Prediction of the SEPRA Diabetes Trial in Healthcare Claims Data
Conditions: Diabetes Mellitus, Type 2
Sponsor: Brigham and Women's Hospital

 
 
 
Prediction of Long Term Comparative Effectiveness of Once 
Weekly Semaglutide Versus Standard of Care in a Real World 
Adult US Population With Type 2 Diabetes - a Randomized 
Pragmatic Trial (SEPRA trial) 
 
DUPLICATE – SEPRA  
 
October 7, 2022 

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1. RCT Details 
This section provides a high-level overview of an ongoing RCT that the described real-world evidence study is trying to replicate 
as closely as possible given the remaining limitations inherent in the healthcare databases. 
 
1.1 Title 
Long Term Comparative Effectiveness of Once Weekly Semaglutide Versus Standard of Care in a Real World Adult US 
Population With Type 2 Diabetes - a Randomized Pragmatic Trial (SEPRA trial) - NCT03596450  
 
1.2 Intended aim(s) 
To evaluate the effects of semaglutide injection (Ozempic®) on hemoglobin A1c (HbA1c) compared to the standard of care 
in patients with type 2 diabetes on metformin who are treated in a practice setting. 
 
1.3 Primary endpoint for replication  
Long-term glycemic control defined as proportion of patients who will achieve an HbA1c of less than 7.0% (53.0 mmol/mol) 
at 365 days after drug initiation. 
 
1.4 Required power for primary endpoint and noninferiority margin (if applicable) 
The trial is estimated to enroll 1,387 patients. 
 
1.5 Secondary endpoint for replication and RCT finding 
Change in HbA1c from baseline at 365 days after drug initiation. 
Number of hypoglycemic episodes leading to an inpatient admission or emergency room encounter. 
 
1.6 Trial estimate 
The trial is ongoing and scheduled to finalize the data collection for the primary outcome on June 9, 2023 (estimated 
primary completion date updated on 28 September 2022). 
 
2. Person responsible for implementation of replication in Aetion 
Elvira D’Andrea, MD, PhD, implemented the study design in the Aetion Evidence Platform and SAS 9.4. She is not responsible for 
the validity of the design and analytic choices. All implementation steps are recorded, and the implementation history is archived 
in the platform. 

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3. Data Source(s) 
Optum® Clinformatics® Data Mart Database 
 
4. Study Design Diagram 
The study design diagram visualizes key aspects of the longitudinal study design for expedited review. 
 
Figure 1. Design Diagram – SEPRA (SEMAGLUTIDE pRCT) TRIAL REPLICATION 
 

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5. Cohort Identification  
 
Note. The feasibility counts were run on Optum® Clinformatics® version of Dec 23, 2021, for the study period between Dec 6, 2017, 
to Jun 30, 2021. The primary analysis will be run by implementing the protocol on refreshed data that includes data up to March 
30, 2022. Therefore, the cohorts for the primary analyses are expected to be larger than those of the initial feasibility analyses 
presented in this protocol. 
 
5.1 Cohort Summary 
This study will involve a new user, parallel group, propensity score-matched, retrospective cohort design comparing injectable 
subcutaneous semaglutide (once weekly) to standard of care, i.e., dipeptidyl peptidase 4 inhibitors (DPP-4i), sodium-glucose 
cotransporter 2 inhibitors (SGLT2i), other glucagon-like peptide-1 receptor agonists (GLP-1 RA) - except for semaglutide oral and 
injection -, or 2nd generation sulfonylureas (SU). Treatments in both arms are administered in combination with metformin. 
Patients will be required to have continuous enrollment during a baseline period of 180 days before initiation of semaglutide or 
standard of care. The analyses will be restricted to individuals with type 2 diabetes mellitus who are on treatment with 
metformin, defined as the presence of at least 1 prescription for metformin within 120 days (90 days + 30 days of grace period) 
before and including cohort entry. The information for emulating the trial implementation is collected from clinicaltrial.gov, 
version submitted on September 7, 2022 (NCT03596450), and questions to the trialists (responses received on September 26, 
2022). 
 
5.2 Important steps for cohort formation 
New use of semaglutide injection (exposure) is defined as no use of the exposure drug within 180 days prior to index date. New 
use of standard of care (comparator) is defined as no use of the DPP-4i, SGLT2i, GLP-1 RA (except semaglutide) or 2nd generation 
SU within 180 days prior to index date. Eligible patients are required to be new users with respect to both exposure and 
comparator groups, defined as no use of both exposure and comparator drugs within at least 180 days prior to index date.  
 
5.2.1 Data Source 
Optum® Clinformatics® Data Mart Database (CDM): Dec 6, 2017 – Jun 30, 2021  
The study will be conducted in the de-identified Optum® CDM because this database is linked with national lab test 
provider chains. Thus, the results for outpatient laboratory tests (including test results of HbA1c) are available for a subset 

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of approximately 45% beneficiaries. 
 
5.2.2 Eligible cohort entry dates 
Semaglutide injection, for subcutaneous use, was first approved by FDA to improve glycemic control in adults with type 2 
diabetes mellitus on Dec 5, 2017 (the approval of the comparator drugs for the same indication was antecedent to 2017). 
Thus, the initial eligible cohort entry date is the first date after the FDA approval available in the data.  
Although the primary analysis of the trial used an “intention-to-treat” (ITT) approach - as implied on clinicaltrial.gov and 
confirmed by the trialists -, we conducted a secondary analysis using an “as-treated” (AT) approach because of the nature 
of the real-world data (please refer to paragraph 6.3.2 for further details). Based on this decision we created two study 
cohorts which differ by the last eligible date of cohort entry: 
- 
COHORT ITT - The last eligible date for the cohort that will be analyzed with an “intent to treat” approach is Aug 31, 
2020, ten months before the end of all available data in Optum® CDM. Since the effects of semaglutide, DPP-4i, 
SGLT2i, GLP-1 RA (except semaglutide) and 2nd generation SU on the outcome will be estimated between 275 and 455 
days after cohort entry, this will allow all eligible patients to contribute to the outcome (see Section 6.3). 
- 
COHORT AT - The last eligible date for the cohort that will be analyzed with an “as-treated” approach is Feb 28, 2021, 
four months before the end of all available data in Optum® CDM. Since the effects of semaglutide, DPP-4i, SGLT2i, 
GLP-1 RA (except semaglutide) and 2nd generation SU on the outcome will be estimated between 91 and 212 days 
after cohort entry, this will allow all eligible patients to contribute to the outcome (see Section 6.3). 
- 
 
 
5.2.3 Specify inclusion/exclusion criteria for cohort entry and define the index date 
Inclusion and exclusion criteria were adapted from the trial as closely as possible. Definitions for all inclusion/exclusion 
are provided in Appendix A and are summarized in the flowcharts below. 
 
