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Comparison of Prescribing Patterns of Intranasal Naloxone in a Veteran Population
Comparison of Prescribing Patterns of Intranasal Naloxone in a Veteran Population
Since 1999, annual deaths attributed to opioid overdose in the United States have increased from about 10,000 to about 50,000 in 2019.1 During the COVID-19 pandemic > 74,000 opioid overdose deaths occurred in the US from April 2020 to April 2021.2,3 Opioid-related overdoses now account for about 75% of all drug-related overdose deaths.1 In 2017, the cost of opioid overdose deaths and opioid use disorder (OUD) reached $1.02 trillion in the United States and $26 million in Indiana.4 The total deaths and costs would likely be higher if it were not for naloxone.
Naloxone hydrochloride was first patented in the 1960s and approved by the US Food and Drug Administration (FDA) in 1971 to treat opioid-related toxicity.1 It is the most frequently prescribed antidote for opioid toxicity due to its activity as a pure υ-opioid receptor competitive antagonist. Naloxone formulations include intramuscular, intravenous, subcutaneous, and intranasal delivery methods.5 According to the Centers for Disease Control and Prevention, clinicians should offer naloxone to patients at high risk for opioid-related adverse events. Risk factors include a history of overdose, opioid dosages of ≥ 50 morphine mg equivalents/day, and concurrent use of opioids with benzodiazepines.6
Intranasal naloxone 4 mg has become more accessible following the classification of opioid use as a public health emergency in 2017 and its over-the-counter availability since 2023. Intranasal naloxone 4 mg was approved by the FDA in 2015 for the prevention of opioid overdoses (accidental or intentional), which can be caused by heroin, fentanyl, carfentanil, hydrocodone, oxycodone, methadone, and other substances. 7 Fentanyl has most recently been associated with xylazine, a nonopioid tranquilizer linked to increased opioid overdose deaths.8 Recent data suggest that 34% of opioid overdose reversals involved ≥ 2 doses of intranasal naloxone 4 mg, which led to FDA approval of an intranasal naloxone 8 mg spray in April 2021.9-11
Veteran Health Indiana (VHI) has implemented several initiatives to promote naloxone prescribing. Established in 2020, the Opioid Overdose Education and Naloxone Distribution (OEND) program sought to prevent opioid-related deaths through education and product distribution. These criteria included an opioid prescription for ≥ 30 days. In 2021, the Stratification Tool for Opioid Risk Mitigation (STORM) was created to identify patients at high risk of opioid overdose and allowing pharmacists to prescribe naloxone for at-risk patients without restrictions, increasing accessibility.12
Recent cases of fentanyl-related overdoses involving stronger fentanyl analogues highlight the need for higher naloxone dosing to prevent overdose. A pharmacokinetic comparison of intranasal naloxone 8 mg vs 4 mg demonstrated maximum plasma concentrations of 10.3 ng/mL and 5.3 ng/mL, respectively. 13 Patients may be at an increased risk of precipitated opioid withdrawal when using intranasal naloxone 8 mg over 4 mg; however, some patients may benefit from achieving higher serum concentrations and therefore require larger doses of naloxone.
No clinical trials have demonstrated a difference in reversal rates between naloxone doses. No clinical practice guidelines support a specific naloxone formulation, and limited US Department of Veterans Affairs (VA)-specific guidance exists. VA Naloxone Rescue: Recommendations for Use states that selection of naloxone 8 mg should be based on shared decision-making between the patient and clinician and based on individual risk factors.12 The purpose of this study is to analyze data to determine if there is a difference in prescribing patterns of intranasal naloxone 4 mg and intranasal naloxone 8 mg.
METHODS
A retrospective chart reviews using the VA Computerized Patient Record System (CPRS) analyzed patients prescribed intranasal naloxone 4 mg or intranasal naloxone 8 mg at VHI. A patient list was generated based on active naloxone prescriptions between April 1, 2022, and April 1, 2023. Data were obtained exclusively through CPRS and patients were not contacted. This study was reviewed and deemed exempt by the Indiana University Health Institutional Review Board and the VHI Research and Development Committee.
Patients were included if they were aged ≥ 18 years and had an active prescription for intranasal naloxone 4 mg or intranasal naloxone 8 mg during the trial period. Patients were excluded if their naloxone prescription was written by a non-VHI clinician, if the dose was not 4 mg or 8 mg, or if the dosage form was other than intranasal spray.
The primary endpoint was the comparison for prescribing patterns for intranasal naloxone 4 mg and intranasal naloxone 8 mg during the study period. Secondary endpoints included total naloxone prescriptions; monthly prescriptions; number of patients with repeated naloxone prescriptions; prescriber type by naloxone dose; clinic type by naloxone dose; and documented indication for naloxone use by dose.
Demographic data collected included baseline age, sex, race, comorbid mental health conditions, and active central nervous system depressant medications on patient profile (ie, opioids, gabapentinoids, benzodiazepines, antidepressants, antipsychotics). Opioid prescriptions that were active or discontinued within the last 3 months were also recorded. Comorbid mental health conditions were collected based on the most recent clinical note before initiating medication.
Prescription-related data included strength of medication prescribed (4 mg, 8 mg, or both), documented use of medication, prescriber name, prescriber discipline, prescription entered by, number of times naloxone was filled or refilled during the study period, indication, clinic location, and clinic name. If > 1 prescription was active during the study period, the number of refills, prescriber name and clinic location of the first prescription in the study period was recorded. Additionally, the indication of OUD was differentiated from substance use disorder (SUD) if the patient was only dependent on opioids, excluding tobacco or alcohol. Patients with SUDs may include opioid dependence in addition to other substance dependence (eg, cannabis, stimulants, gabapentinoids, or benzodiazepines).
Basic descriptive statistics, including mean, ranges, and percentages were used to characterize the study subjects. For nominal data, X2 tests were used. A 2-sided 5% significance level was used for all statistical tests.
RESULTS
A total of 1952 active naloxone prescriptions from 1739 patients met the inclusion criteria; none were eliminated based on the exclusion criteria and some were included multiple times because data were collected for each active prescription during the study period. One hundred one patients were randomized and included in the final analysis (Figure). Most patients identified as White (81%), male (90%), and had a mean (SD) age of 60.9 (14.2) years. Common mental health comorbidities included 59 patients with depression, 50 with tobacco use disorder, and 31 with anxiety. Eighty-four patients had opioid and 60 had antidepressants/antianxiety, and 40 had gabapentinoids prescriptions. Forty-three patients had ≥ 3 mental health comorbidities. Thirty-four patients had 2 active central nervous system depressant prescriptions, 30 had 3 active prescriptions, and 9 had ≥ 4 active prescriptions. Most patients (n = 83) had an active or recently discontinued opioid prescription (Table 1).
The 101 patients received 54 prescriptions for naloxone 8 mg and 47 for 4 mg (Table 2). Five patients received prescriptions for both the 4 mg and 8 mg intranasal naloxone formulations. Sixty-six patients had naloxone filled once (66%) during the study period. Intranasal naloxone 4 mg was prescribed to 30 patients by nurse practitioners, 17 patients by physicians, and not prescribed by pharmacists. Intranasal naloxone 8 mg was prescribed to 40 patients by pharmacists, 13 patients by physicians, and 6 patients by nurses. Patients who received prescriptions for both intranasal naloxone 4 mg and 8 mg were most routinely ordered by physicians (n = 3; 60%) in primary care (n = 2; 40%) for chronic opioid use (n = 2; 40%).
Patients access naloxone from many different VHI clinics. Primary care clinics prescribed the 4 mg formulation to 31 patients, 8 mg to 3 patients, and both to 2 patients. The STORM initiative was used for 37 of 106 prescriptions (35%): 4 mg intranasal naloxone was prescribed to 1 patient, 8 mg to 36 patients, and no patients received both formulations. Chronic opioid use was the most common indication (46%) with 30 patients prescribed intranasal naloxone 4 mg, 14 patients prescribed 8 mg, and 2 patients prescribed both. OUD was the indication for 24% of patients: 2 patients prescribed intranasal naloxone 4 mg, 21 patients prescribed 8 mg, and 1 patient prescribed both.
The 106 intranasal naloxone prescriptions were equally distributed across each month from April 1, 2022, to April 1, 2023. Of the 101 patients, 34 had multiple naloxone prescriptions filled during the study period. Pharmacists wrote 40 of 106 naloxone prescriptions (38%), all for the 8 mg formulation. Nurse practitioners prescribed naloxone 4 mg 30 times and 8 mg 6 times for 36 of 106 prescriptions (34%). Physicians prescribed 30 of 106 prescriptions (28%), including intranasal naloxone 4 mg 17 times and 8 mg 13 times.
Statistics were analyzed using a X2 test; however, it was determined that the expected frequencies made the tests inappropriate. Differences in prescribing patterns between naloxone doses, prescriber disciplines, source of the prescription, or indications were not statistically significant.
DISCUSSION
Many pharmacists possess a scope of practice under state law and/or institution policy to prescribe naloxone. In this study, pharmacists prescribed the most naloxone prescriptions compared to physicians and nurse practitioners. Initiatives such as OEND and STORM have given pharmacists at VHI an avenue to combat the growing opioid epidemic while expanding their scope of practice. A systematic review of 67 studies found that pharmacist-led OEND programs showed a statistically significant increase in naloxone orders. A statistical significance was likely met given the large sample sizes ranging from 10 to 217,000 individuals, whereas this study only assessed a small portion of patients.14 This study contributes to the overwhelming amount of data that highlights pharmacists’ impact on overall naloxone distribution.
The STORM initiative and primary care clinics were responsible for large portions of naloxone prescriptions in this study. STORM was used by pharmacists and contributed to more than half of the higher dose naloxone prescriptions. Following a discussion with members of the pain management team, pharmacists involved in STORM prescribing were revealed to exclusively prescribe intranasal naloxone 8 mg as opposed to 4 mg. At the risk of precipitating withdrawal from higher doses of naloxone, it was agreed that this risk was heavily outweighed by the benefit of successful opioid reversal. In this context, it is expected for this avenue of prescribing to influence naloxone prescribing patterns at VHI.
Prescribing in primary care clinics was shown to be equally as substantial. Primary care-based multidisciplinary transition clinics have been reported to be associated with increased access to OUD treatment.15 Primary care clinics at VHI, or patient aligned care teams (PACT), largely consist of multidisciplinary health care teams. PACT clinicians are heavily involved in transitions of care because one system provides patients with comprehensive acute and chronic care. Continuing to encourage naloxone distribution through primary care and using STORM affords various patient populations access to high-level care.
Notable differences were observed between indications for naloxone use and the corresponding dose. Patients with OUD or SUD were more likely to receive intranasal naloxone 8 mg as opposed to patients receiving intranasal naloxone for chronic opioid use, who were more likely to receive the 4 mg dose. This may be due to a rationale to provide a higher dose of naloxone to combat overdoses in the case of ingesting substances mixed with fentanyl or xylazine.12,13 Without standard of care guidelines, concerns remain for varying outcomes in opioid overdose prevention within vulnerable populations.
Limitations
Chart data were dependent on documentation, which may have omitted pertinent baseline characteristics and risk factors. Additional data collection could have further assessed a patient’s specific risk factors (eg, opioid dose in morphine equivalents) to draw conclusions to the dose of naloxone prescribed. The sample size was small, and the patient population was largely White and male, which minimized the generalizability of the results.
CONCLUSIONS
This study evaluated the differences in intranasal naloxone prescribing patterns within a veteran population at VHI over 12 months. Findings revealed that most prescriptions were written for intranasal naloxone 8 mg, by a pharmacist, in a primary care setting, and for chronic opioid use. The results revealed evidence of differing naloxone prescribing practices, which emphasize the need for clinical guidelines and better defined recommendations in relation to naloxone dosing.
The most evident gap in patient care could be addressed by urging the VA Pharmacy Benefits Management group to update naloxone recommendations for use to include more concrete dosing recommendations. Furthermore, it would be beneficial to re-educate clinicians on naloxone prescribing to increase awareness of different doses and the importance of equipping patients with the correct amount of naloxone in an emergency. Additional research assessing change in prescribing patterns is warranted as the use of higher dose naloxone becomes more routine.
