initiation of an ARNI de novo may be safer compared with trialing an ACE inhibitor or ARB then switching to an ARNI,” and “should be a consideration when beginning guideline-directed medical therapy for patients with HF.”
 

New RAS inhibition with ARNI ‘protective’

Compared with ARNI “new users” who had not received any RAS inhibitor in the prior 6 months, patients in the study who switched from an ACE inhibitor to ARNI (41,548 matched pairs) showed a hazard ratio (HR) for angioedema of 1.62 (95% confidence interval [CI], 0.91-2.89), that is, only a “trend,” the report states.

But that trend became significant when the analysis considered only angioedema cases in the first 14 days after the drug switch: HR, 1.98 (95% CI, 1.11-3.53).

Those switching from an ARB to ARNI, compared with ARNI new users (37,893 matched pairs), showed a significant HR for angioedema of 2.03 (95% CI, 1.16-3.54). The effect was more pronounced when considering only angioedema arising in the first 2 weeks: HR, 2.45 (95% CI, 1.36-4.43).

Compared with new use of ACE inhibitors, new ARNI use (41,998 matched pairs) was “protective,” the report states, with an HR for angioedema of 0.18 (95% CI, 0.11-0.29). So was a switch from ACE inhibitors to the ARNI (69,639 matched pairs), with an HR of 0.31 (95% CI, 0.23-0.43).

But compared with starting with an ARB, ARNI new use (43,755 matched pairs) had a null effect on angioedema risk, HR, 0.59 (95% CI, 0.35-1.01); as did switching from an ARB to ARNI (49,137 matched pairs), HR, 0.85 (95% CI, 0.58-1.26).

The analysis has limitations, Dr. Eworuke acknowledged. The comparator groups probably differed in unknown ways given the limits of propensity matching, for example, and because the FDA’s Sentinel system data can reflect only cases that are reported, the study probably underestimates the true prevalence of angioedema.

For example, a patient may see a clinician for a milder case that resolves without a significant intervention, she noted. But “those types of angioedema would not have been captured by our study.”

Dr. Eworuke disclosed that her comments reflect her views and are not those of the Food and Drug Administration; she and the other authors, as well as editorialist Dr. Page, report no relevant financial relationships.

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

The Food and Drug Administration has granted accelerated approval to pirtobrutinib (Jaypirca) for relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton’s tyrosine kinase inhibitor.

Pirtobrutinib is the first and only noncovalent Bruton’s tyrosine kinase inhibitor approved for use in this MCL setting, manufacturer Eli Lilly noted in a press release.

“The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent Bruton’s tyrosine kinase inhibitor,” senior author Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, said in the release.

The approval was based on efficacy demonstrated in the open-label, single-arm, phase 1/2 BRUIN trial – a multicenter study assessing 200 mg once-daily oral pirtobrutinib monotherapy in 120 patients with MCL who had previously received a Bruton’s tyrosine kinase inhibitor, most often ibrutinib (Imbruvica, 67%) acalabrutinib (Calquence, 30%) and zanubrutinib (Brukinsa, 8%). Pirtobrutinib was continued until disease progression or unacceptable toxicity.

Study participants had a median of three prior lines of therapy, and 83% discontinued their last Bruton’s tyrosine kinase inhibitor because of refractory or progressive disease.

The overall response rate in pirtobrutinib-treated patients was 50% with a complete response rate of 13%. Estimated median duration of response was 8.3 months, and the estimated duration of response at 6 months occurred in nearly two-thirds of patients.

Adverse reactions that occurred in at least 15% of patients included fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included decreased neutrophil counts, lymphocyte counts, and platelet counts.

Prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies, noted the FDA, which granted priority review, fast track designation, and orphan drug designation for the application submitted by Eli Lilly.

“Jaypirca can reestablish Bruton’s tyrosine kinase inhibition in MCL patients previously treated with a covalent Bruton’s tyrosine kinase inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the Bruton’s tyrosine kinase pathway,” according to Eli Lilly’s release.

Dr. Wang added that the agent “has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients.”

Meghan Gutierrez, CEO at the Lymphoma Research Foundation, also noted that “the approval of Jaypirca brings a new treatment option and, along with that, new hope for people with relapsed or refractory MCL.”