Note. Patients who do not start the follow up or are censored between cohort entry and the beginning of the outcome 
assessment window (i.e., COHORT AT: 0-90 days after cohort entry, COHORT ITT: 0-274 days after cohort entry) for the 
reasons reported in the Section 6.3.2 will not contribute to the baseline characteristics of the unmatched or matched 
cohorts. Further details on the number of patients who are excluded from the study cohort are reported in Section 7. 
 
5.3 Flowchart of the study cohort assembly 
Aetion link to the cohort creation of semaglutide vs. standard of care 
COHORT AT: https://bwh-dope.aetion.com/cohorts/details/34150/1673/86399/basics 

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COHORT ITT: https://bwh-dope.aetion.com/cohorts/details/34149/1673/86398/basics 
 
Optum® 
COHORT AT 
Optum® 
COHORT ITT 
Excluded 
Patients 
Remaining 
Patients 
Excluded 
Patients 
Remaining 
Patients 
Patients in dataset 
81,796,156 
 
81,796,156 
Patients meeting cohort entry criteria 
1,391,063 
 
1,267,388 
Excluded due to insufficient enrollment 
-185,893 (13%) 
1,205,170 
-157,177 (12%) 
1,110,211 
Excluded due to prior use of referent 
-1,006,363 (84%) 
198,807 
-943,160 (85%) 
167,051 
Excluded due to prior use of exposure 
-46,187 (23%) 
152,620 
-35,553 (21%) 
131,498 
Excluded because patient qualified in >1 exposure category 
-164 (<1%) 
152,456 
-101 (<1%) 
131,397 
Excluded based on Inclusion Age ≥ 18 
-34 (<1%) 
152,422 
-27 (<1%) 
131,370 
Excluded based on Exclusion for Age missing 
-10 (<1%) 
152,412 
-6 (<1%) 
131,364 
Excluded based on Exclusion for Gender unknown/missing 
-54 (<1%) 
152,358 
-44 (<1%) 
131,320 
Excluded based on Inclusion Type 2 diabetes mellitus 
-8,127 (5%) 
144,231 
-6,929 (5%) 
124,391 
Excluded based on Inclusion Use of Metformin  
-49,397 (34%) 
94,834 
-41,708 (34%) 
82,683 
Excluded based on Inclusion At least 2 HbA1c records within the prior 280 days 
-48,281 (51%) 
46,553 
-42,342 (51%) 
40,341 
Excluded based on Inclusion At least 1 HbA1c record ≥ 7% within the prior 90 days 
-5,365 (12%) 
41,188 
-4,644 (12%) 
35,697 
Excluded based on Exclusion Use of any other anti-diabetes medications 
-893 (2%) 
40,295 
-857 (2%) 
34,840 
Excluded based on Exclusion Any insulin use 
-2,114 (5%) 
38,181 
-1,881 (5%) 
32,959 
Excluded based on Exclusion Pregnancy 
-3 (<1%) 
38,178 
-2 (<1%) 
32,957 
Excluded based on Exclusion Multiple Endocrine Neoplasia syndrome type 2 
-0 (<1%) 
38,178 
-0 (<1%) 
32,957 
Excluded based on Exclusion CKD stage 5, ESRD, dialysis or renal transplant 
-6 (<1%) 
38,172 
-5 (<1%) 
32,952 
Excluded based on Exclusion Nursing home admission 
-129 (<1%) 
38,043 
-112 (<1%) 
32,840 
Patients in Exposure Group (Semaglutide injectable) 
1,083 
 
796 
Patients in Referent Group (DPP-4i, SGLT2i, GLP-1 RA except semag., 2nd gen SU) 
36,960 
 
32,044 
Final cohort 
38,043 
 
32,840 
 
6. Variables  
 
6.1 Exposure-related variables:  

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Study drug:  
New initiation of injectable subcutaneous semaglutide (once weekly), a glucagon-like peptide-1 receptor agonist. New initiation 
is defined as no use of semaglutide within 180 days before treatment initiation (washout period). New users of semaglutide are 
not allowed to receive DPP-4i, SGLT2i, GLP-1 RA (except semaglutide) or 2nd generation SU within 180 days prior to treatment 
initiation. Concurrent use of metformin is required. 
 
Comparator agent: 
New initiation of “standard of care” (oral). New initiation is defined as no use of DPP-4i, SGLT2i, GLP-1 RA (except semaglutide) 
or 2nd generation SU within 180 days before treatment initiation (washout period). New users of DPP-4i, SGLT2i, GLP-1 RA 
(except semaglutide) or 2nd generation SU are not allowed to receive semaglutide within 180 days prior to treatment initiation. 
Concurrent use of metformin is required. In the pragmatic trial, “standard of care” was defined as commercially available 
antidiabetic medication other than semaglutide. In sensitivity analyses we will compare semaglutide with each of the drug 
classes included in the standard of care separately. 
 
6.2 Preliminary Covariates: 
 Age 
 Gender 
 Combined Comorbidity Index (CCI), measured over the baseline covariate assessment period, defined as 180 days prior to 
and including index date. 
 
Covariates listed above represent only a small subset of covariates that will ultimately be controlled for in the design and 
analysis. We use the covariates above only for initial feasibility analyses to judge whether there is likely to be sufficient overlap 
between treatment groups to proceed with the study. Remaining covariates are defined only after the study has passed the 
initial feasibility analysis and the initial power assessment and are listed in Table 1 (Appendix B).  
 