- Britch SC, Walsh SL. Treatment of opioid overdose: current approaches and recent advances. Psychopharmacology (Berl). 2022;239(7):2063-2081. doi:10.1007/s00213-022-06125-5
- Ahmad FB, Cisewski JA, Rossen LM, Sutton P. Provisional Drug Overdose Death Counts. National Center for Health Statistics, Centers for Disease Control and Prevention; 2023. Accessed April 10, 2025. https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm
- O’Donnell J, Tanz LJ, Gladden RM, Davis NL, Bitting J. Trends in and characteristics of drug overdose deaths involving illicitly manufactured fentanyls — United States, 2019–2020. MMWR Morb Mortal Wkly Rep. 2021;70:1740-1746. doi:10.15585/mmwr.mm7050e3
- Luo F, Li M, Florence C. State-level economic costs of opioid use disorder and fatal opioid overdose — United States, 2017. MMWR Morb Mortal Wkly Rep. 2021;70:541-546. doi:10.15585/mmwr.mm7015a1
- Lexicomp. Lexicomp Online. Accessed April 10, 2025. http://online.lexi.com
- Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC Clinical practice guideline for prescribing opioids for pain — United States, 2022. MMWR Recomm Rep. 2022;71(3):1-95. doi:10.15585/mmwr.rr7103a1
- Narcan (naloxone) FDA approval history. Drugs.com. Accessed April 10, 2025. https://www.drugs.com/history/narcan.html
- Centers for Disease Control and Prevention. What you should know about xylazine. May 16, 2024. Accessed April 10, 2025. https://www.cdc.gov/overdose-prevention/about/what-you-should-know-about-xylazine.html
- Avetian GK, Fiuty P, Mazzella S, Koppa D, Heye V, Hebbar P. Use of naloxone nasal spray 4 mg in the community setting: a survey of use by community organizations. Curr Med Res Opin. 2018;34(4):573-576. doi:10.1080/03007995.2017.1334637
- Kloxxado [package insert]. Hikma Pharmaceuticals USA Inc; 2021.
- FDA approves higher dosage of naloxone nasal spray to treat opioid overdose. News release. FDA. April 30, 2021. Accessed April 10, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-higher-dosage-naloxone-nasal-spray-treat-opioid-overdose
- US Department of Veterans Affairs, Pharmacy Benefits Management Services and National Formulary Committee in Collaboration with the VA National Harm Reduction Support & Development Workgroup. Naloxone Rescue: Recommendations for Use. June 2014. Updated March 2024. Accessed April 10, 2025. https://www.va.gov/formularyadvisor/DOC_PDF/CRE_Naloxone_Rescue_Guidance_March_2024.pdf
- Krieter P, Chiang N, Gyaw S, et al. Pharmacokinetic properties and human use characteristics of an FDA-approved intranasal naloxone product for the treatment of opioid overdose. J Clin Pharmacol. 2016;56(10):1243-1253. doi:10.1002/jcph.759
- Rawal S, Osae SP, Cobran EK, Albert A, Young HN. Pharmacists’ naloxone services beyond community pharmacy settings: a systematic review. Res Social Adm Pharm. 2023;19(2):243-265. doi:10.1016/j.sapharm.2022.09.002
- Incze MA, Sehgal SL, Hansen A, Garcia L, Stolebarger L. Evaluation of a primary care-based multidisciplinary transition clinic for patients newly initiated on buprenorphine in the emergency department. Subst Abus. 2023;44(3):220-225. doi:10.1177/08897077231188592
Since 1999, annual deaths attributed to opioid overdose in the United States have increased from about 10,000 to about 50,000 in 2019.1 During the COVID-19 pandemic > 74,000 opioid overdose deaths occurred in the US from April 2020 to April 2021.2,3 Opioid-related overdoses now account for about 75% of all drug-related overdose deaths.1 In 2017, the cost of opioid overdose deaths and opioid use disorder (OUD) reached $1.02 trillion in the United States and $26 million in Indiana.4 The total deaths and costs would likely be higher if it were not for naloxone.
Naloxone hydrochloride was first patented in the 1960s and approved by the US Food and Drug Administration (FDA) in 1971 to treat opioid-related toxicity.1 It is the most frequently prescribed antidote for opioid toxicity due to its activity as a pure υ-opioid receptor competitive antagonist. Naloxone formulations include intramuscular, intravenous, subcutaneous, and intranasal delivery methods.5 According to the Centers for Disease Control and Prevention, clinicians should offer naloxone to patients at high risk for opioid-related adverse events. Risk factors include a history of overdose, opioid dosages of ≥ 50 morphine mg equivalents/day, and concurrent use of opioids with benzodiazepines.6
Intranasal naloxone 4 mg has become more accessible following the classification of opioid use as a public health emergency in 2017 and its over-the-counter availability since 2023. Intranasal naloxone 4 mg was approved by the FDA in 2015 for the prevention of opioid overdoses (accidental or intentional), which can be caused by heroin, fentanyl, carfentanil, hydrocodone, oxycodone, methadone, and other substances. 7 Fentanyl has most recently been associated with xylazine, a nonopioid tranquilizer linked to increased opioid overdose deaths.8 Recent data suggest that 34% of opioid overdose reversals involved ≥ 2 doses of intranasal naloxone 4 mg, which led to FDA approval of an intranasal naloxone 8 mg spray in April 2021.9-11
Veteran Health Indiana (VHI) has implemented several initiatives to promote naloxone prescribing. Established in 2020, the Opioid Overdose Education and Naloxone Distribution (OEND) program sought to prevent opioid-related deaths through education and product distribution. These criteria included an opioid prescription for ≥ 30 days. In 2021, the Stratification Tool for Opioid Risk Mitigation (STORM) was created to identify patients at high risk of opioid overdose and allowing pharmacists to prescribe naloxone for at-risk patients without restrictions, increasing accessibility.12
Recent cases of fentanyl-related overdoses involving stronger fentanyl analogues highlight the need for higher naloxone dosing to prevent overdose. A pharmacokinetic comparison of intranasal naloxone 8 mg vs 4 mg demonstrated maximum plasma concentrations of 10.3 ng/mL and 5.3 ng/mL, respectively. 13 Patients may be at an increased risk of precipitated opioid withdrawal when using intranasal naloxone 8 mg over 4 mg; however, some patients may benefit from achieving higher serum concentrations and therefore require larger doses of naloxone.
No clinical trials have demonstrated a difference in reversal rates between naloxone doses. No clinical practice guidelines support a specific naloxone formulation, and limited US Department of Veterans Affairs (VA)-specific guidance exists. VA Naloxone Rescue: Recommendations for Use states that selection of naloxone 8 mg should be based on shared decision-making between the patient and clinician and based on individual risk factors.12 The purpose of this study is to analyze data to determine if there is a difference in prescribing patterns of intranasal naloxone 4 mg and intranasal naloxone 8 mg.
METHODS
A retrospective chart reviews using the VA Computerized Patient Record System (CPRS) analyzed patients prescribed intranasal naloxone 4 mg or intranasal naloxone 8 mg at VHI. A patient list was generated based on active naloxone prescriptions between April 1, 2022, and April 1, 2023. Data were obtained exclusively through CPRS and patients were not contacted. This study was reviewed and deemed exempt by the Indiana University Health Institutional Review Board and the VHI Research and Development Committee.
Patients were included if they were aged ≥ 18 years and had an active prescription for intranasal naloxone 4 mg or intranasal naloxone 8 mg during the trial period. Patients were excluded if their naloxone prescription was written by a non-VHI clinician, if the dose was not 4 mg or 8 mg, or if the dosage form was other than intranasal spray.
The primary endpoint was the comparison for prescribing patterns for intranasal naloxone 4 mg and intranasal naloxone 8 mg during the study period. Secondary endpoints included total naloxone prescriptions; monthly prescriptions; number of patients with repeated naloxone prescriptions; prescriber type by naloxone dose; clinic type by naloxone dose; and documented indication for naloxone use by dose.
Demographic data collected included baseline age, sex, race, comorbid mental health conditions, and active central nervous system depressant medications on patient profile (ie, opioids, gabapentinoids, benzodiazepines, antidepressants, antipsychotics). Opioid prescriptions that were active or discontinued within the last 3 months were also recorded. Comorbid mental health conditions were collected based on the most recent clinical note before initiating medication.
Prescription-related data included strength of medication prescribed (4 mg, 8 mg, or both), documented use of medication, prescriber name, prescriber discipline, prescription entered by, number of times naloxone was filled or refilled during the study period, indication, clinic location, and clinic name. If > 1 prescription was active during the study period, the number of refills, prescriber name and clinic location of the first prescription in the study period was recorded. Additionally, the indication of OUD was differentiated from substance use disorder (SUD) if the patient was only dependent on opioids, excluding tobacco or alcohol. Patients with SUDs may include opioid dependence in addition to other substance dependence (eg, cannabis, stimulants, gabapentinoids, or benzodiazepines).
Basic descriptive statistics, including mean, ranges, and percentages were used to characterize the study subjects. For nominal data, X2 tests were used. A 2-sided 5% significance level was used for all statistical tests.
RESULTS
A total of 1952 active naloxone prescriptions from 1739 patients met the inclusion criteria; none were eliminated based on the exclusion criteria and some were included multiple times because data were collected for each active prescription during the study period. One hundred one patients were randomized and included in the final analysis (Figure). Most patients identified as White (81%), male (90%), and had a mean (SD) age of 60.9 (14.2) years. Common mental health comorbidities included 59 patients with depression, 50 with tobacco use disorder, and 31 with anxiety. Eighty-four patients had opioid and 60 had antidepressants/antianxiety, and 40 had gabapentinoids prescriptions. Forty-three patients had ≥ 3 mental health comorbidities. Thirty-four patients had 2 active central nervous system depressant prescriptions, 30 had 3 active prescriptions, and 9 had ≥ 4 active prescriptions. Most patients (n = 83) had an active or recently discontinued opioid prescription (Table 1).
The 101 patients received 54 prescriptions for naloxone 8 mg and 47 for 4 mg (Table 2). Five patients received prescriptions for both the 4 mg and 8 mg intranasal naloxone formulations. Sixty-six patients had naloxone filled once (66%) during the study period. Intranasal naloxone 4 mg was prescribed to 30 patients by nurse practitioners, 17 patients by physicians, and not prescribed by pharmacists. Intranasal naloxone 8 mg was prescribed to 40 patients by pharmacists, 13 patients by physicians, and 6 patients by nurses. Patients who received prescriptions for both intranasal naloxone 4 mg and 8 mg were most routinely ordered by physicians (n = 3; 60%) in primary care (n = 2; 40%) for chronic opioid use (n = 2; 40%).
Patients access naloxone from many different VHI clinics. Primary care clinics prescribed the 4 mg formulation to 31 patients, 8 mg to 3 patients, and both to 2 patients. The STORM initiative was used for 37 of 106 prescriptions (35%): 4 mg intranasal naloxone was prescribed to 1 patient, 8 mg to 36 patients, and no patients received both formulations. Chronic opioid use was the most common indication (46%) with 30 patients prescribed intranasal naloxone 4 mg, 14 patients prescribed 8 mg, and 2 patients prescribed both. OUD was the indication for 24% of patients: 2 patients prescribed intranasal naloxone 4 mg, 21 patients prescribed 8 mg, and 1 patient prescribed both.
The 106 intranasal naloxone prescriptions were equally distributed across each month from April 1, 2022, to April 1, 2023. Of the 101 patients, 34 had multiple naloxone prescriptions filled during the study period. Pharmacists wrote 40 of 106 naloxone prescriptions (38%), all for the 8 mg formulation. Nurse practitioners prescribed naloxone 4 mg 30 times and 8 mg 6 times for 36 of 106 prescriptions (34%). Physicians prescribed 30 of 106 prescriptions (28%), including intranasal naloxone 4 mg 17 times and 8 mg 13 times.
Statistics were analyzed using a X2 test; however, it was determined that the expected frequencies made the tests inappropriate. Differences in prescribing patterns between naloxone doses, prescriber disciplines, source of the prescription, or indications were not statistically significant.