The drug is expected to be available in the United States in the coming weeks, and the confirmatory phase 3 BRUIN trial is currently enrolling patients, Eli Lilly announced. The company also indicated the list price would be $21,000 for a 30-day supply of the 200-mg dose.

Serious adverse events believed to be associated with the use of pirtobrutinib or any medicine or device should be reported to the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

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

The Food and Drug Administration has granted accelerated approval to pirtobrutinib (Jaypirca) for relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton’s tyrosine kinase inhibitor.

Pirtobrutinib is the first and only noncovalent Bruton’s tyrosine kinase inhibitor approved for use in this MCL setting, manufacturer Eli Lilly noted in a press release.

“The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent Bruton’s tyrosine kinase inhibitor,” senior author Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, said in the release.

The approval was based on efficacy demonstrated in the open-label, single-arm, phase 1/2 BRUIN trial – a multicenter study assessing 200 mg once-daily oral pirtobrutinib monotherapy in 120 patients with MCL who had previously received a Bruton’s tyrosine kinase inhibitor, most often ibrutinib (Imbruvica, 67%) acalabrutinib (Calquence, 30%) and zanubrutinib (Brukinsa, 8%). Pirtobrutinib was continued until disease progression or unacceptable toxicity.

Study participants had a median of three prior lines of therapy, and 83% discontinued their last Bruton’s tyrosine kinase inhibitor because of refractory or progressive disease.

The overall response rate in pirtobrutinib-treated patients was 50% with a complete response rate of 13%. Estimated median duration of response was 8.3 months, and the estimated duration of response at 6 months occurred in nearly two-thirds of patients.

Adverse reactions that occurred in at least 15% of patients included fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included decreased neutrophil counts, lymphocyte counts, and platelet counts.

Prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies, noted the FDA, which granted priority review, fast track designation, and orphan drug designation for the application submitted by Eli Lilly.

“Jaypirca can reestablish Bruton’s tyrosine kinase inhibition in MCL patients previously treated with a covalent Bruton’s tyrosine kinase inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the Bruton’s tyrosine kinase pathway,” according to Eli Lilly’s release.

Dr. Wang added that the agent “has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients.”

Meghan Gutierrez, CEO at the Lymphoma Research Foundation, also noted that “the approval of Jaypirca brings a new treatment option and, along with that, new hope for people with relapsed or refractory MCL.”

The drug is expected to be available in the United States in the coming weeks, and the confirmatory phase 3 BRUIN trial is currently enrolling patients, Eli Lilly announced. The company also indicated the list price would be $21,000 for a 30-day supply of the 200-mg dose.

Serious adverse events believed to be associated with the use of pirtobrutinib or any medicine or device should be reported to the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

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

The Food and Drug Administration has granted accelerated approval to pirtobrutinib (Jaypirca) for relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton’s tyrosine kinase inhibitor.

Pirtobrutinib is the first and only noncovalent Bruton’s tyrosine kinase inhibitor approved for use in this MCL setting, manufacturer Eli Lilly noted in a press release.

“The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent Bruton’s tyrosine kinase inhibitor,” senior author Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, said in the release.

The approval was based on efficacy demonstrated in the open-label, single-arm, phase 1/2 BRUIN trial – a multicenter study assessing 200 mg once-daily oral pirtobrutinib monotherapy in 120 patients with MCL who had previously received a Bruton’s tyrosine kinase inhibitor, most often ibrutinib (Imbruvica, 67%) acalabrutinib (Calquence, 30%) and zanubrutinib (Brukinsa, 8%). Pirtobrutinib was continued until disease progression or unacceptable toxicity.

Study participants had a median of three prior lines of therapy, and 83% discontinued their last Bruton’s tyrosine kinase inhibitor because of refractory or progressive disease.

The overall response rate in pirtobrutinib-treated patients was 50% with a complete response rate of 13%. Estimated median duration of response was 8.3 months, and the estimated duration of response at 6 months occurred in nearly two-thirds of patients.

Adverse reactions that occurred in at least 15% of patients included fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included decreased neutrophil counts, lymphocyte counts, and platelet counts.

Prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies, noted the FDA, which granted priority review, fast track designation, and orphan drug designation for the application submitted by Eli Lilly.