6.3 Outcome variables and study follow-up:  
 
6.3.1 Outcome variables 
 
Effectiveness outcome variables of interest (definitions provided in Appendix A): 

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 Primary outcome:  
o Proportion of patients who achieve an HbA1c of less than 7.0% (53.0 mmol/mol) at the HbA1c test closest to 365 
days (allowable range: 275 to 455 days) after treatment initiation (ITT analysis, see paragraph 6.3.2.2). 
 Secondary outcome:  
o Proportion of participants who will achieve an HbA1c of less than 7.0% (53.0 mmol/mol) at the HbA1c test closest 
to 26 weeks (allowable range: 12 weeks to 30 weeks) after treatment initiation (AT analysis, see paragraph 6.3.2.1)  
o Changes in HbA1c from baseline to 26 weeks (AT analysis, see paragraph 6.3.2.1) or to 52 weeks (ITT analysis, see 
paragraph 6.3.2.2) after treatment initiation. 
o Number of hypoglycemic episodes leading to an inpatient admission or emergency room encounter (AT analysis, 
see paragraph 6.3.2.1) 
 
Note. In the emulation, as well as in the pragmatic trial, the HbA1c at baseline is defined as the last recorded HbA1c value measured 
within 91 days before and including cohort entry date. The HbA1c at the end of follow-up is defined as the recorded HbA1c value 
closest to 365 days and measured between 275 and 455 days (1 year +/- 90 days) after cohort entry for the ITT analysis and the 
recorded HbA1c value closest to 182 days (26 weeks) and measured between 91 and 212 days (12-30 weeks) after cohort entry for 
the AT analysis.  
 
 
6.3.2 Primary analysis and study follow-up 
Based on the information reported on clinicaltrial.gov and the answers received after contacting the SEPRA trialists, we learnt 
that dedicated study visits are programmed at randomization, at year 1, and at year 2 post-randomization. The study will also 
capture data collected at the sites during routine diabetic care visits, i.e., office visits and other patient contacts that occur as 
part of routine clinical practice. Routine diabetic care visits will occur per study physician’s routine clinical practice, therefore the 
number of visits and data available may differ from site to site and patient to patient. The outcome (HbA1c value) at baseline is 
defined as an HbA1c value recorded ≤ 90 days prior to randomization visit (week 0). The dedicated visit at 1 year is performed by 
the trialists at 52 (± 10) weeks) after randomization. If endpoint data at year 1 is missing or outside of 52 ± 10 weeks, then the 
routine diabetic care data closest to 52 weeks post-randomization ±10 weeks will be used. If no routine diabetic care data are 
available 52 (± 10) weeks post-randomization, then year 1 endpoint data will be considered missing and imputed, if applicable. 

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Because of anticipated shorter follow-up time in our data, we will not replicate the results of the trial at 2 years post-
randomization. 
Our RWE study will use an ITT analysis that disregards changes in treatment over the course of 1 year follow up as the primary 
analysis. However, to address potential differences in adherence due to measures or initiatives applied by the researchers of the 
SEPRA trial (e.g., routine calls, incentives etc.) and the high discontinuation rates in clinical practice, our emulation will include a 
secondary analysis focused on “as-treated” (AT) analysis which censors patients when they discontinue or switch treatments. In 
both ITT and AT analyses, the treatment drug will be defined as the index drug assigned on the day of cohort entry. Both 
analyses will use 1:1 nearest-neighbor matching on the propensity score to adjust for confounding with a matching caliper of 
0.01. 
6.3.2.1 
ITT analysis 
In the ITT analysis patients will be followed between 275 and 455 days after cohort entry (1 year +/- 3 months). The outcome 
assessment window will start 275 days after cohort entry date and will continue until the earliest date of the following events:  
 Occurrence of the outcome of interest (HbA1c value measured closest to 365 days after cohort entry), 
 End of continuous registration in the database (disenrollment or end of available data), 
 End of the study period, 
 Death, 
 Nursing home admission. 
 
6.3.2.2 
AT analysis 
In the AT analysis patients will be followed between 91 and 212 days after cohort entry. The outcome assessment window will 
start 91 days after cohort entry date and will continue until the earliest date of the following events:  
 Occurrence of the outcome of interest (HbA1c value closest to 182 days, measured between 91 and 212 days after cohort 
entry), 
 End of continuous registration in the database (disenrollment or end of available data), 
 End of the study period, 
 Death, 

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 Index drug discontinuation (discontinuation is defined by a gap of more than 60 days following the last days supply, episodes 
of treatment less than 60 days apart are bridged and treated as continuously exposed during the gap), 
 Crossover or addition of drug from the other treatment group, 
 Switching between the drug classes of the comparator group (i.e., DPP-4i to SGLT2i or SU or GLP-1 RA except semaglutide, 
SGLT2i to DPP-4i or SU or GLP-1 RA except semaglutide, SU to DPP-4i or SGLT2i or GLP-1 RA except semaglutide) 
 Addition of any other anti-diabetic medications, 
 Nursing home admission (nursing home admissions are considered a censoring event because the data sources utilized 
typically provide little to no data on drug utilization after admission. For the same reason we will exclude nursing home 
residents from our cohorts). 
 
6.3.2.3 
ITT analysis 
In the ITT analysis patients will be followed between 275 and 455 days after cohort entry (1 year +/- 3 months). The outcome 
assessment window will start 275 days after cohort entry date and will continue until the earliest date of the following events:  
 Occurrence of the outcome of interest (HbA1c value measured closest to 365 days after cohort entry), 
 End of continuous registration in the database (disenrollment or end of available data), 
 End of the study period, 
 Death, 
 Nursing home admission. 
 