DISCUSSION
Many pharmacists possess a scope of practice under state law and/or institution policy to prescribe naloxone. In this study, pharmacists prescribed the most naloxone prescriptions compared to physicians and nurse practitioners. Initiatives such as OEND and STORM have given pharmacists at VHI an avenue to combat the growing opioid epidemic while expanding their scope of practice. A systematic review of 67 studies found that pharmacist-led OEND programs showed a statistically significant increase in naloxone orders. A statistical significance was likely met given the large sample sizes ranging from 10 to 217,000 individuals, whereas this study only assessed a small portion of patients.14 This study contributes to the overwhelming amount of data that highlights pharmacists’ impact on overall naloxone distribution.
The STORM initiative and primary care clinics were responsible for large portions of naloxone prescriptions in this study. STORM was used by pharmacists and contributed to more than half of the higher dose naloxone prescriptions. Following a discussion with members of the pain management team, pharmacists involved in STORM prescribing were revealed to exclusively prescribe intranasal naloxone 8 mg as opposed to 4 mg. At the risk of precipitating withdrawal from higher doses of naloxone, it was agreed that this risk was heavily outweighed by the benefit of successful opioid reversal. In this context, it is expected for this avenue of prescribing to influence naloxone prescribing patterns at VHI.
Prescribing in primary care clinics was shown to be equally as substantial. Primary care-based multidisciplinary transition clinics have been reported to be associated with increased access to OUD treatment.15 Primary care clinics at VHI, or patient aligned care teams (PACT), largely consist of multidisciplinary health care teams. PACT clinicians are heavily involved in transitions of care because one system provides patients with comprehensive acute and chronic care. Continuing to encourage naloxone distribution through primary care and using STORM affords various patient populations access to high-level care.
Notable differences were observed between indications for naloxone use and the corresponding dose. Patients with OUD or SUD were more likely to receive intranasal naloxone 8 mg as opposed to patients receiving intranasal naloxone for chronic opioid use, who were more likely to receive the 4 mg dose. This may be due to a rationale to provide a higher dose of naloxone to combat overdoses in the case of ingesting substances mixed with fentanyl or xylazine.12,13 Without standard of care guidelines, concerns remain for varying outcomes in opioid overdose prevention within vulnerable populations.
Limitations
Chart data were dependent on documentation, which may have omitted pertinent baseline characteristics and risk factors. Additional data collection could have further assessed a patient’s specific risk factors (eg, opioid dose in morphine equivalents) to draw conclusions to the dose of naloxone prescribed. The sample size was small, and the patient population was largely White and male, which minimized the generalizability of the results.
CONCLUSIONS
This study evaluated the differences in intranasal naloxone prescribing patterns within a veteran population at VHI over 12 months. Findings revealed that most prescriptions were written for intranasal naloxone 8 mg, by a pharmacist, in a primary care setting, and for chronic opioid use. The results revealed evidence of differing naloxone prescribing practices, which emphasize the need for clinical guidelines and better defined recommendations in relation to naloxone dosing.
The most evident gap in patient care could be addressed by urging the VA Pharmacy Benefits Management group to update naloxone recommendations for use to include more concrete dosing recommendations. Furthermore, it would be beneficial to re-educate clinicians on naloxone prescribing to increase awareness of different doses and the importance of equipping patients with the correct amount of naloxone in an emergency. Additional research assessing change in prescribing patterns is warranted as the use of higher dose naloxone becomes more routine.
Since 1999, annual deaths attributed to opioid overdose in the United States have increased from about 10,000 to about 50,000 in 2019.1 During the COVID-19 pandemic > 74,000 opioid overdose deaths occurred in the US from April 2020 to April 2021.2,3 Opioid-related overdoses now account for about 75% of all drug-related overdose deaths.1 In 2017, the cost of opioid overdose deaths and opioid use disorder (OUD) reached $1.02 trillion in the United States and $26 million in Indiana.4 The total deaths and costs would likely be higher if it were not for naloxone.
Naloxone hydrochloride was first patented in the 1960s and approved by the US Food and Drug Administration (FDA) in 1971 to treat opioid-related toxicity.1 It is the most frequently prescribed antidote for opioid toxicity due to its activity as a pure υ-opioid receptor competitive antagonist. Naloxone formulations include intramuscular, intravenous, subcutaneous, and intranasal delivery methods.5 According to the Centers for Disease Control and Prevention, clinicians should offer naloxone to patients at high risk for opioid-related adverse events. Risk factors include a history of overdose, opioid dosages of ≥ 50 morphine mg equivalents/day, and concurrent use of opioids with benzodiazepines.6
Intranasal naloxone 4 mg has become more accessible following the classification of opioid use as a public health emergency in 2017 and its over-the-counter availability since 2023. Intranasal naloxone 4 mg was approved by the FDA in 2015 for the prevention of opioid overdoses (accidental or intentional), which can be caused by heroin, fentanyl, carfentanil, hydrocodone, oxycodone, methadone, and other substances. 7 Fentanyl has most recently been associated with xylazine, a nonopioid tranquilizer linked to increased opioid overdose deaths.8 Recent data suggest that 34% of opioid overdose reversals involved ≥ 2 doses of intranasal naloxone 4 mg, which led to FDA approval of an intranasal naloxone 8 mg spray in April 2021.9-11
Veteran Health Indiana (VHI) has implemented several initiatives to promote naloxone prescribing. Established in 2020, the Opioid Overdose Education and Naloxone Distribution (OEND) program sought to prevent opioid-related deaths through education and product distribution. These criteria included an opioid prescription for ≥ 30 days. In 2021, the Stratification Tool for Opioid Risk Mitigation (STORM) was created to identify patients at high risk of opioid overdose and allowing pharmacists to prescribe naloxone for at-risk patients without restrictions, increasing accessibility.12
Recent cases of fentanyl-related overdoses involving stronger fentanyl analogues highlight the need for higher naloxone dosing to prevent overdose. A pharmacokinetic comparison of intranasal naloxone 8 mg vs 4 mg demonstrated maximum plasma concentrations of 10.3 ng/mL and 5.3 ng/mL, respectively. 13 Patients may be at an increased risk of precipitated opioid withdrawal when using intranasal naloxone 8 mg over 4 mg; however, some patients may benefit from achieving higher serum concentrations and therefore require larger doses of naloxone.
No clinical trials have demonstrated a difference in reversal rates between naloxone doses. No clinical practice guidelines support a specific naloxone formulation, and limited US Department of Veterans Affairs (VA)-specific guidance exists. VA Naloxone Rescue: Recommendations for Use states that selection of naloxone 8 mg should be based on shared decision-making between the patient and clinician and based on individual risk factors.12 The purpose of this study is to analyze data to determine if there is a difference in prescribing patterns of intranasal naloxone 4 mg and intranasal naloxone 8 mg.
METHODS
A retrospective chart reviews using the VA Computerized Patient Record System (CPRS) analyzed patients prescribed intranasal naloxone 4 mg or intranasal naloxone 8 mg at VHI. A patient list was generated based on active naloxone prescriptions between April 1, 2022, and April 1, 2023. Data were obtained exclusively through CPRS and patients were not contacted. This study was reviewed and deemed exempt by the Indiana University Health Institutional Review Board and the VHI Research and Development Committee.
Patients were included if they were aged ≥ 18 years and had an active prescription for intranasal naloxone 4 mg or intranasal naloxone 8 mg during the trial period. Patients were excluded if their naloxone prescription was written by a non-VHI clinician, if the dose was not 4 mg or 8 mg, or if the dosage form was other than intranasal spray.
The primary endpoint was the comparison for prescribing patterns for intranasal naloxone 4 mg and intranasal naloxone 8 mg during the study period. Secondary endpoints included total naloxone prescriptions; monthly prescriptions; number of patients with repeated naloxone prescriptions; prescriber type by naloxone dose; clinic type by naloxone dose; and documented indication for naloxone use by dose.
Demographic data collected included baseline age, sex, race, comorbid mental health conditions, and active central nervous system depressant medications on patient profile (ie, opioids, gabapentinoids, benzodiazepines, antidepressants, antipsychotics). Opioid prescriptions that were active or discontinued within the last 3 months were also recorded. Comorbid mental health conditions were collected based on the most recent clinical note before initiating medication.
Prescription-related data included strength of medication prescribed (4 mg, 8 mg, or both), documented use of medication, prescriber name, prescriber discipline, prescription entered by, number of times naloxone was filled or refilled during the study period, indication, clinic location, and clinic name. If > 1 prescription was active during the study period, the number of refills, prescriber name and clinic location of the first prescription in the study period was recorded. Additionally, the indication of OUD was differentiated from substance use disorder (SUD) if the patient was only dependent on opioids, excluding tobacco or alcohol. Patients with SUDs may include opioid dependence in addition to other substance dependence (eg, cannabis, stimulants, gabapentinoids, or benzodiazepines).
Basic descriptive statistics, including mean, ranges, and percentages were used to characterize the study subjects. For nominal data, X2 tests were used. A 2-sided 5% significance level was used for all statistical tests.
RESULTS
A total of 1952 active naloxone prescriptions from 1739 patients met the inclusion criteria; none were eliminated based on the exclusion criteria and some were included multiple times because data were collected for each active prescription during the study period. One hundred one patients were randomized and included in the final analysis (Figure). Most patients identified as White (81%), male (90%), and had a mean (SD) age of 60.9 (14.2) years. Common mental health comorbidities included 59 patients with depression, 50 with tobacco use disorder, and 31 with anxiety. Eighty-four patients had opioid and 60 had antidepressants/antianxiety, and 40 had gabapentinoids prescriptions. Forty-three patients had ≥ 3 mental health comorbidities. Thirty-four patients had 2 active central nervous system depressant prescriptions, 30 had 3 active prescriptions, and 9 had ≥ 4 active prescriptions. Most patients (n = 83) had an active or recently discontinued opioid prescription (Table 1).
The 101 patients received 54 prescriptions for naloxone 8 mg and 47 for 4 mg (Table 2). Five patients received prescriptions for both the 4 mg and 8 mg intranasal naloxone formulations. Sixty-six patients had naloxone filled once (66%) during the study period. Intranasal naloxone 4 mg was prescribed to 30 patients by nurse practitioners, 17 patients by physicians, and not prescribed by pharmacists. Intranasal naloxone 8 mg was prescribed to 40 patients by pharmacists, 13 patients by physicians, and 6 patients by nurses. Patients who received prescriptions for both intranasal naloxone 4 mg and 8 mg were most routinely ordered by physicians (n = 3; 60%) in primary care (n = 2; 40%) for chronic opioid use (n = 2; 40%).
Patients access naloxone from many different VHI clinics. Primary care clinics prescribed the 4 mg formulation to 31 patients, 8 mg to 3 patients, and both to 2 patients. The STORM initiative was used for 37 of 106 prescriptions (35%): 4 mg intranasal naloxone was prescribed to 1 patient, 8 mg to 36 patients, and no patients received both formulations. Chronic opioid use was the most common indication (46%) with 30 patients prescribed intranasal naloxone 4 mg, 14 patients prescribed 8 mg, and 2 patients prescribed both. OUD was the indication for 24% of patients: 2 patients prescribed intranasal naloxone 4 mg, 21 patients prescribed 8 mg, and 1 patient prescribed both.
The 106 intranasal naloxone prescriptions were equally distributed across each month from April 1, 2022, to April 1, 2023. Of the 101 patients, 34 had multiple naloxone prescriptions filled during the study period. Pharmacists wrote 40 of 106 naloxone prescriptions (38%), all for the 8 mg formulation. Nurse practitioners prescribed naloxone 4 mg 30 times and 8 mg 6 times for 36 of 106 prescriptions (34%). Physicians prescribed 30 of 106 prescriptions (28%), including intranasal naloxone 4 mg 17 times and 8 mg 13 times.
Statistics were analyzed using a X2 test; however, it was determined that the expected frequencies made the tests inappropriate. Differences in prescribing patterns between naloxone doses, prescriber disciplines, source of the prescription, or indications were not statistically significant.
DISCUSSION
Many pharmacists possess a scope of practice under state law and/or institution policy to prescribe naloxone. In this study, pharmacists prescribed the most naloxone prescriptions compared to physicians and nurse practitioners. Initiatives such as OEND and STORM have given pharmacists at VHI an avenue to combat the growing opioid epidemic while expanding their scope of practice. A systematic review of 67 studies found that pharmacist-led OEND programs showed a statistically significant increase in naloxone orders. A statistical significance was likely met given the large sample sizes ranging from 10 to 217,000 individuals, whereas this study only assessed a small portion of patients.14 This study contributes to the overwhelming amount of data that highlights pharmacists’ impact on overall naloxone distribution.