“Jaypirca can reestablish Bruton’s tyrosine kinase inhibition in MCL patients previously treated with a covalent Bruton’s tyrosine kinase inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the Bruton’s tyrosine kinase pathway,” according to Eli Lilly’s release.

Dr. Wang added that the agent “has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients.”

Meghan Gutierrez, CEO at the Lymphoma Research Foundation, also noted that “the approval of Jaypirca brings a new treatment option and, along with that, new hope for people with relapsed or refractory MCL.”

The drug is expected to be available in the United States in the coming weeks, and the confirmatory phase 3 BRUIN trial is currently enrolling patients, Eli Lilly announced. The company also indicated the list price would be $21,000 for a 30-day supply of the 200-mg dose.

Serious adverse events believed to be associated with the use of pirtobrutinib or any medicine or device should be reported to the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

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

A small potential increased risk of retinopathy worsening at 1 year with injected semaglutide (Ozempic, Novo Nordisk), a glucagon-like peptide 1 (GLP-1) agonist approved for type 2 diabetes, doesn’t outweigh the drug’s cardiovascular benefits but does highlight the need for baseline ophthalmologic evaluation before initiating treatment and ongoing retinal monitoring, researchers say.

That conclusion was based on data from a meta-analysis of the seven major cardiovascular outcomes trials of GLP-1 agonists currently on the market.

memorisz/iStock/Getty Images

The findings were recently published in Diabetes & Metabolic Syndrome: Clinical Research & Reviews, by Stewart G. Albert, MD, and colleagues.

Concerns about retinopathy worsening with the GLP-1 agonist drug class first arose from the SUSTAIN-6 cardiovascular outcomes trial for injectable semaglutide, although a subsequent analysis of data from that trial appeared to suggest the problem is likely due to rapid glucose-lowering in already vulnerable patients rather than a drug-specific effect. This effect had been previously reported, most notably in the landmark Diabetes Control and Complications Trial.

In this new meta-analysis, “we showed that with improvements in A1c there were correlations with decreases in the rate of cardiovascular events but increases in the rate of retinopathy,” Dr. Albert, of St. Louis University, told this news organization.

“As a class of drugs, we did not find an increased rate of retinopathy. The effect of GLP-1 agonists on retinopathy did not appear to be due to an immediate direct toxic effect of the drug. The worsening of the rate of retinopathy was seen with semaglutide after 1 year of therapy and when there was a decrease in A1c of 1%,” he explained.

He noted that because the increased risk was seen primarily among those who already had retinopathy at baseline, “it would seem prudent to know the level of retinopathy either before or plan for close ophthalmologic monitoring around the time of drug initiation ... We routinely evaluate patients with known type 2 diabetes mellitus at yearly intervals for retinopathy. From our data, we saw worsening at 1 year of drug exposure, but we do not know the exact time when the changes occurred during that year.”

The Ozempic label advises that “patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy” but doesn’t specifically mention baseline assessment at the time of drug initiation.
 

No increase in retinopathy risk for GLP-1 agonist class overall

The seven trials in the meta-analysis comprised 56,004 participants, with baseline retinopathy prevalence ranging from 9% to 31%.

For the GLP-1 agonist class overall, there was no significant increase in the relative rate (RR) of retinopathy (RR, 1.09; P = .36), while there were significant reductions in relative rates of major adverse cardiac events, overall deaths, and cardiovascular deaths (all P < .001 or P = .001).

The increased retinopathy risk was seen only in the subcutaneous semaglutide group (RR, 1.73; P = .02).

The overall number needed to harm was 1,000 and the number to treat was 77. For semaglutide, those values were 77 and 43, respectively.

There was a significant correlation between a decrease in major adverse cardiac events and a decrease in A1c (P = .014), while for retinopathy, the risk increased with improved A1c (P = .076).
 

Semaglutide subanalysis finds increased retinopathy worsening

Dr. Albert and colleagues conducted a separate subanalysis of 11 studies of semaglutide that enrolled 11,894 patients, of which 6 studies (n = 5,610) were of oral semaglutide (Rybelsus) and 5 studies were of subcutaneous semaglutide (Ozempic; n = 6,284).

In the subanalysis, there was an overall increase in relative rates of new or worsening retinopathy (RR, 1.218; P = .049).