6.3.3 Sensitivity analyses:  
 Evaluate primary and secondary outcomes using fine stratification on the propensity score instead of 1:1 matching to 
boost power 
 Evaluate primary and secondary outcomes using each of the 3 drug classes included in the standard of care definition as 
the comparator (DPP-4i, SGLT2i, GLP-1 RA except semaglutide, or 2nd generation SU) to better understand class effects 
 
Note. To decrease the incidence of missing values of the outcome, we required that the eligible patients had at least 2 HbA1c 
measurements recorded within 280 days before and including cohort entry. This increases the probability of including in the final 
cohort patients who are adherent to a routinely HbA1c testing and, consequently, will decrease the frequency of missing values of the 

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outcome. After assessing the diagnostics for different techniques to handle missing values (i.e., complete case analysis, multiple 
imputation, and IPCW) of the outcome, we decided to apply the multiple imputation technique to the primary analysis and test the 
robustness of the results with a sensitivity analysis applying the complete case analysis technique.  
 
7. Initial Feasibility Analysis  
Aetion report name: 
For semaglutide vs. standard of care 
Optum® CDM [AT analysis: proper outcome assessed within 91-212 days after cohort entry]: https://bwh-
dope.aetion.com/projects/details/1673/rwrs/86429 
Optum® CDM [ITT analysis: proper outcome assessed within 275-455 days after cohort entry]: https://bwh-
dope.aetion.com/projects/details/1673/rwrs/86428 
Optum® CDM [AT analysis: dummy outcome assessed within 91-212 days after cohort entry]: https://bwh-
dope.aetion.com/projects/details/1673/rwrs/86431 
Optum® CDM [ITT analysis: dummy outcome assessed within 275-455 days after cohort entry]: https://bwh-
dope.aetion.com/projects/details/1673/rwrs/86430 
 
Date conducted: 09/29/2022 
 
Complete Aetion feasibility analysis using age and CCI as the only covariates and the primary outcome (Section 6.3). No measures of 
association will be computed nor will mean and standard deviation of the HbA1c outcome stratified by treatment group. 
 
 Report patient characteristics by treatment group 
For semaglutide vs. standard of care  
 

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BEFORE 1:1 PS MATCHING on AGE, CCI 
 
Optum CDM – COHORT AT 
Optum CDM – COHORT ITT 
 
Standard of care- 
Comparator 
Semaglutide inj. - 
Exposure 
Difference 
Standard of care- 
Comparator 
Semaglutide inj. - 
Exposure 
Difference 
Number of patients * 
18,706 
682 
- (-, -) 
26,541 
635 
- (-, -) 
Age 
 
 
 
...mean (sd) 
65.27 (11.34) 
56.87 (11.91) 
8.40 (7.49, 9.31) 
64.75 (11.55) 
56.80 (11.95) 
7.94 (7.00, 8.89) 
...median [IQR] 
67.00 [59.00, 73.00] 
57.00 [48.00, 66.00] 
- (-, -) 
67.00 [58.00, 73.00] 
57.00 [48.00, 67.00] 
- (-, -) 
Gender 
 
 
 
 
 
 
...M = MALE; n (%) 
10,545 (56.4%) 
331 (48.5%) 
7.8% (3.9%, 11.7%) 
14,310 (53.9%) 
302 (47.6%) 
6.4% (2.3%, 10.4%) 
...F = FEMALE; n (%) 
8,161 (43.6%) 
351 (51.5%) 
-7.8% (-11.7%, -3.9%) 
12,231 (46.1%) 
333 (52.4%) 
-6.4% (-10.4%, -2.3%) 
Combined Comorbidity Score - 
CCI (180 days) 
 
 
 
...mean (sd) 
1.31 (1.97) 
1.11 (1.68) 
0.20 (0.07, 0.33) 
1.37 (1.98) 
1.06 (1.60) 
0.31 (0.19, 0.44) 
...median [IQR] 
1.00 [0.00, 2.00] 
1.00 [0.00, 2.00] 
- (-, -) 
1.00 [0.00, 2.00] 
1.00 [0.00, 2.00] 
- (-, -) 
* Patients who were censored between cohort entry and the beginning of the outcome assessment window are excluded and will not contribute to the 
unmatched or matched cohorts. 

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AFTER 1:1 PS MATCHING on AGE, CCI 
 
Optum CDM – COHORT AT 
Optum CDM – COHORT ITT 
 
Standard of care- 
Comparator** 
Semaglutide inj. - 
Exposure 
Difference 
Standard of care- 
Comparator** 
Semaglutide inj. - 
Exposure 
Difference 
Number of patients * 
682 
682 
- (-, -) 
635 
635 
- (-, -) 
Age 
 
 
 
...mean (sd) 
56.87 (11.91) 
56.87 (11.91) 
0.00 (-1.26, 1.26) 
56.80 (11.95) 
56.80 (11.95) 
0.00 (-1.32, 1.32) 
...median [IQR] 
57.00 [48.00, 66.00] 
57.00 [48.00, 66.00] 
- (-, -) 
57.00 [48.00, 67.00] 
57.00 [48.00, 67.00] 
- (-, -) 
Gender 
 
 
 
 
 
 
...M = MALE; n (%) 
402 (58.9%) 
331 (48.5%) 
10.4% (5.0%, 15.8%) 
366 (57.6%) 
302 (47.6%) 
10.1% (4.5%, 15.7%) 
...F = FEMALE; n (%) 
280 (41.1%) 
351 (51.5%) 
-10.4% (-15.8%, -
5.0%) 
269 (42.4%) 
333 (52.4%) 
-10.1% (-15.7%, -
4.5%) 
Combined Comorbidity Score - 
CCI (180 days) 
 
 
 
...mean (sd) 
0.97 (1.72) 
1.11 (1.68) 
-0.14 (-0.32, 0.04) 
1.02 (1.81) 
1.06 (1.60) 
-0.05 (-0.23, 0.14) 
...median [IQR] 
1.00 [0.00, 2.00] 
1.00 [0.00, 2.00] 
- (-, -) 
1.00 [0.00, 2.00] 
1.00 [0.00, 2.00] 
- (-, -) 
* Patients who were censored between cohort entry and the beginning of the outcome assessment window are excluded and will not contribute to the 
unmatched or matched cohorts. 
 