The STORM initiative and primary care clinics were responsible for large portions of naloxone prescriptions in this study. STORM was used by pharmacists and contributed to more than half of the higher dose naloxone prescriptions. Following a discussion with members of the pain management team, pharmacists involved in STORM prescribing were revealed to exclusively prescribe intranasal naloxone 8 mg as opposed to 4 mg. At the risk of precipitating withdrawal from higher doses of naloxone, it was agreed that this risk was heavily outweighed by the benefit of successful opioid reversal. In this context, it is expected for this avenue of prescribing to influence naloxone prescribing patterns at VHI.
Prescribing in primary care clinics was shown to be equally as substantial. Primary care-based multidisciplinary transition clinics have been reported to be associated with increased access to OUD treatment.15 Primary care clinics at VHI, or patient aligned care teams (PACT), largely consist of multidisciplinary health care teams. PACT clinicians are heavily involved in transitions of care because one system provides patients with comprehensive acute and chronic care. Continuing to encourage naloxone distribution through primary care and using STORM affords various patient populations access to high-level care.
Notable differences were observed between indications for naloxone use and the corresponding dose. Patients with OUD or SUD were more likely to receive intranasal naloxone 8 mg as opposed to patients receiving intranasal naloxone for chronic opioid use, who were more likely to receive the 4 mg dose. This may be due to a rationale to provide a higher dose of naloxone to combat overdoses in the case of ingesting substances mixed with fentanyl or xylazine.12,13 Without standard of care guidelines, concerns remain for varying outcomes in opioid overdose prevention within vulnerable populations.
Limitations
Chart data were dependent on documentation, which may have omitted pertinent baseline characteristics and risk factors. Additional data collection could have further assessed a patient’s specific risk factors (eg, opioid dose in morphine equivalents) to draw conclusions to the dose of naloxone prescribed. The sample size was small, and the patient population was largely White and male, which minimized the generalizability of the results.
CONCLUSIONS
This study evaluated the differences in intranasal naloxone prescribing patterns within a veteran population at VHI over 12 months. Findings revealed that most prescriptions were written for intranasal naloxone 8 mg, by a pharmacist, in a primary care setting, and for chronic opioid use. The results revealed evidence of differing naloxone prescribing practices, which emphasize the need for clinical guidelines and better defined recommendations in relation to naloxone dosing.
The most evident gap in patient care could be addressed by urging the VA Pharmacy Benefits Management group to update naloxone recommendations for use to include more concrete dosing recommendations. Furthermore, it would be beneficial to re-educate clinicians on naloxone prescribing to increase awareness of different doses and the importance of equipping patients with the correct amount of naloxone in an emergency. Additional research assessing change in prescribing patterns is warranted as the use of higher dose naloxone becomes more routine.
- Britch SC, Walsh SL. Treatment of opioid overdose: current approaches and recent advances. Psychopharmacology (Berl). 2022;239(7):2063-2081. doi:10.1007/s00213-022-06125-5
- Ahmad FB, Cisewski JA, Rossen LM, Sutton P. Provisional Drug Overdose Death Counts. National Center for Health Statistics, Centers for Disease Control and Prevention; 2023. Accessed April 10, 2025. https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm
- O’Donnell J, Tanz LJ, Gladden RM, Davis NL, Bitting J. Trends in and characteristics of drug overdose deaths involving illicitly manufactured fentanyls — United States, 2019–2020. MMWR Morb Mortal Wkly Rep. 2021;70:1740-1746. doi:10.15585/mmwr.mm7050e3
- Luo F, Li M, Florence C. State-level economic costs of opioid use disorder and fatal opioid overdose — United States, 2017. MMWR Morb Mortal Wkly Rep. 2021;70:541-546. doi:10.15585/mmwr.mm7015a1
- Lexicomp. Lexicomp Online. Accessed April 10, 2025. http://online.lexi.com
- Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC Clinical practice guideline for prescribing opioids for pain — United States, 2022. MMWR Recomm Rep. 2022;71(3):1-95. doi:10.15585/mmwr.rr7103a1
- Narcan (naloxone) FDA approval history. Drugs.com. Accessed April 10, 2025. https://www.drugs.com/history/narcan.html
- Centers for Disease Control and Prevention. What you should know about xylazine. May 16, 2024. Accessed April 10, 2025. https://www.cdc.gov/overdose-prevention/about/what-you-should-know-about-xylazine.html
- Avetian GK, Fiuty P, Mazzella S, Koppa D, Heye V, Hebbar P. Use of naloxone nasal spray 4 mg in the community setting: a survey of use by community organizations. Curr Med Res Opin. 2018;34(4):573-576. doi:10.1080/03007995.2017.1334637
- Kloxxado [package insert]. Hikma Pharmaceuticals USA Inc; 2021.
- FDA approves higher dosage of naloxone nasal spray to treat opioid overdose. News release. FDA. April 30, 2021. Accessed April 10, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-higher-dosage-naloxone-nasal-spray-treat-opioid-overdose
- US Department of Veterans Affairs, Pharmacy Benefits Management Services and National Formulary Committee in Collaboration with the VA National Harm Reduction Support & Development Workgroup. Naloxone Rescue: Recommendations for Use. June 2014. Updated March 2024. Accessed April 10, 2025. https://www.va.gov/formularyadvisor/DOC_PDF/CRE_Naloxone_Rescue_Guidance_March_2024.pdf
- Krieter P, Chiang N, Gyaw S, et al. Pharmacokinetic properties and human use characteristics of an FDA-approved intranasal naloxone product for the treatment of opioid overdose. J Clin Pharmacol. 2016;56(10):1243-1253. doi:10.1002/jcph.759
- Rawal S, Osae SP, Cobran EK, Albert A, Young HN. Pharmacists’ naloxone services beyond community pharmacy settings: a systematic review. Res Social Adm Pharm. 2023;19(2):243-265. doi:10.1016/j.sapharm.2022.09.002
- Incze MA, Sehgal SL, Hansen A, Garcia L, Stolebarger L. Evaluation of a primary care-based multidisciplinary transition clinic for patients newly initiated on buprenorphine in the emergency department. Subst Abus. 2023;44(3):220-225. doi:10.1177/08897077231188592
- Britch SC, Walsh SL. Treatment of opioid overdose: current approaches and recent advances. Psychopharmacology (Berl). 2022;239(7):2063-2081. doi:10.1007/s00213-022-06125-5
- Ahmad FB, Cisewski JA, Rossen LM, Sutton P. Provisional Drug Overdose Death Counts. National Center for Health Statistics, Centers for Disease Control and Prevention; 2023. Accessed April 10, 2025. https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm
- O’Donnell J, Tanz LJ, Gladden RM, Davis NL, Bitting J. Trends in and characteristics of drug overdose deaths involving illicitly manufactured fentanyls — United States, 2019–2020. MMWR Morb Mortal Wkly Rep. 2021;70:1740-1746. doi:10.15585/mmwr.mm7050e3
- Luo F, Li M, Florence C. State-level economic costs of opioid use disorder and fatal opioid overdose — United States, 2017. MMWR Morb Mortal Wkly Rep. 2021;70:541-546. doi:10.15585/mmwr.mm7015a1
- Lexicomp. Lexicomp Online. Accessed April 10, 2025. http://online.lexi.com
- Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC Clinical practice guideline for prescribing opioids for pain — United States, 2022. MMWR Recomm Rep. 2022;71(3):1-95. doi:10.15585/mmwr.rr7103a1
- Narcan (naloxone) FDA approval history. Drugs.com. Accessed April 10, 2025. https://www.drugs.com/history/narcan.html
- Centers for Disease Control and Prevention. What you should know about xylazine. May 16, 2024. Accessed April 10, 2025. https://www.cdc.gov/overdose-prevention/about/what-you-should-know-about-xylazine.html
- Avetian GK, Fiuty P, Mazzella S, Koppa D, Heye V, Hebbar P. Use of naloxone nasal spray 4 mg in the community setting: a survey of use by community organizations. Curr Med Res Opin. 2018;34(4):573-576. doi:10.1080/03007995.2017.1334637
- Kloxxado [package insert]. Hikma Pharmaceuticals USA Inc; 2021.
- FDA approves higher dosage of naloxone nasal spray to treat opioid overdose. News release. FDA. April 30, 2021. Accessed April 10, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-higher-dosage-naloxone-nasal-spray-treat-opioid-overdose
- US Department of Veterans Affairs, Pharmacy Benefits Management Services and National Formulary Committee in Collaboration with the VA National Harm Reduction Support & Development Workgroup. Naloxone Rescue: Recommendations for Use. June 2014. Updated March 2024. Accessed April 10, 2025. https://www.va.gov/formularyadvisor/DOC_PDF/CRE_Naloxone_Rescue_Guidance_March_2024.pdf
- Krieter P, Chiang N, Gyaw S, et al. Pharmacokinetic properties and human use characteristics of an FDA-approved intranasal naloxone product for the treatment of opioid overdose. J Clin Pharmacol. 2016;56(10):1243-1253. doi:10.1002/jcph.759
- Rawal S, Osae SP, Cobran EK, Albert A, Young HN. Pharmacists’ naloxone services beyond community pharmacy settings: a systematic review. Res Social Adm Pharm. 2023;19(2):243-265. doi:10.1016/j.sapharm.2022.09.002
- Incze MA, Sehgal SL, Hansen A, Garcia L, Stolebarger L. Evaluation of a primary care-based multidisciplinary transition clinic for patients newly initiated on buprenorphine in the emergency department. Subst Abus. 2023;44(3):220-225. doi:10.1177/08897077231188592
Comparison of Prescribing Patterns of Intranasal Naloxone in a Veteran Population
Comparison of Prescribing Patterns of Intranasal Naloxone in a Veteran Population
Long-Term Assessment of Weight Loss Medications in a Veteran Population
The Centers for Disease Control and Prevention (CDC) classifies individuals with a body mass index (BMI) of 25 to 29.9as overweight and those with a BMI > 30 as obese (obesity classes: I, BMI 30 to 34.9; II, BMI 35 to 39.9; and III, BMI ≥ 40).1 In 2011, the CDC estimated that 27.4% of adults in the United States were obese; less than a decade later, that number increased to 31.9%.1 In that same period, the percentage of adults in Indiana classified as obese increased from 30.8% to 36.8%.1 About 1 in 14 individuals in the US have class III obesity and 86% of veterans are either overweight or obese.2
High medical expenses can likely be attributed to the long-term health consequences of obesity. Compared to those with a healthy weight, individuals who are overweight or obese are at an increased risk for high blood pressure, high low-density lipoprotein cholesterol levels, low high-density lipoprotein cholesterol levels, high triglyceride levels, type 2 diabetes mellitus (T2DM), coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, cancer, mental health disorders, body pain, low quality of life, and death.3 Many of these conditions lead to increased health care needs, medication needs, hospitalizations, and overall health care system use.
