Estimating the Impact of Obesity Medications on Clinical and Economic Outcomes

Incretin-based therapies that work by mimicking the action of the natural hormone GLP-1 and GLP-1/GIP have garnered the most excitement and demonstrated promising results in the management of obesity. This project seeks to estimate the impact of incretin-based obesity medications on clinical and economic outcomes in real-world settings. It proposes to fill gaps in the current literature by focusing on patients from self-insured organizations, measuring direct and indirect costs, establishing a long-term cohort, and by merging claims with electronic health record (EHR) data for more comprehensive measures.

The impact of incretin-based obesity medications on clinical and economic outcomes will be assessed in a dynamic cohort design. The cohort will be drawn from the employees and their working age dependents of large, self-insured (or "self-funded") organizations in the state of Indiana (i.e., "employers"). Employer organizations agreeing to participate will provide medical and pharmacy claims as well as data on workplace performance (if available) from 2018-2029. The primary exposure of interest is documented receipt of any GLP-1 obesity medication (regardless of manufacturer or brand name). A series of fixed-effects regression models will estimate the association between exposure to incretin-based obesity medications and clinical, utilization, and cost outcomes. This dynamic cohort approach, 1) individuals and participating employer organizations may enter and exit the cohort over time and 2) individuals may switch between on or off exposure over time.

• Incretin-based therapies (GLP-1 and GLP-1/GIP) (Drug), also known as Zepbound, Tirzepatide, Wegovy, Semaglutide, Saxenda, Liraglutide: Documented receipt of any GLP-1 and GLP-1/GIP obesity medication during an observation period.

Primary outcomes

• Change in subject body weight. [6 months periods from 2018 to 2029]: Measured in pounds.
• Change in subject body mass index (BMI). [6 months periods from 2018 to 2029]: Defined as Weight (kg) / height (m)2.
• Change in obesity and overweight classification. [6 months periods from 2018 to 2029]: Body mass index categorized according to Centers for Disease Control \& Prevention groupings (i.e., normal, overweight, class 1 obesity, class 2 obesity, class 3 obesity)

Secondary outcomes

• Change in emergency department visits. [6 months periods from 2018 to 2029]: Total visits
• Change in obesity-related emergency department visits. [6 months periods from 2018 to 2029]: Visit with obesity-related diagnosis code (E66.1-E66.3, Z68.30-768.45), metabolic syndrome, type 2 diabetes, chronic kidney disease, cardiovascular disease, osteoarthritis of the knee, depression, anxiety, metabolic dysfunction-associated steatohepatitis, nonalcoholic fatty liver disease \& steatohepatitis, obstructive sleep apnea, hyperlipidemia, hypertension, cerebrovascular disease, asthma, gastroesophageal reflux disease (GERD), or chronic obstructive pulmonary disease (COPD).
• Change in non-obesity related emergency department visits. [6 months periods from 2018 to 2029]: Visit without any of the following: obesity-related diagnosis code (E66.1-E66.3, Z68.30-768.45), metabolic syndrome, type 2 diabetes, chronic kidney disease, cardiovascular disease, osteoarthritis of the knee, depression, anxiety, metabolic dysfunction-associated steatohepatitis, nonalcoholic fatty liver disease \& steatohepatitis, obstructive sleep apnea, hyperlipidemia, hypertension, cerebrovascular disease, asthma, gastroesophageal reflux disease (GERD), or chronic obstructive pulmonary disease (COPD).
• Change in preventable emergency department visits. [6 months periods from 2018 to 2029]: Preventable visits include those that are: 1. non-emergent (the patient's initial complaint, presenting symptoms, vital signs, medical history, and age indicated that immediate medical care was not required within 12 hours), or 2. emergent/primary care treatable (based on information in the record, treatment was required within 12 hours, but care could have been provided effectively and safely in a primary care setting. The complaint did not require continuous observation, and no procedures were performed or resources used that are not available in a primary care setting), or 3. preventable/avoidable (Emergency department care was required based on the complaint or procedures performed/resources used, but the emergent nature of the condition was potentially preventable/avoidable if timely and effective ambulatory care had been received during the episode of illness).
• Change in non-preventable emergency department visits. [6 months periods from 2018 to 2029]: Non-preventable visits are defined as emergency department care was required and ambulatory care treatment could not have prevented the condition.
• Change in inpatient admissions. [6 months periods from 2018 to 2029]: Total number of distinct hospitalizations (i.e. admissions).
• Change in obesity-related inpatient admissions. [6 months periods from 2018 to 2029]: Total hospitalizations with obesity-related diagnosis code (E66.1-E66.3, Z68.30-768.45), metabolic syndrome, type 2 diabetes, chronic kidney disease, cardiovascular disease, osteoarthritis of the knee, depression, anxiety, metabolic dysfunction-associated steatohepatitis, nonalcoholic fatty liver disease \& steatohepatitis, obstructive sleep apnea, hyperlipidemia, hypertension, cerebrovascular disease, asthma, gastroesophageal reflux disease (GERD), or chronic obstructive pulmonary disease (COPD).
• Change in non-obesity-related inpatient admissions. [6 months periods from 2018 to 2029]: Total hospitalizations without obesity-related diagnosis code (E66.1-E66.3, Z68.30-768.45), metabolic syndrome, type 2 diabetes, chronic kidney disease, cardiovascular disease, osteoarthritis of the knee, depression, anxiety, metabolic dysfunction-associated steatohepatitis, nonalcoholic fatty liver disease \& steatohepatitis, obstructive sleep apnea, hyperlipidemia, hypertension, cerebrovascular disease, asthma, gastroesophageal reflux disease (GERD), or chronic obstructive pulmonary disease (COPD).
• Change in inpatient admissions that began in the emergency department. [6 months periods from 2018 to 2029]: Total hospitalizations where the subject was admitted from the emergency department.
• Change in direct admit inpatient admissions [6 months periods from 2018 to 2029]: Total hospitalizations that were admitted directly from the community, i.e. not transferred from the emergency department.
• Change in 30 day inpatient readmissions. [6 months periods from 2018 to 2029]: Count of hospital admissions (to any facility) occurring within 30 days of a hospital stay.
• Change in outpatient visits. [6 months periods from 2018 to 2029]: Any in-person office visits with primary care, family medicine, internal medicine, or any specialty (including behavioral health); excludes phone visits. Total visits, as well as separated by obesity-related vs non-obesity related.
• Change in obesity-related outpatient visits. [6 months periods from 2018 to 2029]: Total in-person office visits with primary care, family medicine, internal medicine, or any specialty (including behavioral health) with any of the following: obesity-related diagnosis code (E66.1-E66.3, Z68.30-768.45), metabolic syndrome, type 2 diabetes, chronic kidney disease, cardiovascular disease, osteoarthritis of the knee, depression, anxiety, metabolic dysfunction-associated steatohepatitis, nonalcoholic fatty liver disease \& steatohepatitis, obstructive sleep apnea, hyperlipidemia, hypertension, cerebrovascular disease, asthma, gastroesophageal reflux disease (GERD), or chronic obstructive pulmonary disease (COPD). Excludes: phone visits.
• Change in non-obesity-related outpatient visits [6 months periods from 2018 to 2029]: Total in-person office visits with primary care, family medicine, internal medicine, or any specialty (including behavioral health) without any of the following: obesity-related diagnosis code (E66.1-E66.3, Z68.30-768.45), metabolic syndrome, type 2 diabetes, chronic kidney disease, cardiovascular disease, osteoarthritis of the knee, depression, anxiety, metabolic dysfunction-associated steatohepatitis, nonalcoholic fatty liver disease \& steatohepatitis, obstructive sleep apnea, hyperlipidemia, hypertension, cerebrovascular disease, asthma, gastroesophageal reflux disease (GERD), or chronic obstructive pulmonary disease (COPD). Excludes: phone visits.
• Change in total medical spending. [6 months periods from 2018 to 2029]: All medical costs paid (inpatient, outpatient, emergency department, and rehabilitation costs).
• Change in total pharmacy spending. [6 months periods from 2018 to 2029]: All pharmacy costs paid.
• Change in total pharmacy spending excluding incretin-based medications. [6 months periods from 2018 to 2029]: All pharmacy costs excluding the cost of incretin obesity medications
• Change in total spending on obesity-related complications [6 months periods from 2018 to 2029]: All medical costs paid where the claim is associated with any of the following: obesity-related diagnosis code (E66.1-E66.3, Z68.30-768.45), metabolic syndrome, type 2 diabetes, chronic kidney disease, cardiovascular disease, osteoarthritis of the knee, depression, anxiety, metabolic dysfunction-associated steatohepatitis, nonalcoholic fatty liver disease \& steatohepatitis, obstructive sleep apnea, hyperlipidemia, hypertension, cerebrovascular disease, asthma, gastroesophageal reflux disease (GERD), or chronic obstructive pulmonary disease (COPD). Excludes: telehealth / phone visits.