The change in relative rate of retinopathy was predominantly found for subcutaneous semaglutide given for longer than 1 year (RR, 1.559; P = .022) and decreases in A1c of more than 1.0% (RR, 1.590; P = .016). No such differences were seen with oral semaglutide.

A further evaluation of the data without the SUSTAIN 6 trial showed no effect on retinopathy but the analysis lacked power.

Dr. Albert told this news organization: “We did not find an immediate toxic effect of any drug. However, we cannot rule out that there was a cumulative effect of the dose over longer times.”

No disclosures were given.

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

A small potential increased risk of retinopathy worsening at 1 year with injected semaglutide (Ozempic, Novo Nordisk), a glucagon-like peptide 1 (GLP-1) agonist approved for type 2 diabetes, doesn’t outweigh the drug’s cardiovascular benefits but does highlight the need for baseline ophthalmologic evaluation before initiating treatment and ongoing retinal monitoring, researchers say.

That conclusion was based on data from a meta-analysis of the seven major cardiovascular outcomes trials of GLP-1 agonists currently on the market.

memorisz/iStock/Getty Images

The findings were recently published in Diabetes & Metabolic Syndrome: Clinical Research & Reviews, by Stewart G. Albert, MD, and colleagues.

Concerns about retinopathy worsening with the GLP-1 agonist drug class first arose from the SUSTAIN-6 cardiovascular outcomes trial for injectable semaglutide, although a subsequent analysis of data from that trial appeared to suggest the problem is likely due to rapid glucose-lowering in already vulnerable patients rather than a drug-specific effect. This effect had been previously reported, most notably in the landmark Diabetes Control and Complications Trial.

In this new meta-analysis, “we showed that with improvements in A1c there were correlations with decreases in the rate of cardiovascular events but increases in the rate of retinopathy,” Dr. Albert, of St. Louis University, told this news organization.

“As a class of drugs, we did not find an increased rate of retinopathy. The effect of GLP-1 agonists on retinopathy did not appear to be due to an immediate direct toxic effect of the drug. The worsening of the rate of retinopathy was seen with semaglutide after 1 year of therapy and when there was a decrease in A1c of 1%,” he explained.

He noted that because the increased risk was seen primarily among those who already had retinopathy at baseline, “it would seem prudent to know the level of retinopathy either before or plan for close ophthalmologic monitoring around the time of drug initiation ... We routinely evaluate patients with known type 2 diabetes mellitus at yearly intervals for retinopathy. From our data, we saw worsening at 1 year of drug exposure, but we do not know the exact time when the changes occurred during that year.”

The Ozempic label advises that “patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy” but doesn’t specifically mention baseline assessment at the time of drug initiation.
 

No increase in retinopathy risk for GLP-1 agonist class overall

The seven trials in the meta-analysis comprised 56,004 participants, with baseline retinopathy prevalence ranging from 9% to 31%.

For the GLP-1 agonist class overall, there was no significant increase in the relative rate (RR) of retinopathy (RR, 1.09; P = .36), while there were significant reductions in relative rates of major adverse cardiac events, overall deaths, and cardiovascular deaths (all P < .001 or P = .001).

The increased retinopathy risk was seen only in the subcutaneous semaglutide group (RR, 1.73; P = .02).

The overall number needed to harm was 1,000 and the number to treat was 77. For semaglutide, those values were 77 and 43, respectively.

There was a significant correlation between a decrease in major adverse cardiac events and a decrease in A1c (P = .014), while for retinopathy, the risk increased with improved A1c (P = .076).
 

Semaglutide subanalysis finds increased retinopathy worsening

Dr. Albert and colleagues conducted a separate subanalysis of 11 studies of semaglutide that enrolled 11,894 patients, of which 6 studies (n = 5,610) were of oral semaglutide (Rybelsus) and 5 studies were of subcutaneous semaglutide (Ozempic; n = 6,284).

In the subanalysis, there was an overall increase in relative rates of new or worsening retinopathy (RR, 1.218; P = .049).

The change in relative rate of retinopathy was predominantly found for subcutaneous semaglutide given for longer than 1 year (RR, 1.559; P = .022) and decreases in A1c of more than 1.0% (RR, 1.590; P = .016). No such differences were seen with oral semaglutide.