Guidelines for the prevention and treatment of obesity have been produced by the American Heart Association, American College of Cardiology, and The Obesity Society; the Endocrine Society; the American Diabetes Association; and the US Departments of Veterans Affairs (VA) and Defense. Each follows a general algorithm to manage and prevent adverse effects (AEs) related to obesity. General practice is to assess a patient for elevated BMI (> 25), implement intense lifestyle modifications including calorie restriction and exercise, reassess for a maintained 5% to 10% weight loss for cardiovascular benefits, and potentially assess for pharmacological or surgical intervention to assist in weight loss.2,4-6
While some weight loss medications (eg, phentermine/topiramate, naltrexone/bupropion, orlistat, and lorcaserin) tend to have unfavorable AEs or mixed efficacy, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have provided new options.7-10 Lorcaserin, for example, was removed from the market in 2020 due to its association with cancer risks.11 The GLP-1RAs liraglutide and semaglutide received US Food and Drug Administration (FDA) approval for weight loss in 2014 and 2021, respectively.12,13 GLP-1RAs have shown the greatest efficacy and benefits in reducing hemoglobin A1c (HbA1c); they are the preferred agents for patients who qualify for pharmacologic intervention for weight loss, especially those with T2DM. However, these studies have not evaluated the long-term outcomes of using these medications for weight loss and may not reflect the veteran population.14,15
At Veteran Health Indiana (VHI), clinicians may use several weight loss medications for patients to achieve 5% to 10% weight loss. The medications most often used include liraglutide, phentermine/topiramate, naltrexone/bupropion, orlistat, and phentermine alone. However, more research is needed to determine which weight loss medication is the most beneficial for veterans, particularly following FDA approval of GLP-1RAs. At VHI, phentermine/topiramate is the preferred first-line agent unless patients have contraindications for use, in which case naltrexone/bupropion is recommended. These are considered first-line due to their ease of use in pill form, lower cost, and comparable weight loss to the GLP-1 medication class.2 However, for patients with prediabetes, T2DM, BMI > 40, or BMI > 35 with specific comorbid conditions, liraglutide is preferred because of its beneficial effects for both weight loss and blood glucose control.2
This study aimed to expand on the 2021 Hood and colleagues study that examined total weight loss and weight loss as a percentage of baseline weight in patients with obesity at 3, 6, 12, and > 12 months of pharmacologic therapy by extending the time frame to 48 months.16 This study excluded semaglutide because few patients were prescribed the medication for weight loss during the study.
METHODS
We conducted a single-center, retrospective chart review of patients prescribed weight loss medications at VHI. A patient list was generated based on prescription fills from June 1, 2017, to July 31, 2021. Data were obtained from the Computerized Patient Record System; patients were not contacted. This study was approved by the Indiana University Health Institutional Review Board and VHI Research and Development Committee.
At the time of this study, liraglutide, phentermine/topiramate, naltrexone/bupropion, orlistat, and phentermine alone were available at VHI for patients who met the clinical criteria for use. All patients must have been enrolled in dietary and lifestyle management programs, including the VA MOVE! program, to be approved for these medications. After the MOVE! orientation, patients could participate in group or individual 12-week programs that included weigh-ins, goal-setting strategies, meal planning, and habit modification support. If patients could not meet in person, phone and other telehealth opportunities were available.
Patients were included in the study if they were aged ≥ 18 years, received a prescription for any of the 5 available medications for weight loss during the enrollment period, and were on the medication for ≥ 6 consecutive months. Patients were excluded if they received a prescription, were treated outside the VA system, or were pregnant. The primary indication for the included medication was not weight loss; the primary indication for the GLP-1RA was T2DM, or the weight loss was attributed to another disease. Adherence was not a measured outcome of this study; if patients were filling the medication, it was assumed they were taking it. Data were collected for each instance of medication use; as a result, a few patients were included more than once. Data collection for a failed medication ended when failure was documented. New data points began when new medication was prescribed; all data were per medication, not per patient. This allowed us to account for medication failure and provide accurate weight loss results based on medication choice within VHI.
Primary outcomes included total weight loss and weight loss as a percentage ofbaseline weight during the study period at 3, 6, 12, 24, 36, and 48 months of therapy. Secondary outcomes included the percentage of patients who lost 5% to 10% of their body weight from baseline; the percentage of patients who maintained ≥ 5% weight loss from baseline to 12, 24, 36, and 48 months if maintained on medication for that duration; duration of medication treatment in weeks; medication discontinuation rate; reason for medication discontinuation; enrollment in the MOVE! clinic and the time enrolled; percentage of patients with a BMI of 18 to 24.9 at the end of the study; and change in HbA1c at 3, 6, 12, 24, 36, and 48 months.
Demographic data included race, age, sex, baseline weight, height, baseline BMI, and comorbid conditions (collected based on the most recent primary care clinical note before initiating medication). Medication data collected included medications used to manage comorbidities. Data related to weight management medication included prescribing clinic, maintenance dose of medication, duration of medication during the study period, the reason for medication discontinuation, or bariatric surgery intervention if applicable.
Basic descriptive statistics were used to characterize study participants. For continuous data, analysis of variance tests were used; if those results were not normal, then nonparametric tests were used, followed by pairwise tests between medication groups if the overall test was significant using the Fisher significant differences test. For nominal data, χ2 or Fisher exact tests were used. For comparisons of primary and secondary outcomes, if the analyses needed to include adjustment for confounding variables, analysis of covariance was used for continuous data. A 2-sided 5% significance level was used for all tests.
RESULTS
A total of 228 instances of medication use were identified based on prescription fills; 123 did not meet inclusion criteria (117 for < 6 consecutive months of medication use) (Figure). The study included 105 participants with a mean age of 56 years; 80 were male (76.2%), and 85 identified as White race (81.0%). Mean (SD) weight was 130.1 kg (26.8) and BMI was 41.6 (7.2). The most common comorbid disease states among patients included hypertension, dyslipidemia, obstructive sleep apnea, and T2DM (Table 1). The baseline characteristics were comparable to those of Hood and colleagues.16
Most patients at VHI started on liraglutide (63%) or phentermine/topiramate (28%). For primary and secondary outcomes, statistics were calculated to determine whether the results were statistically significant for comparing the liraglutide and phentermine/topiramate subgroups. Sample sizes were too small for statistical analysis for bupropion/naltrexone, phentermine, and orlistat.
Primary Outcomes
The mean (SD) weight of participants dropped 8.1% from 130.1 kg to 119.5 kg over the patient-specific duration of weight management medication therapy for an absolute difference of 10.6 kg (9.7). Duration of individual medication use varied from 6 to 48 months. Weight loss was recorded at 6, 12, 24, 36, and 48 months of weight management therapy. Patient weight was not recorded after the medication was discontinued.
When classified by medication choice, the mean change in weight over the duration of the study was −23.9 kg for 2 patients using orlistat, −10.2 kg for 46 patients using liraglutide, −11.0 kg for 25 patients using phentermine/topiramate, -7.4 kg for 1 patient using phentermine, and -13.0 kg for 4 patients using naltrexone/bupropion. Patients without a weight documented at the end of their therapy or at the conclusion of the data collection period were not included in the total weight loss at the end of therapy. There were 78 documented instances of weight loss at the end of therapy (Table 2).
Body weight loss percentage was recorded at 6, 12, 24, 36, and 48 months of weight management therapy. The mean (SD) body weight loss percentage over the duration of the study was 9.2% (11.2). When classified by medication choice, the mean percentage of body weight loss was 16.8% for 2 patients using orlistat, 9.4% for 46 patients using liraglutide, 8.2% for 25 patients using phentermine/topiramate, 6.0% for 1 patient using phentermine alone, and 10.6% for 4 patients using naltrexone/bupropion (Table 3).
Secondary Outcomes
While none of the secondary outcomes were statistically significant, the results of this study suggest that both medications may contribute to weight loss in many patients included in this study. Almost two-thirds of the included patients analyzed lost ≥ 5% of weight from baseline while taking weight management medication. Sixty-six patients (63%) lost ≥ 5% of body weight at any time during the data collection period. When stratified by liraglutide and phentermine/topiramate, 41 patients (63%) taking liraglutide and 20 patients (67%) taking phentermine/topiramate lost ≥ 5% of weight from baseline. Of the 66 patients who lost ≥ 5% of body weight from baseline, 36 (55%) lost ≥ 10% of body weight from baseline at any time during the data collection period.
The mean (SD) duration for weight management medication use was 23 months (14.9). Phentermine/topiramate was tolerated longer than liraglutide: 22.7 months vs 21.7 months, respectively (Table 4).
The average overall documented medication discontinuation rate was 35.2%. Reasons for discontinuation included 21 patient-elected discontinuations, 8 patients no longer met criteria for use, 4 medications were no longer indicated, and 4 patients experienced AEs. It is unknown whether weight management medication was discontinued or not in 18 patients (17.2%).
DISCUSSION
This study evaluated the use and outcomes of weight loss medications over a longer period (up to 48 months) than what was previously studied among patients at VHI (12 months). The study aimed to better understand the long-term effect of weight loss medications, determine which medication had better long-term outcomes, and examine the reasons for medication discontinuation.
The results of this study displayed some similarities and differences compared with the Hood and colleagues study.16 Both yielded similar results for 5% of body weight loss and 10% of body weight loss. The largest difference was mean weight loss over the study period. In this study, patients lost a mean 10.6 kg over the course of weight loss medication use compared to 15.8 kg found by Hood and colleagues.16 A reason patients in the current study lost less weight overall could be the difference in time frames. The current study encompassed the COVID-19 pandemic, meaning fewer overall in-person patient appointments, which led to patients being lost to follow-up, missing weigh-ins during the time period, and gaps in care. For some patients, the pandemic possibly contributed to depression, missed medication doses, and a more sedentary lifestyle, leading to more weight gain.17 Telemedicine services at VHI expanded during the pandemic in an attempt to increase patient monitoring and counseling. It is unclear whether this expansion was enough to replace the in-person contact necessary to promote a healthy lifestyle.
VA pharmacists now care for patients through telehealth and are more involved in weight loss management. Since the conclusion of the Hood and colleagues study and start of this research, 2 pharmacists at VHI have been assigned to follow patients for obesity management to help with adherence to medication and lifestyle changes, management of AEs, dispense logistics, interventions for medications that may cause weight gain, and case management of glycemic control and weight loss with GLP-1RAs. Care management by pharmacists at VHI helps improve the logistics of titratable orders and save money by improving the use of high-cost items like GLP-1RAs. VA clinical pharmacy practitioners already monitor GLP-1RAs for patients with T2DM, so they are prepared to educate and assist patients with these medications.
It is important to continue developing a standardized process for weight loss medication management across the VA to improve the quality of patient care and optimize prescription outcomes. VA facilities differ in how weight loss management care is delivered and the level at which pharmacists are involved. Given the high rate of obesity among patients at the VA, the advent of new prescription options for weight loss, and the high cost associated with these medications, there has been increased attention to obesity care. Some Veterans Integrated Service Networks are forming a weight management community of practice groups to create standard operating procedures and algorithms to standardize care. Developing consistent processes is necessary to improve weight loss and patient care for veterans regardless where they receive treatment.
Limitations
The data used in this study were dependent on clinician documentation. Because of a lack of documentation in many instances, it was difficult to determine the full efficacy of the medications studied due to missing weight recordings. The lack of documentation made it difficult to determine whether patients were enrolled and active in the MOVE! program. It is required that patients enroll in MOVE! to obtain medications, but many did not have any follow-up MOVE! visits after initially obtaining their weight loss medication.
In this study, differences in the outcomes of patients with and without T2DM were not compared. It is the VA standard of care to prefer liraglutide over phentermine/topiramate in patients with T2DM or prediabetes.2 This makes it difficult to assess whether phentermine/topiramate or liraglutide is more effective for weight loss in patients with T2DM. Weight gain after the discontinuation of weight loss medications was not assessed. Collecting this data may help determine whether a certain weight loss medication is less likely to cause rebound weight gain when discontinued.
Other limitations to this study consisted of excluding patients who discontinued therapy within 6 months, small sample sizes on some medications, and lack of data on adherence. Adherence was based on medication refills, which means that if a patient refilled the medication, it was assumed they were taking it. This is not always the case, and while accurate data on adherence is difficult to gather, it can impact how results may be interpreted. These additional limitations make it difficult to accurately determine the efficacy of the medications in this study.
CONCLUSIONS
This study found similar outcomes to what has been observed in larger clinical trials regarding weight loss medications. Nevertheless, there was a lack of accurate clinical documentation for most patients, which limits the conclusions. This lack of documentation potentially led to inaccurate results. It revealed that many patients at VHI did not uniformly receive consistent follow-up after starting a weight loss medication during the study period. With more standardized processes implemented at VA facilities, increased pharmacist involvement in weight loss medication management, and increased use of established telehealth services, patients could have the opportunity for closer follow-up that may lead to better weight loss outcomes. With these changes, there is more reason for additional studies to be conducted to assess follow-up, medication management, and weight loss overall.