 
 Report summary parameters of study population FEASIBILITY- FOR STUDY OUTCOME 
For semaglutide vs. standard of care 
 

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Optum CDM 
COHORT AT 
Optum CDM 
COHORT ITT 
Number of patients in full cohort 
38,043 
32,840 
Number of patients who did not begin follow-up * 
18,655 
5,664 
Number of patients in the analytic cohort 
19,388 
27,176 
Number of events** 
4,203 
6,481 
Number of patients with an HbA1c value recorded during follow-up 
9,671 
16,965 
Number of patients in group (before matching): Standard of care 
18,706 
26,541 
Number of patients in group (before matching): Semaglutide 
682 
635 
Number of patients in group (after matching): Standard of care 
682 
635 
Number of patients in group (after matching): Semaglutide 
682 
635 
Risk per 1,000 patients 
216.78 
238.48 
* Patients who were censored between cohort entry and the beginning of the outcome assessment window. 
** Patients with HbA1c < 7% recorded between 91-212 days after cohort entry in the cohort AT and between 275-455 days after cohort entry in the cohort ITT.  
 
 
 
 Report median follow-up time by treatment group 
For semaglutide vs. standard of care 
 
 
Median Follow-Up Time (Days) [IQR] – AT analysis* 
Median Follow-Up Time (Days) [IQR] – ITT analysis* 
Patient Group 
Optum CDM – COHORT AT 
Optum CDM - COHORT ITT 
Overall Patient Population 
70 [37, 121] 
165 [66, 180] 
Referent 
86 [51, 121] 
180 [82, 180] 
Exposure 
58 [28, 116] 
122 [54, 180] 
* The median follow-up time is defined as the median number of days that a patient is followed within the outcome assessment window, which begins 91 days 
and ends 212 days after the cohort entry date for the COHORT AT, and it begins 275 days and ends 455 days after the cohort entry date for the COHORT ITT 
 
 
 Report reasons for censoring in the overall study population after matching 

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For semaglutide vs. standard of care – COHORT AT 
 
Overall 
N = 1,364 
Standard care (DPP-4i, 
SGLT-2ra, SU) 
N = 682 
Semaglutide 
N = 682 
Dummy outcome* 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Death 
1 (0.1%) 
1 (0.1%) 
0 (0.0%) 
Maximum follow-up time 
667 (48.9%) 
349 (51.2%) 
318 (46.6%) 
End of patient data 
58 (4.3%) 
22 (3.2%) 
36 (5.3%) 
End of patient enrollment 
96 (7.0%) 
48 (7.0%) 
48 (7.0%) 
Augmentation or Switching to other antidiabetic drugs; switching 
between comparator classes; nursing home admission; 
discontinuation of metformin, semaglutide or standard of care 
(with 60 days of grace period) 
542 (39.7%) 
262 (38.4%) 
280 (41.1%) 
* dummy outcome of a 90-day gap in database enrollment 
 
For semaglutide vs. standard of care – COHORT ITT 
 
Overall 
N = 1,270 
Standard care (DPP-4i, 
SGLT-2ra, SU) 
N = 635 
Semaglutide 
N = 635 
Dummy outcome* 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Death 
6 (0.5%) 
4 (0.6%) 
2 (0.3%) 
Maximum follow-up time 
861 (67.8%) 
472 (74.3%) 
389 (61.3%) 
End of patient data 
267 (21.0%) 
80 (12.6%) 
187 (29.4%) 
End of patient enrollment 
123 (9.7%) 
73 (11.5%) 
50 (7.9%) 
Nursing home admission 
13 (1.0%) 
6 (0.9%) 
7 (1.1%) 
* dummy outcome of a 90-day gap in database enrollment 
 
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
15
 Report the overall risk of the primary outcome 
For semaglutide vs. standard of care  
 
COHORT AT 
Semaglutide vs Standard of care 
COHORT ITT 
Semaglutide vs Standard of care 
Outcome 
216.78 
238.48 
 
 
8. Initial Power Assessment 
 
Analysis report name: 
For semaglutide vs. standard of care 
Optum® CDM [AT analysis – outcome window within 91-212 days after cohort entry]: https://bwh-
dope.aetion.com/projects/details/1673/rwrs/86429 
Optum® CDM [ITT analysis – outcome window within 275-455 days after cohort entry]: https://bwh-
dope.aetion.com/projects/details/1673/rwrs/86428 
 
 
Without the SEPRA protocol, we were unable to ascertain the assumptions of the trial’s power calculation. However, we assume that 
our power is similar to the power in the trial because we anticipate that the refreshed Optum Clinformatics data on which we will run 
our primary analysis will result in cohorts that exceed the target number of participants in each arm of the trial (see Table below).” 
 
N. patients in the trial
N. of patients in the matched 
COHORT AT*
N. of patients in the matched 
COHORT ITT*
All patients
1,378
1,364
1,270
Reference
689
682
635
Exposed
689
682
635
* The feasibility counts were run on Optum® Clinformatics® version released on Dec 23, 2021, for the study period of Dec 6, 2017, to Jun 30, 2021. 
The primary analysis will be run by implementing the protocol on refreshed data that includes data up to March 30, 2022. Therefore, the cohorts 
for the primary analyses are expected to be larger than those of the initial feasibility analyses presented in this protocol.  
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
16
Date conducted: 09/29/2022 
 
In order to complete the initial power analysis, the dummy outcome of a 90-day gap in database enrollment will be used. This 
outcome is used to ensure that no information on the comparative risks of the outcomes of interest are available at this stage. 
Complete a 1:1 PS-matched comparative analysis using this outcome. PS should include only 3 covariates: age, gender and combined 
comorbidity index.  
 
 Stop analyses until feasibility and power are reviewed by primary investigators and FDA. Reviewers evaluate the results of the 
analyses described above in Sections 7 and 8, including numbers of patients, patient characteristics, follow-up time, and reasons 
for censoring by treatment group, as well as overall rates of outcomes and study power. These parameters are re-evaluated and 
reported in the subsequent sections, after incorporating feedback and refining the protocol. 
 