A further evaluation of the data without the SUSTAIN 6 trial showed no effect on retinopathy but the analysis lacked power.

Dr. Albert told this news organization: “We did not find an immediate toxic effect of any drug. However, we cannot rule out that there was a cumulative effect of the dose over longer times.”

No disclosures were given.

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

A small potential increased risk of retinopathy worsening at 1 year with injected semaglutide (Ozempic, Novo Nordisk), a glucagon-like peptide 1 (GLP-1) agonist approved for type 2 diabetes, doesn’t outweigh the drug’s cardiovascular benefits but does highlight the need for baseline ophthalmologic evaluation before initiating treatment and ongoing retinal monitoring, researchers say.

That conclusion was based on data from a meta-analysis of the seven major cardiovascular outcomes trials of GLP-1 agonists currently on the market.

memorisz/iStock/Getty Images

The findings were recently published in Diabetes & Metabolic Syndrome: Clinical Research & Reviews, by Stewart G. Albert, MD, and colleagues.

Concerns about retinopathy worsening with the GLP-1 agonist drug class first arose from the SUSTAIN-6 cardiovascular outcomes trial for injectable semaglutide, although a subsequent analysis of data from that trial appeared to suggest the problem is likely due to rapid glucose-lowering in already vulnerable patients rather than a drug-specific effect. This effect had been previously reported, most notably in the landmark Diabetes Control and Complications Trial.

In this new meta-analysis, “we showed that with improvements in A1c there were correlations with decreases in the rate of cardiovascular events but increases in the rate of retinopathy,” Dr. Albert, of St. Louis University, told this news organization.

“As a class of drugs, we did not find an increased rate of retinopathy. The effect of GLP-1 agonists on retinopathy did not appear to be due to an immediate direct toxic effect of the drug. The worsening of the rate of retinopathy was seen with semaglutide after 1 year of therapy and when there was a decrease in A1c of 1%,” he explained.

He noted that because the increased risk was seen primarily among those who already had retinopathy at baseline, “it would seem prudent to know the level of retinopathy either before or plan for close ophthalmologic monitoring around the time of drug initiation ... We routinely evaluate patients with known type 2 diabetes mellitus at yearly intervals for retinopathy. From our data, we saw worsening at 1 year of drug exposure, but we do not know the exact time when the changes occurred during that year.”

The Ozempic label advises that “patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy” but doesn’t specifically mention baseline assessment at the time of drug initiation.
 

No increase in retinopathy risk for GLP-1 agonist class overall

The seven trials in the meta-analysis comprised 56,004 participants, with baseline retinopathy prevalence ranging from 9% to 31%.

For the GLP-1 agonist class overall, there was no significant increase in the relative rate (RR) of retinopathy (RR, 1.09; P = .36), while there were significant reductions in relative rates of major adverse cardiac events, overall deaths, and cardiovascular deaths (all P < .001 or P = .001).

The increased retinopathy risk was seen only in the subcutaneous semaglutide group (RR, 1.73; P = .02).

The overall number needed to harm was 1,000 and the number to treat was 77. For semaglutide, those values were 77 and 43, respectively.

There was a significant correlation between a decrease in major adverse cardiac events and a decrease in A1c (P = .014), while for retinopathy, the risk increased with improved A1c (P = .076).
 

Semaglutide subanalysis finds increased retinopathy worsening

Dr. Albert and colleagues conducted a separate subanalysis of 11 studies of semaglutide that enrolled 11,894 patients, of which 6 studies (n = 5,610) were of oral semaglutide (Rybelsus) and 5 studies were of subcutaneous semaglutide (Ozempic; n = 6,284).

In the subanalysis, there was an overall increase in relative rates of new or worsening retinopathy (RR, 1.218; P = .049).

The change in relative rate of retinopathy was predominantly found for subcutaneous semaglutide given for longer than 1 year (RR, 1.559; P = .022) and decreases in A1c of more than 1.0% (RR, 1.590; P = .016). No such differences were seen with oral semaglutide.

A further evaluation of the data without the SUSTAIN 6 trial showed no effect on retinopathy but the analysis lacked power.

Dr. Albert told this news organization: “We did not find an immediate toxic effect of any drug. However, we cannot rule out that there was a cumulative effect of the dose over longer times.”

No disclosures were given.

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