1. Overweight & obesity. Centers for Disease Control and Prevention. Updated September 21, 2023. Accessed April 23, 2024. https://www.cdc.gov/obesity/index.html
2. US Department of Defense, US Department of Veterans Affairs. The Management of Adult Overweight and Obesity Working Group. VA/DoD Clinical Practice Guideline for the Management of Adult Overweight and Obesity. Updated July 2020. Accessed April 23, 2024. https://www.healthquality.va.gov/guidelines/CD/obesity/VADoDObesityCPGFinal5087242020.pdf
3. Health effects of overweight and obesity. Centers for Disease Control and Prevention. Updated September 24, 2022. Accessed April 23, 2024. https://www.cdc.gov/healthyweight/effects/index.html
4. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63(25 Pt B):2985-3023. doi:10.1016/j.jacc.2013.11.004
5. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342-362. doi:10.1210/jc.2014-3415
6. American Diabetes Association Professional Practice Committee. 3. Prevention or delay of type 2 diabetes and associated comorbidities: standards of medical care in diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S39-S45. doi:10.2337/dc22-S003
7. Phentermine and topiramate extended-release. Package insert. Vivus, Inc; 2012. Accessed April 23, 2024. https://qsymia.com/patient/include/media/pdf/prescribing-information.pdf
8. Naltrexone and bupropion extended-release. Package insert. Orexigen Therapeutics, Inc; 2014. Accessed April 23, 2024. https://contrave.com/wp-content/uploads/2024/01/Contrave-label-113023.pdf
9. Orlistat. Package insert. Roche Laboratories, Inc; 2009. Accessed April 23, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020766s026lbl.pdf
10. Lorcaserin. Package insert. Arena Pharmaceuticals; 2012. Accessed April 23, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022529lbl.pdf
11. FDA requests the withdrawal of the weight-loss drug Belviq, Belviq XR (lorcaserin) from the market. News release. US Food & Drug Administration. February 13, 2020. Accessed April 23, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-withdrawal-weight-loss-drug-belviq-belviq-xr-lorcaserin-market
12. Saxenda Injection (Liraglutide [rDNA origin]). Novo Nordisk, Inc. October 1, 2015. Accessed April 23, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206321Orig1s000TOC.cfm
13. FDA approves new drug treatment for chronic weight management, first since 2014. News release. US Food & Drug Administration. June 4, 2021. Accessed April 23, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
14. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New Engl J Med. 2015;373:11-22. doi:10.1056/NEJMoa1411892
15. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. New Engl J Med 2021;384:989-1002. doi:10.1056/NEJMoa2032183
16. Hood SR, Berkeley AW, Moore EA. Evaluation of pharmacologic interventions for weight management in a veteran population. Fed Pract. 2021;38(5):220-226. doi:10.12788/fp.0117
17. Melamed OC, Selby P, Taylor VH. Mental health and obesity during the COVID-19 pandemic. Curr Obes Rep. 2022;11(1):23-31. doi:10.1007/s13679-021-00466-6
The Centers for Disease Control and Prevention (CDC) classifies individuals with a body mass index (BMI) of 25 to 29.9as overweight and those with a BMI > 30 as obese (obesity classes: I, BMI 30 to 34.9; II, BMI 35 to 39.9; and III, BMI ≥ 40).1 In 2011, the CDC estimated that 27.4% of adults in the United States were obese; less than a decade later, that number increased to 31.9%.1 In that same period, the percentage of adults in Indiana classified as obese increased from 30.8% to 36.8%.1 About 1 in 14 individuals in the US have class III obesity and 86% of veterans are either overweight or obese.2
High medical expenses can likely be attributed to the long-term health consequences of obesity. Compared to those with a healthy weight, individuals who are overweight or obese are at an increased risk for high blood pressure, high low-density lipoprotein cholesterol levels, low high-density lipoprotein cholesterol levels, high triglyceride levels, type 2 diabetes mellitus (T2DM), coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, cancer, mental health disorders, body pain, low quality of life, and death.3 Many of these conditions lead to increased health care needs, medication needs, hospitalizations, and overall health care system use.
Guidelines for the prevention and treatment of obesity have been produced by the American Heart Association, American College of Cardiology, and The Obesity Society; the Endocrine Society; the American Diabetes Association; and the US Departments of Veterans Affairs (VA) and Defense. Each follows a general algorithm to manage and prevent adverse effects (AEs) related to obesity. General practice is to assess a patient for elevated BMI (> 25), implement intense lifestyle modifications including calorie restriction and exercise, reassess for a maintained 5% to 10% weight loss for cardiovascular benefits, and potentially assess for pharmacological or surgical intervention to assist in weight loss.2,4-6
While some weight loss medications (eg, phentermine/topiramate, naltrexone/bupropion, orlistat, and lorcaserin) tend to have unfavorable AEs or mixed efficacy, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have provided new options.7-10 Lorcaserin, for example, was removed from the market in 2020 due to its association with cancer risks.11 The GLP-1RAs liraglutide and semaglutide received US Food and Drug Administration (FDA) approval for weight loss in 2014 and 2021, respectively.12,13 GLP-1RAs have shown the greatest efficacy and benefits in reducing hemoglobin A1c (HbA1c); they are the preferred agents for patients who qualify for pharmacologic intervention for weight loss, especially those with T2DM. However, these studies have not evaluated the long-term outcomes of using these medications for weight loss and may not reflect the veteran population.14,15
At Veteran Health Indiana (VHI), clinicians may use several weight loss medications for patients to achieve 5% to 10% weight loss. The medications most often used include liraglutide, phentermine/topiramate, naltrexone/bupropion, orlistat, and phentermine alone. However, more research is needed to determine which weight loss medication is the most beneficial for veterans, particularly following FDA approval of GLP-1RAs. At VHI, phentermine/topiramate is the preferred first-line agent unless patients have contraindications for use, in which case naltrexone/bupropion is recommended. These are considered first-line due to their ease of use in pill form, lower cost, and comparable weight loss to the GLP-1 medication class.2 However, for patients with prediabetes, T2DM, BMI > 40, or BMI > 35 with specific comorbid conditions, liraglutide is preferred because of its beneficial effects for both weight loss and blood glucose control.2
This study aimed to expand on the 2021 Hood and colleagues study that examined total weight loss and weight loss as a percentage of baseline weight in patients with obesity at 3, 6, 12, and > 12 months of pharmacologic therapy by extending the time frame to 48 months.16 This study excluded semaglutide because few patients were prescribed the medication for weight loss during the study.
METHODS
We conducted a single-center, retrospective chart review of patients prescribed weight loss medications at VHI. A patient list was generated based on prescription fills from June 1, 2017, to July 31, 2021. Data were obtained from the Computerized Patient Record System; patients were not contacted. This study was approved by the Indiana University Health Institutional Review Board and VHI Research and Development Committee.
At the time of this study, liraglutide, phentermine/topiramate, naltrexone/bupropion, orlistat, and phentermine alone were available at VHI for patients who met the clinical criteria for use. All patients must have been enrolled in dietary and lifestyle management programs, including the VA MOVE! program, to be approved for these medications. After the MOVE! orientation, patients could participate in group or individual 12-week programs that included weigh-ins, goal-setting strategies, meal planning, and habit modification support. If patients could not meet in person, phone and other telehealth opportunities were available.
Patients were included in the study if they were aged ≥ 18 years, received a prescription for any of the 5 available medications for weight loss during the enrollment period, and were on the medication for ≥ 6 consecutive months. Patients were excluded if they received a prescription, were treated outside the VA system, or were pregnant. The primary indication for the included medication was not weight loss; the primary indication for the GLP-1RA was T2DM, or the weight loss was attributed to another disease. Adherence was not a measured outcome of this study; if patients were filling the medication, it was assumed they were taking it. Data were collected for each instance of medication use; as a result, a few patients were included more than once. Data collection for a failed medication ended when failure was documented. New data points began when new medication was prescribed; all data were per medication, not per patient. This allowed us to account for medication failure and provide accurate weight loss results based on medication choice within VHI.
Primary outcomes included total weight loss and weight loss as a percentage ofbaseline weight during the study period at 3, 6, 12, 24, 36, and 48 months of therapy. Secondary outcomes included the percentage of patients who lost 5% to 10% of their body weight from baseline; the percentage of patients who maintained ≥ 5% weight loss from baseline to 12, 24, 36, and 48 months if maintained on medication for that duration; duration of medication treatment in weeks; medication discontinuation rate; reason for medication discontinuation; enrollment in the MOVE! clinic and the time enrolled; percentage of patients with a BMI of 18 to 24.9 at the end of the study; and change in HbA1c at 3, 6, 12, 24, 36, and 48 months.
Demographic data included race, age, sex, baseline weight, height, baseline BMI, and comorbid conditions (collected based on the most recent primary care clinical note before initiating medication). Medication data collected included medications used to manage comorbidities. Data related to weight management medication included prescribing clinic, maintenance dose of medication, duration of medication during the study period, the reason for medication discontinuation, or bariatric surgery intervention if applicable.
Basic descriptive statistics were used to characterize study participants. For continuous data, analysis of variance tests were used; if those results were not normal, then nonparametric tests were used, followed by pairwise tests between medication groups if the overall test was significant using the Fisher significant differences test. For nominal data, χ2 or Fisher exact tests were used. For comparisons of primary and secondary outcomes, if the analyses needed to include adjustment for confounding variables, analysis of covariance was used for continuous data. A 2-sided 5% significance level was used for all tests.
RESULTS
A total of 228 instances of medication use were identified based on prescription fills; 123 did not meet inclusion criteria (117 for < 6 consecutive months of medication use) (Figure). The study included 105 participants with a mean age of 56 years; 80 were male (76.2%), and 85 identified as White race (81.0%). Mean (SD) weight was 130.1 kg (26.8) and BMI was 41.6 (7.2). The most common comorbid disease states among patients included hypertension, dyslipidemia, obstructive sleep apnea, and T2DM (Table 1). The baseline characteristics were comparable to those of Hood and colleagues.16
Most patients at VHI started on liraglutide (63%) or phentermine/topiramate (28%). For primary and secondary outcomes, statistics were calculated to determine whether the results were statistically significant for comparing the liraglutide and phentermine/topiramate subgroups. Sample sizes were too small for statistical analysis for bupropion/naltrexone, phentermine, and orlistat.
Primary Outcomes
The mean (SD) weight of participants dropped 8.1% from 130.1 kg to 119.5 kg over the patient-specific duration of weight management medication therapy for an absolute difference of 10.6 kg (9.7). Duration of individual medication use varied from 6 to 48 months. Weight loss was recorded at 6, 12, 24, 36, and 48 months of weight management therapy. Patient weight was not recorded after the medication was discontinued.
When classified by medication choice, the mean change in weight over the duration of the study was −23.9 kg for 2 patients using orlistat, −10.2 kg for 46 patients using liraglutide, −11.0 kg for 25 patients using phentermine/topiramate, -7.4 kg for 1 patient using phentermine, and -13.0 kg for 4 patients using naltrexone/bupropion. Patients without a weight documented at the end of their therapy or at the conclusion of the data collection period were not included in the total weight loss at the end of therapy. There were 78 documented instances of weight loss at the end of therapy (Table 2).
Body weight loss percentage was recorded at 6, 12, 24, 36, and 48 months of weight management therapy. The mean (SD) body weight loss percentage over the duration of the study was 9.2% (11.2). When classified by medication choice, the mean percentage of body weight loss was 16.8% for 2 patients using orlistat, 9.4% for 46 patients using liraglutide, 8.2% for 25 patients using phentermine/topiramate, 6.0% for 1 patient using phentermine alone, and 10.6% for 4 patients using naltrexone/bupropion (Table 3).
Secondary Outcomes
While none of the secondary outcomes were statistically significant, the results of this study suggest that both medications may contribute to weight loss in many patients included in this study. Almost two-thirds of the included patients analyzed lost ≥ 5% of weight from baseline while taking weight management medication. Sixty-six patients (63%) lost ≥ 5% of body weight at any time during the data collection period. When stratified by liraglutide and phentermine/topiramate, 41 patients (63%) taking liraglutide and 20 patients (67%) taking phentermine/topiramate lost ≥ 5% of weight from baseline. Of the 66 patients who lost ≥ 5% of body weight from baseline, 36 (55%) lost ≥ 10% of body weight from baseline at any time during the data collection period.
The mean (SD) duration for weight management medication use was 23 months (14.9). Phentermine/topiramate was tolerated longer than liraglutide: 22.7 months vs 21.7 months, respectively (Table 4).