Other outcomes

• Change in absenteeism. [6 months periods from 2018 to 2029]: Total number of sick leave days (costs estimated from published estimates or salary information if available).
• Change in retention / turnover. [6 months periods from 2018 to 2029]: Percent of employees that end employment for any reason.
• Change in disability claims. [6 months periods from 2018 to 2029]: Total worker's compensation claims regardless of disability period.
• Change in clinical A1C laboratory values. [6 months periods from 2018 to 2029]: hemoglobin A1C or HbA1c values
• Change in blood pressure laboratory values. [6 months periods from 2018 to 2029]: Systolic and diastolic
• Change in cholesterol laboratory values. [6 months periods from 2018 to 2029]: cholesterol blood test (a lipid panel or lipid profile

Sex: All, ages: 18 Years to 64 Years

The study cohort is limited to employees and adult dependents aged 18-64 who receive their health insurance coverage from self-insured Indiana employers that agree to participate in the study.

To be included in the study, the individuals must:

1. Be an Indiana resident;
2. Have health insurance benefits provided by participating employers (includes employees and dependents);
3. Be between the ages of 18 and 64;
4. Meet the eligibility criteria for an obesity medication prescription:

   1. BMI of ≥ 30 (obesity) or
   2. BMI of ≥ 25 (overweight) and at least one body weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea, or cardiovascular disease). If the prescribing eligibility criteria are updated in the future, we will update accordingly.
5. Individuals must have at least 6 months of enrollment prior to study inclusion (i.e., prior to the index date), though we may use additional pre-treatment data if available.

An individual who meets any of the following criteria will be excluded from participation in the cohort:

1. Has a condition associated with weight loss: a diagnosis of cancer (except for non-melanoma skin cancer), pancreatitis, eating disorders (e.g., anorexia nervosa and avoidant restrictive food intake disorder), HIV, unintentional weight loss, or cirrhosis at baseline;
2. Has a condition for which obesity medications are contraindicated (for example, medullary thyroid carcinoma, multiple endocrine neoplasia, etc.).
3. Receipt of diabetes-indicated incretin-based medications. If an individual has a claim for a related incretin-based therapy diabetes medication (e.g., Mounjaro, Ozempic, Rybelsus, Victoza) without an obesity-medication claim during the study period, the individual will be excluded from analysis.
4. Prior bariatric surgery.
5. Evidence of prior use of incretin-based obesity medications for weight loss.

• Joshua R Vest, PhD, MPH, Principal investigator, Indiana University