Reviewed by PI: 
Shirley Wang 
Date reviewed: 
 
Reviewed by FDA: 
Ken Quinto 
Date reviewed: 
 
Reasons for stopping 
analysis (if required): 
 
 
 
9. Balance Assessment 
For semaglutide vs. standard of care 
Optum® CDM [AT analysis – outcome window within 91-212 days after cohort entry]: https://bwh-
dope.aetion.com/projects/details/1673/rwrs/86487 
Optum® CDM [ITT analysis – outcome window within 275-455 days after cohort entry]: https://bwh-
dope.aetion.com/projects/details/1673/rwrs/86486 
 
Date conducted:  
 
After review of initial feasibility and power analyses, complete creation of the remaining covariates from Section 6.2. Again, using the 
dummy outcome of a 90-day gap in database enrollment, complete a 1:1 PS-matched analysis. The PS should include the complete 
list of covariates. In the feasibility analysis, calendar time is included in the PS model as continuous variable, using quarters as unit of 
measurement, while in the primary analysis the unit measurement for calendar time will be days. 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
17
 Provide plot of PS distributions stratified by treatment group. 
 
Note- Please refer to Appendix B.  
 
 
 Report covariate balance after matching. 
 
Note- For Table 1, please refer to Appendix B.  
 
 Report follow-up time by treatment group after matching. 
For semaglutide vs. standard of care 
 
 
Median Follow-Up Time (Days) [IQR] – AT analysis* 
Median Follow-Up Time (Days) [IQR] – ITT analysis* 
Patient Group 
Optum CDM – COHORT AT 
Optum CDM - COHORT ITT 
Overall Patient Population 
80 [42, 121] 
129 [60, 180] 
Referent 
81 [43, 121] 
136 [66, 180] 
Exposure 
58 [28, 116] 
122 [54, 180] 
* The median follow-up time is defined as the median number of days that a patient is followed within the outcome assessment window, which begins 91 days 
and ends 212 days after the cohort entry date for the COHORT AT, and it begins 275 days and ends 455 days after the cohort entry date for the COHORT ITT 
 
 Report reasons for censoring by treatment group after matching. 
For semaglutide vs. standard of care – COHORT AT 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
18
Overall 
N = 1,352 
Standard care (DPP-4i, 
SGLT-2ra, SU) 
N = 678 
Semaglutide 
N = 678 
Dummy outcome* 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Death 
1 (0.1%) 
1 (0.1%) 
0 (0.0%) 
Maximum follow-up time 
667 (49.2%) 
351 (51.8%) 
316 (46.6%) 
End of patient data 
75 (5.5%) 
39 (5.8%) 
36 (5.3%) 
End of patient enrollment 
95 (7.0%) 
48 (7.1%) 
47 (6.9%) 
Augmentation or Switching to other antidiabetic drugs; switching 
between comparator classes; nursing home admission; 
discontinuation of metformin, semaglutide or standard of care 
(with 60 days of grace period) 
518 (38.2%) 
239 (35.3%) 
279 (41.2%) 
* dummy outcome of a 90-day gap in database enrollment 
 
For semaglutide vs. standard of care – COHORT ITT 
Overall 
N = 1266 
Standard care (DPP-4i, 
SGLT-2ra, SU) 
N = 633 
Semaglutide 
N = 633 
Dummy outcome* 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Death 
5 (0.4%) 
3 (0.5%) 
2 (0.3%) 
Maximum follow-up time 
743 (58.7%) 
355 (56.1%) 
388 (61.3%) 
End of patient data 
406 (32.1%) 
219 (34.6%) 
187 (29.5%) 
End of patient enrollment 
102 (8.1%) 
53 (8.4%) 
49 (7.7%) 
Nursing home admission 
10 (0.8%) 
3 (0.5%) 
7 (1.1%) 
* dummy outcome of a 90-day gap in database enrollment 
 
 
 
 
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
19
 Report the overall risk of the primary outcome 
 
COHORT AT 
Semaglutide vs Standard of care 
COHORT ITT 
Semaglutide vs Standard of care 
Outcome 
214.57 
232.60 
 
 
10. Final Power Assessment 
 
Date conducted: 9/30/2022 
 
Analysis report name: 
For semaglutide vs. standard of care 
Optum® CDM [AT analysis – outcome window within 91-212 days after cohort entry]: https://bwh-
dope.aetion.com/projects/details/1673/rwrs/86433 
Optum® CDM [ITT analysis – outcome window within 275-455 days after cohort entry]: https://bwh-
dope.aetion.com/projects/details/1673/rwrs/86432 
 
Without the SEPRA protocol, we were unable to ascertain the assumptions of the trial’s power calculation. However, we assume that 
our power is similar to the power in the trial because we anticipate that the refreshed Optum Clinformatics data on which we will run 
our primary analysis will result in cohorts that exceed the target number of participants in each arm of the trial (see Table below).” 
 
N. patients in the trial
N. of patients in the matched 
COHORT AT*
N. of patients in the matched 
COHORT ITT*
All patients
1,378
1,352
1,266
Reference
689
678
633
Exposed
689
678
633
* The feasibility counts were run on Optum® Clinformatics® version released on Dec 23, 2021, for the study period of Dec 6, 2017, to Jun 30, 2021. 
The primary analysis will be run by implementing the protocol on refreshed data that includes data up to March 30, 2022. Therefore, the cohorts 
for the primary analyses are expected to be larger than those of the initial feasibility analyses presented in this protocol.  
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
20
 Stop analyses until balance and final power assessment are reviewed by primary investigators, FDA, and assigned members of 
advisory board. 
Reviewed by PI: 
 
Date reviewed: 
 
Reviewed by FDA: 
 
Date reviewed: 
 
Reasons for stopping 
analysis (if required): 
 
 
11. Study Confidence and Concerns 
 
Deadline for voting on study confidence and listing concerns: 
Date votes and concerns are summarized:    
 
 If final feasibility and power analyses are reviewed and approved, proceed to the remaining protocol steps. 
 All study team and advisory board members that review this protocol should at this stage provide their level of confidence for the 
success of the RWD study in the Google Form. This form also provides space for reviewers to list any concerns that they feel may 
contribute to a failure to replicate the findings of the RCT, including differences in study populations, poor measurement of study 
variables, or residual confounding. All responses will be kept confidential and individual-level results will only be shared with the 
individual respondent. 
 After the deadline for voting has passed, provide the distribution of responses and summarize all concerns here. 
 