The average overall documented medication discontinuation rate was 35.2%. Reasons for discontinuation included 21 patient-elected discontinuations, 8 patients no longer met criteria for use, 4 medications were no longer indicated, and 4 patients experienced AEs. It is unknown whether weight management medication was discontinued or not in 18 patients (17.2%).
DISCUSSION
This study evaluated the use and outcomes of weight loss medications over a longer period (up to 48 months) than what was previously studied among patients at VHI (12 months). The study aimed to better understand the long-term effect of weight loss medications, determine which medication had better long-term outcomes, and examine the reasons for medication discontinuation.
The results of this study displayed some similarities and differences compared with the Hood and colleagues study.16 Both yielded similar results for 5% of body weight loss and 10% of body weight loss. The largest difference was mean weight loss over the study period. In this study, patients lost a mean 10.6 kg over the course of weight loss medication use compared to 15.8 kg found by Hood and colleagues.16 A reason patients in the current study lost less weight overall could be the difference in time frames. The current study encompassed the COVID-19 pandemic, meaning fewer overall in-person patient appointments, which led to patients being lost to follow-up, missing weigh-ins during the time period, and gaps in care. For some patients, the pandemic possibly contributed to depression, missed medication doses, and a more sedentary lifestyle, leading to more weight gain.17 Telemedicine services at VHI expanded during the pandemic in an attempt to increase patient monitoring and counseling. It is unclear whether this expansion was enough to replace the in-person contact necessary to promote a healthy lifestyle.
VA pharmacists now care for patients through telehealth and are more involved in weight loss management. Since the conclusion of the Hood and colleagues study and start of this research, 2 pharmacists at VHI have been assigned to follow patients for obesity management to help with adherence to medication and lifestyle changes, management of AEs, dispense logistics, interventions for medications that may cause weight gain, and case management of glycemic control and weight loss with GLP-1RAs. Care management by pharmacists at VHI helps improve the logistics of titratable orders and save money by improving the use of high-cost items like GLP-1RAs. VA clinical pharmacy practitioners already monitor GLP-1RAs for patients with T2DM, so they are prepared to educate and assist patients with these medications.
It is important to continue developing a standardized process for weight loss medication management across the VA to improve the quality of patient care and optimize prescription outcomes. VA facilities differ in how weight loss management care is delivered and the level at which pharmacists are involved. Given the high rate of obesity among patients at the VA, the advent of new prescription options for weight loss, and the high cost associated with these medications, there has been increased attention to obesity care. Some Veterans Integrated Service Networks are forming a weight management community of practice groups to create standard operating procedures and algorithms to standardize care. Developing consistent processes is necessary to improve weight loss and patient care for veterans regardless where they receive treatment.
Limitations
The data used in this study were dependent on clinician documentation. Because of a lack of documentation in many instances, it was difficult to determine the full efficacy of the medications studied due to missing weight recordings. The lack of documentation made it difficult to determine whether patients were enrolled and active in the MOVE! program. It is required that patients enroll in MOVE! to obtain medications, but many did not have any follow-up MOVE! visits after initially obtaining their weight loss medication.
In this study, differences in the outcomes of patients with and without T2DM were not compared. It is the VA standard of care to prefer liraglutide over phentermine/topiramate in patients with T2DM or prediabetes.2 This makes it difficult to assess whether phentermine/topiramate or liraglutide is more effective for weight loss in patients with T2DM. Weight gain after the discontinuation of weight loss medications was not assessed. Collecting this data may help determine whether a certain weight loss medication is less likely to cause rebound weight gain when discontinued.
Other limitations to this study consisted of excluding patients who discontinued therapy within 6 months, small sample sizes on some medications, and lack of data on adherence. Adherence was based on medication refills, which means that if a patient refilled the medication, it was assumed they were taking it. This is not always the case, and while accurate data on adherence is difficult to gather, it can impact how results may be interpreted. These additional limitations make it difficult to accurately determine the efficacy of the medications in this study.
CONCLUSIONS
This study found similar outcomes to what has been observed in larger clinical trials regarding weight loss medications. Nevertheless, there was a lack of accurate clinical documentation for most patients, which limits the conclusions. This lack of documentation potentially led to inaccurate results. It revealed that many patients at VHI did not uniformly receive consistent follow-up after starting a weight loss medication during the study period. With more standardized processes implemented at VA facilities, increased pharmacist involvement in weight loss medication management, and increased use of established telehealth services, patients could have the opportunity for closer follow-up that may lead to better weight loss outcomes. With these changes, there is more reason for additional studies to be conducted to assess follow-up, medication management, and weight loss overall.
The Centers for Disease Control and Prevention (CDC) classifies individuals with a body mass index (BMI) of 25 to 29.9as overweight and those with a BMI > 30 as obese (obesity classes: I, BMI 30 to 34.9; II, BMI 35 to 39.9; and III, BMI ≥ 40).1 In 2011, the CDC estimated that 27.4% of adults in the United States were obese; less than a decade later, that number increased to 31.9%.1 In that same period, the percentage of adults in Indiana classified as obese increased from 30.8% to 36.8%.1 About 1 in 14 individuals in the US have class III obesity and 86% of veterans are either overweight or obese.2
High medical expenses can likely be attributed to the long-term health consequences of obesity. Compared to those with a healthy weight, individuals who are overweight or obese are at an increased risk for high blood pressure, high low-density lipoprotein cholesterol levels, low high-density lipoprotein cholesterol levels, high triglyceride levels, type 2 diabetes mellitus (T2DM), coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, cancer, mental health disorders, body pain, low quality of life, and death.3 Many of these conditions lead to increased health care needs, medication needs, hospitalizations, and overall health care system use.
Guidelines for the prevention and treatment of obesity have been produced by the American Heart Association, American College of Cardiology, and The Obesity Society; the Endocrine Society; the American Diabetes Association; and the US Departments of Veterans Affairs (VA) and Defense. Each follows a general algorithm to manage and prevent adverse effects (AEs) related to obesity. General practice is to assess a patient for elevated BMI (> 25), implement intense lifestyle modifications including calorie restriction and exercise, reassess for a maintained 5% to 10% weight loss for cardiovascular benefits, and potentially assess for pharmacological or surgical intervention to assist in weight loss.2,4-6
While some weight loss medications (eg, phentermine/topiramate, naltrexone/bupropion, orlistat, and lorcaserin) tend to have unfavorable AEs or mixed efficacy, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have provided new options.7-10 Lorcaserin, for example, was removed from the market in 2020 due to its association with cancer risks.11 The GLP-1RAs liraglutide and semaglutide received US Food and Drug Administration (FDA) approval for weight loss in 2014 and 2021, respectively.12,13 GLP-1RAs have shown the greatest efficacy and benefits in reducing hemoglobin A1c (HbA1c); they are the preferred agents for patients who qualify for pharmacologic intervention for weight loss, especially those with T2DM. However, these studies have not evaluated the long-term outcomes of using these medications for weight loss and may not reflect the veteran population.14,15
At Veteran Health Indiana (VHI), clinicians may use several weight loss medications for patients to achieve 5% to 10% weight loss. The medications most often used include liraglutide, phentermine/topiramate, naltrexone/bupropion, orlistat, and phentermine alone. However, more research is needed to determine which weight loss medication is the most beneficial for veterans, particularly following FDA approval of GLP-1RAs. At VHI, phentermine/topiramate is the preferred first-line agent unless patients have contraindications for use, in which case naltrexone/bupropion is recommended. These are considered first-line due to their ease of use in pill form, lower cost, and comparable weight loss to the GLP-1 medication class.2 However, for patients with prediabetes, T2DM, BMI > 40, or BMI > 35 with specific comorbid conditions, liraglutide is preferred because of its beneficial effects for both weight loss and blood glucose control.2
This study aimed to expand on the 2021 Hood and colleagues study that examined total weight loss and weight loss as a percentage of baseline weight in patients with obesity at 3, 6, 12, and > 12 months of pharmacologic therapy by extending the time frame to 48 months.16 This study excluded semaglutide because few patients were prescribed the medication for weight loss during the study.
METHODS
We conducted a single-center, retrospective chart review of patients prescribed weight loss medications at VHI. A patient list was generated based on prescription fills from June 1, 2017, to July 31, 2021. Data were obtained from the Computerized Patient Record System; patients were not contacted. This study was approved by the Indiana University Health Institutional Review Board and VHI Research and Development Committee.
At the time of this study, liraglutide, phentermine/topiramate, naltrexone/bupropion, orlistat, and phentermine alone were available at VHI for patients who met the clinical criteria for use. All patients must have been enrolled in dietary and lifestyle management programs, including the VA MOVE! program, to be approved for these medications. After the MOVE! orientation, patients could participate in group or individual 12-week programs that included weigh-ins, goal-setting strategies, meal planning, and habit modification support. If patients could not meet in person, phone and other telehealth opportunities were available.
Patients were included in the study if they were aged ≥ 18 years, received a prescription for any of the 5 available medications for weight loss during the enrollment period, and were on the medication for ≥ 6 consecutive months. Patients were excluded if they received a prescription, were treated outside the VA system, or were pregnant. The primary indication for the included medication was not weight loss; the primary indication for the GLP-1RA was T2DM, or the weight loss was attributed to another disease. Adherence was not a measured outcome of this study; if patients were filling the medication, it was assumed they were taking it. Data were collected for each instance of medication use; as a result, a few patients were included more than once. Data collection for a failed medication ended when failure was documented. New data points began when new medication was prescribed; all data were per medication, not per patient. This allowed us to account for medication failure and provide accurate weight loss results based on medication choice within VHI.
Primary outcomes included total weight loss and weight loss as a percentage ofbaseline weight during the study period at 3, 6, 12, 24, 36, and 48 months of therapy. Secondary outcomes included the percentage of patients who lost 5% to 10% of their body weight from baseline; the percentage of patients who maintained ≥ 5% weight loss from baseline to 12, 24, 36, and 48 months if maintained on medication for that duration; duration of medication treatment in weeks; medication discontinuation rate; reason for medication discontinuation; enrollment in the MOVE! clinic and the time enrolled; percentage of patients with a BMI of 18 to 24.9 at the end of the study; and change in HbA1c at 3, 6, 12, 24, 36, and 48 months.
Demographic data included race, age, sex, baseline weight, height, baseline BMI, and comorbid conditions (collected based on the most recent primary care clinical note before initiating medication). Medication data collected included medications used to manage comorbidities. Data related to weight management medication included prescribing clinic, maintenance dose of medication, duration of medication during the study period, the reason for medication discontinuation, or bariatric surgery intervention if applicable.
Basic descriptive statistics were used to characterize study participants. For continuous data, analysis of variance tests were used; if those results were not normal, then nonparametric tests were used, followed by pairwise tests between medication groups if the overall test was significant using the Fisher significant differences test. For nominal data, χ2 or Fisher exact tests were used. For comparisons of primary and secondary outcomes, if the analyses needed to include adjustment for confounding variables, analysis of covariance was used for continuous data. A 2-sided 5% significance level was used for all tests.
RESULTS
A total of 228 instances of medication use were identified based on prescription fills; 123 did not meet inclusion criteria (117 for < 6 consecutive months of medication use) (Figure). The study included 105 participants with a mean age of 56 years; 80 were male (76.2%), and 85 identified as White race (81.0%). Mean (SD) weight was 130.1 kg (26.8) and BMI was 41.6 (7.2). The most common comorbid disease states among patients included hypertension, dyslipidemia, obstructive sleep apnea, and T2DM (Table 1). The baseline characteristics were comparable to those of Hood and colleagues.16
Most patients at VHI started on liraglutide (63%) or phentermine/topiramate (28%). For primary and secondary outcomes, statistics were calculated to determine whether the results were statistically significant for comparing the liraglutide and phentermine/topiramate subgroups. Sample sizes were too small for statistical analysis for bupropion/naltrexone, phentermine, and orlistat.
Primary Outcomes
The mean (SD) weight of participants dropped 8.1% from 130.1 kg to 119.5 kg over the patient-specific duration of weight management medication therapy for an absolute difference of 10.6 kg (9.7). Duration of individual medication use varied from 6 to 48 months. Weight loss was recorded at 6, 12, 24, 36, and 48 months of weight management therapy. Patient weight was not recorded after the medication was discontinued.
When classified by medication choice, the mean change in weight over the duration of the study was −23.9 kg for 2 patients using orlistat, −10.2 kg for 46 patients using liraglutide, −11.0 kg for 25 patients using phentermine/topiramate, -7.4 kg for 1 patient using phentermine, and -13.0 kg for 4 patients using naltrexone/bupropion. Patients without a weight documented at the end of their therapy or at the conclusion of the data collection period were not included in the total weight loss at the end of therapy. There were 78 documented instances of weight loss at the end of therapy (Table 2).
Body weight loss percentage was recorded at 6, 12, 24, 36, and 48 months of weight management therapy. The mean (SD) body weight loss percentage over the duration of the study was 9.2% (11.2). When classified by medication choice, the mean percentage of body weight loss was 16.8% for 2 patients using orlistat, 9.4% for 46 patients using liraglutide, 8.2% for 25 patients using phentermine/topiramate, 6.0% for 1 patient using phentermine alone, and 10.6% for 4 patients using naltrexone/bupropion (Table 3).
Secondary Outcomes
While none of the secondary outcomes were statistically significant, the results of this study suggest that both medications may contribute to weight loss in many patients included in this study. Almost two-thirds of the included patients analyzed lost ≥ 5% of weight from baseline while taking weight management medication. Sixty-six patients (63%) lost ≥ 5% of body weight at any time during the data collection period. When stratified by liraglutide and phentermine/topiramate, 41 patients (63%) taking liraglutide and 20 patients (67%) taking phentermine/topiramate lost ≥ 5% of weight from baseline. Of the 66 patients who lost ≥ 5% of body weight from baseline, 36 (55%) lost ≥ 10% of body weight from baseline at any time during the data collection period.
The mean (SD) duration for weight management medication use was 23 months (14.9). Phentermine/topiramate was tolerated longer than liraglutide: 22.7 months vs 21.7 months, respectively (Table 4).
The average overall documented medication discontinuation rate was 35.2%. Reasons for discontinuation included 21 patient-elected discontinuations, 8 patients no longer met criteria for use, 4 medications were no longer indicated, and 4 patients experienced AEs. It is unknown whether weight management medication was discontinued or not in 18 patients (17.2%).
DISCUSSION
This study evaluated the use and outcomes of weight loss medications over a longer period (up to 48 months) than what was previously studied among patients at VHI (12 months). The study aimed to better understand the long-term effect of weight loss medications, determine which medication had better long-term outcomes, and examine the reasons for medication discontinuation.
The results of this study displayed some similarities and differences compared with the Hood and colleagues study.16 Both yielded similar results for 5% of body weight loss and 10% of body weight loss. The largest difference was mean weight loss over the study period. In this study, patients lost a mean 10.6 kg over the course of weight loss medication use compared to 15.8 kg found by Hood and colleagues.16 A reason patients in the current study lost less weight overall could be the difference in time frames. The current study encompassed the COVID-19 pandemic, meaning fewer overall in-person patient appointments, which led to patients being lost to follow-up, missing weigh-ins during the time period, and gaps in care. For some patients, the pandemic possibly contributed to depression, missed medication doses, and a more sedentary lifestyle, leading to more weight gain.17 Telemedicine services at VHI expanded during the pandemic in an attempt to increase patient monitoring and counseling. It is unclear whether this expansion was enough to replace the in-person contact necessary to promote a healthy lifestyle.
VA pharmacists now care for patients through telehealth and are more involved in weight loss management. Since the conclusion of the Hood and colleagues study and start of this research, 2 pharmacists at VHI have been assigned to follow patients for obesity management to help with adherence to medication and lifestyle changes, management of AEs, dispense logistics, interventions for medications that may cause weight gain, and case management of glycemic control and weight loss with GLP-1RAs. Care management by pharmacists at VHI helps improve the logistics of titratable orders and save money by improving the use of high-cost items like GLP-1RAs. VA clinical pharmacy practitioners already monitor GLP-1RAs for patients with T2DM, so they are prepared to educate and assist patients with these medications.
It is important to continue developing a standardized process for weight loss medication management across the VA to improve the quality of patient care and optimize prescription outcomes. VA facilities differ in how weight loss management care is delivered and the level at which pharmacists are involved. Given the high rate of obesity among patients at the VA, the advent of new prescription options for weight loss, and the high cost associated with these medications, there has been increased attention to obesity care. Some Veterans Integrated Service Networks are forming a weight management community of practice groups to create standard operating procedures and algorithms to standardize care. Developing consistent processes is necessary to improve weight loss and patient care for veterans regardless where they receive treatment.
Limitations
The data used in this study were dependent on clinician documentation. Because of a lack of documentation in many instances, it was difficult to determine the full efficacy of the medications studied due to missing weight recordings. The lack of documentation made it difficult to determine whether patients were enrolled and active in the MOVE! program. It is required that patients enroll in MOVE! to obtain medications, but many did not have any follow-up MOVE! visits after initially obtaining their weight loss medication.
In this study, differences in the outcomes of patients with and without T2DM were not compared. It is the VA standard of care to prefer liraglutide over phentermine/topiramate in patients with T2DM or prediabetes.2 This makes it difficult to assess whether phentermine/topiramate or liraglutide is more effective for weight loss in patients with T2DM. Weight gain after the discontinuation of weight loss medications was not assessed. Collecting this data may help determine whether a certain weight loss medication is less likely to cause rebound weight gain when discontinued.
Other limitations to this study consisted of excluding patients who discontinued therapy within 6 months, small sample sizes on some medications, and lack of data on adherence. Adherence was based on medication refills, which means that if a patient refilled the medication, it was assumed they were taking it. This is not always the case, and while accurate data on adherence is difficult to gather, it can impact how results may be interpreted. These additional limitations make it difficult to accurately determine the efficacy of the medications in this study.
CONCLUSIONS
This study found similar outcomes to what has been observed in larger clinical trials regarding weight loss medications. Nevertheless, there was a lack of accurate clinical documentation for most patients, which limits the conclusions. This lack of documentation potentially led to inaccurate results. It revealed that many patients at VHI did not uniformly receive consistent follow-up after starting a weight loss medication during the study period. With more standardized processes implemented at VA facilities, increased pharmacist involvement in weight loss medication management, and increased use of established telehealth services, patients could have the opportunity for closer follow-up that may lead to better weight loss outcomes. With these changes, there is more reason for additional studies to be conducted to assess follow-up, medication management, and weight loss overall.
1. Overweight & obesity. Centers for Disease Control and Prevention. Updated September 21, 2023. Accessed April 23, 2024. https://www.cdc.gov/obesity/index.html
2. US Department of Defense, US Department of Veterans Affairs. The Management of Adult Overweight and Obesity Working Group. VA/DoD Clinical Practice Guideline for the Management of Adult Overweight and Obesity. Updated July 2020. Accessed April 23, 2024. https://www.healthquality.va.gov/guidelines/CD/obesity/VADoDObesityCPGFinal5087242020.pdf
3. Health effects of overweight and obesity. Centers for Disease Control and Prevention. Updated September 24, 2022. Accessed April 23, 2024. https://www.cdc.gov/healthyweight/effects/index.html
4. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63(25 Pt B):2985-3023. doi:10.1016/j.jacc.2013.11.004
5. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342-362. doi:10.1210/jc.2014-3415
6. American Diabetes Association Professional Practice Committee. 3. Prevention or delay of type 2 diabetes and associated comorbidities: standards of medical care in diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S39-S45. doi:10.2337/dc22-S003
7. Phentermine and topiramate extended-release. Package insert. Vivus, Inc; 2012. Accessed April 23, 2024. https://qsymia.com/patient/include/media/pdf/prescribing-information.pdf
8. Naltrexone and bupropion extended-release. Package insert. Orexigen Therapeutics, Inc; 2014. Accessed April 23, 2024. https://contrave.com/wp-content/uploads/2024/01/Contrave-label-113023.pdf
9. Orlistat. Package insert. Roche Laboratories, Inc; 2009. Accessed April 23, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020766s026lbl.pdf
10. Lorcaserin. Package insert. Arena Pharmaceuticals; 2012. Accessed April 23, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022529lbl.pdf
11. FDA requests the withdrawal of the weight-loss drug Belviq, Belviq XR (lorcaserin) from the market. News release. US Food & Drug Administration. February 13, 2020. Accessed April 23, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-withdrawal-weight-loss-drug-belviq-belviq-xr-lorcaserin-market
12. Saxenda Injection (Liraglutide [rDNA origin]). Novo Nordisk, Inc. October 1, 2015. Accessed April 23, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206321Orig1s000TOC.cfm
13. FDA approves new drug treatment for chronic weight management, first since 2014. News release. US Food & Drug Administration. June 4, 2021. Accessed April 23, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
14. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New Engl J Med. 2015;373:11-22. doi:10.1056/NEJMoa1411892
15. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. New Engl J Med 2021;384:989-1002. doi:10.1056/NEJMoa2032183
16. Hood SR, Berkeley AW, Moore EA. Evaluation of pharmacologic interventions for weight management in a veteran population. Fed Pract. 2021;38(5):220-226. doi:10.12788/fp.0117
17. Melamed OC, Selby P, Taylor VH. Mental health and obesity during the COVID-19 pandemic. Curr Obes Rep. 2022;11(1):23-31. doi:10.1007/s13679-021-00466-6
1. Overweight & obesity. Centers for Disease Control and Prevention. Updated September 21, 2023. Accessed April 23, 2024. https://www.cdc.gov/obesity/index.html
2. US Department of Defense, US Department of Veterans Affairs. The Management of Adult Overweight and Obesity Working Group. VA/DoD Clinical Practice Guideline for the Management of Adult Overweight and Obesity. Updated July 2020. Accessed April 23, 2024. https://www.healthquality.va.gov/guidelines/CD/obesity/VADoDObesityCPGFinal5087242020.pdf
3. Health effects of overweight and obesity. Centers for Disease Control and Prevention. Updated September 24, 2022. Accessed April 23, 2024. https://www.cdc.gov/healthyweight/effects/index.html
4. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63(25 Pt B):2985-3023. doi:10.1016/j.jacc.2013.11.004
5. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342-362. doi:10.1210/jc.2014-3415
6. American Diabetes Association Professional Practice Committee. 3. Prevention or delay of type 2 diabetes and associated comorbidities: standards of medical care in diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S39-S45. doi:10.2337/dc22-S003
7. Phentermine and topiramate extended-release. Package insert. Vivus, Inc; 2012. Accessed April 23, 2024. https://qsymia.com/patient/include/media/pdf/prescribing-information.pdf
8. Naltrexone and bupropion extended-release. Package insert. Orexigen Therapeutics, Inc; 2014. Accessed April 23, 2024. https://contrave.com/wp-content/uploads/2024/01/Contrave-label-113023.pdf
9. Orlistat. Package insert. Roche Laboratories, Inc; 2009. Accessed April 23, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020766s026lbl.pdf
10. Lorcaserin. Package insert. Arena Pharmaceuticals; 2012. Accessed April 23, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022529lbl.pdf
11. FDA requests the withdrawal of the weight-loss drug Belviq, Belviq XR (lorcaserin) from the market. News release. US Food & Drug Administration. February 13, 2020. Accessed April 23, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-withdrawal-weight-loss-drug-belviq-belviq-xr-lorcaserin-market
12. Saxenda Injection (Liraglutide [rDNA origin]). Novo Nordisk, Inc. October 1, 2015. Accessed April 23, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206321Orig1s000TOC.cfm
13. FDA approves new drug treatment for chronic weight management, first since 2014. News release. US Food & Drug Administration. June 4, 2021. Accessed April 23, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
14. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New Engl J Med. 2015;373:11-22. doi:10.1056/NEJMoa1411892
15. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. New Engl J Med 2021;384:989-1002. doi:10.1056/NEJMoa2032183
16. Hood SR, Berkeley AW, Moore EA. Evaluation of pharmacologic interventions for weight management in a veteran population. Fed Pract. 2021;38(5):220-226. doi:10.12788/fp.0117
17. Melamed OC, Selby P, Taylor VH. Mental health and obesity during the COVID-19 pandemic. Curr Obes Rep. 2022;11(1):23-31. doi:10.1007/s13679-021-00466-6