12. Register study protocol on clinicalTrials.gov 
 
Date conducted:    
 
 Register the study on clinicalTrials.gov and upload this document. 
 
 
 
 
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
21
13. Comparative Analyses 
 
Aetion report name: 
Date conducted:    
 
13.1 
For primary analysis:  
 
13.2 
For sensitivity analyses: 
 
 
14.  Requested Results  
 
14.1 
Table 1: Baseline characteristics before and after adjustment 
 
Variable 
 
Before adjustment 
After adjustment 
Referent 
Exposure 
Std. diff. 
Referent 
Exposure 
Std. diff. 
Number of patients 
 
 
- 
 
 
- 
Age categories 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
14.2 
Table 2: Follow-up time 
 
Patient Group 
Median Follow-Up Time (Days) [IQR] 
Overall Patient Population 
 
Referent 
 
Exposure 
 
 
 
 
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
22
 
14.3 
Table 3: Censoring events 
 
 
Overall 
Referent 
Exposure 
Outcome 
 
 
 
Death 
 
 
 
Start of an additional exposure 
 
 
 
End of index exposure 
 
 
 
Specified date reached 
 
 
 
End of patient data 
 
 
 
End of patient enrollment 
 
 
 
… 
 
 
 
 
14.4 
Table 4: Results from primary analyses. 
 
Analysis 
No. exposed events 
No. referent events 
Exposed rate 
Referent rate 
HR (95% CI) 
Crude 
 
 
 
 
 
Analysis 1 
 
 
 
 
 
Analysis 2 
 
 
 
 
 
... 
 
 
 
 
 
HR, Hazard Ratio; CI, Confidence Interval. 
 
14.5 
Table 5: Results from secondary analyses. 
 
15. References 
ClinicalTrials.gov Identifier: NCT03596450. Long Term Comparative Effectiveness of Once Weekly Semaglutide Versus Standard of 
Care in a Real World Adult US Population With Type 2 Diabetes - a Randomized Pragmatic Trial. Available at: 
https://clinicaltrials.gov/ct2/show/NCT03596450 Accessed 9/28/2022. 

#
References/Rationale
Color coding
Please see the following Google Drive for further details or any missing information: 
https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV?usp=sharing
Criteria
ICD-10 codes are not listed in this document because of excel cell size limitations and excessive number of ICD-
10 codes. Full ICD-10 code lists will be available in the above Google Drive Folder (link above). ICD-9 to ICD-10 
code conversions were completed using a SAS macro that implements forward/ backward mapping based on 
the CMS ICD-9 to ICD-10 mapping:
 https://www.nber.org/data/icd9-icd-10-cm-and-pcs-crosswalk-general-equivalence-mapping.html
Adequate mapping in claims
Intermediate mapping in claims
Arm
Intervention/Treatment
Poor mapping or cannot be measured in claims 
Exposure: Semaglutide injection (Ozempic®) in addition to metformin monotherapy 
as treatment intensification in the course of routine clinical practice. 
Reference: Standard of care (oral or injectable) in addition to metformin 
monotherapy as treatment intensification in the course of routine clinical practice. 
Standard of care is defined as commercially available oral or injectable antidiabetic 
medication other than semaglutide.
Aim: To evaluate the effects of semaglutide injection (Ozempic®) compared to other 
treatments on HbA1c reduction in patients with type 2 diabetes in a practice 
setting.
Exposure: new use of Semaglutide injection (washout 180 days) in combination with 
metformin 
NDC Generic Name:
SEMAGLUTIDE [route of administration: injection, subcutaneous]
NDC Brand name:
OZEMPIC
Reference: new use of GLP-1ra (except for semaglutide oral or inj.), DPP-4i, SGLT-2i, 2nd 
generation sulfonylureas (washout 180 days) 
NDC Name:
please refer to "Reference name list"
Cannot be measured in claims but not important for the analysis
Not reported in the list of eligibility criteria but included in the emulation for specific reasons
Hemoglobin A1c (HbA1c) less than 7.0% (53 mmol/mol) (yes/no)
[Time frame 1 year]
Measured as recorded HbA1c value [binary: <7% or ≥7%] between 275 and 455 days and 
closest to 365 days after drug initiation (ITT ANALYSIS) or closest to 182 days between 91 
and 212 days after cohort initiation (AT ANALYSIS): 
Loinc codes:
17855-8, 17856-6, 41995-2, 43150-2, 4548-4, 4549-2, 55454-3, 71875-9, 74246-0
The Loinc codes have been selected based on an evaluation of all available Loinc codes for HbA1c in the claims
#
Informed consent obtained before any study-related activities. Study-related 
activities are any procedures that are carried out as part of the study.
N/A
1
Male or female, age 18 years or older at the time of signing informed consent.
Female and male, ≥ 18 years at the time of drug initiation
2
Type 2 diabetes mellitus diagnosis
Measured from the time of enrollment to the day of drug initiation in inpatient (any 
position) or outpatient (any position) settings:
Type 2 diabetes:
ICD 9 diagnosis: 250.00, 250.02, 250.10, 250.12, 250.20, 250.22, 250.30, 250.32, 250.40, 
250.42, 250.50, 250.52, 250.60, 250.62, 250.70, 250.72, 250.80, 250.82, 250.90, 250.92
ICD 10 diagnosis: E11.x
3
Treatment with either 1 or 2 oral antidiabetic medications.
3.1 At least one prescription of metformin within 90 days (+30 days) before cohort entry in 
both treatment groups
Generic name:
Metformin Hcl
(see also exclusion criterion #1)
4
Recorded HbAlc value within last 90 days prior to randomization.
4.1 Selection of all patients with 2 measurements of HbA1c values (between 2-20%) 
recorded within 280 days prior to and including cohort entry:
Loinc codes:
17855-8, 17856-6, 41995-2, 43150-2, 4548-4, 4549-2, 55454-3, 71875-9, 74246-0 
4.2 Selection of patients with at least one measurement of HbA1c ≥7% value recorded 
within the last 91 days prior to and including cohort entry:
Loinc codes:
17855-8, 17856-6, 41995-2, 43150-2, 4548-4, 4549-2, 55454-3, 71875-9, 74246-0 
#
Further intensification with an additional antidiabetic oral or injectable medication 
is indicated to achieve glycemic target at the discretion of the study physician 
according to approved labelling
N/A
#
Current member of a commercial or Medicare health plan with pharmacy benefits.
Optum (The database has been selected due to the information on the laboratory 
results/values of HbA1c)
SEPRA Trial
Trial details - clinicaltrial.gov NCT03596450
EXPOSURE FROM Trial 
EXCLUSION CRITERIA
PRIMARY OUTCOME
INCLUSION CRITERIA
Appendix A: Flowchart

#
Previous randomization in this study
N/A
#
Participation in another clinical trial
N/A
1
Treatment with any medication for the indication of diabetes other than metformin 
in a period of 30 days before the day of eligibility assessment.
Measured 180 days prior to and including the day of drug initiation inpatient (any position), 
outpatient (any position):
The list of drugs (generic names) is reported under "Other anti-diabetic treatments (other 
than insulin)" in the tab "Other anti-diabetic treatments"
NB. Washout period extended to 180 days consistently with the washout period of the ther 2nd line thrapy 
agents (comparator group: standard of care) and insulin
2
Treatment with insulin (Temporary/emergency use of any type of insulin is allowed, 
as is prior insulin treatment for gestational diabetes)
Measured 180 days prior to and including day of drug initiation:
NDC Generic Name:
The definition of insulin (generic names) is reported under "Insulin" in the tab "Other anti-
diabetic treatments"
NB. Washout period extended to 180 days to exclude prevalent users (i.e. patients on active insulin therapy) 
from the cohort.
3
Female who is pregnant, breastfeeding or intends to become pregnant
Measured 180 days prior to and including day of drug initiation in any diagnosis position and 
inpatient or outpatient care setting:
Please refer to "Pregnancy definition"
4
Contraindications to semaglutide according to the Food and Drug Administration 
approved label
Measured 1825 days prior to and including day of drug initiation in any diagnosis position 
and inpatient or outpatient care setting:
Contraindications to Semaglutide as reported on the FDA approved label:
Personal or family history of medullary thyroid carcinoma:
n/a
Multiple Endocrine Neoplasia syndrome type 2:
ICD-9 diagnosis: 258.02, 258.03
ICD-10 diagnosis: E31.22, E31.23
5
CKD stage 5, End-stage renal disease, dialysis or renal transplant 
Measured 180 days prior to and including day of drug initiation in any diagnosis position and 
inpatient or outpatient care setting:
CKD stage 5, End-stage renal disease, dialysis or renal transplant:
ICD-9 diagnosis: 585.5, 585.6, 996.81, V42.0, V45.1x, V56.xx
ICD-9 procedure: 39.95, 54.98, 55.6x
ICD-10 diagnosis: N18.5, N18.6, R88.0, T82.41, T82.42, T82.49, T85.611, T85.621, T85.631, 
T86.1x, Y84.1, Z48.22, Z49.xx, Z91.15, Z94.0, Z99.2
ICD-10 procedure: 0TY00Zx, 0TY10Zx, 3E1M39Z, 5A1Dx0Z
CPT: 50360, 50365, 90920, 90921, 90924, 90925, 90935, 90937, 90939, 90940, 90945, 90947, 
90957, 90958, 90959, 90960, 90961, 90962, 90965, 90966, 90969, 90970, 90989, 90993, 
90999, 90997, 99512, 99559, 99512, G0257, G0314, G0315, G0316, G0317, G0318, G0319, 
G0322, G0323, G0326, G0327, S9335, S9339
N.B. criterion added to address potential residual confounding for the comparisons Semaglutide vs SGLT2i as a 
control reference 
N.B.2 Metformin - required by the study design in both exposure and comparator group - is contraindicated in 
patients with chronic kidney disease (CKD) with a glomerular filtration rate (GFR) < 30 mL/min.
6
Nursing home admission
Measured 180 days prior to and including day of drug initiation in any diagnosis position and 
inpatient or outpatient care setting:
Place of Service Code:
31 = SKILLED NURSING FACILITY
32 = NURSING FACILITY
33 = CUSTODIAL CARE FACILITY
34 = HOSPICE
Discharge Status Code is any of:
03 = DISCHARGED/TRANSFERRED TO SKILLED NURSING FACILITY (SNF)WITH MEDICARE
64 = DISCHARGED/TRANSFERRED TO A NURSING FACILITY CERT UND MEDICARE
83 = RESERVED FOR NATIONAL ASSIGNMENT
92 = RESERVED FOR NATIONAL ASSIGNMENT
N.B. criterion added to address in real-world data potential outcome misclassification bias due to the lack of 
available information in most patients admitted in nursing home facilities
Appendix A: Flowchart

OPTUM
Semaglutide vs standard of care 
Optum® 
COHORT AT 
Optum® 
COHORT ITT 
 
Less Excluded 
Patients 
Less Excluded 
Patients 
Patients in dataset 
 
Patients meeting cohort entry criteria 
 
Excluded due to insufficient enrollment 
-185,893 (13%) 
-157,177 (12%) 
Excluded due to prior use of referent 
-1,006,363 (84%) 
-943,160 (85%) 
Excluded due to prior use of exposure 
-46,187 (23%) 
-35,553 (21%) 
Excluded because patient qualified in >1 exposure category 
-164 (<1%) 
-101 (<1%) 
Excluded based on Inclusion Age ≥ 18 
-34 (<1%) 
-27 (<1%) 
Excluded based on Exclusion for Age missing 
-10 (<1%) 
-6 (<1%) 
Excluded based on Exclusion for Gender unknown/missing 
-54 (<1%) 
-44 (<1%) 
Excluded based on Inclusion Type 2 diabetes mellitus 
-8,127 (5%) 
-6,929 (5%) 
Excluded based on Inclusion Use of Metformin  
-49,397 (34%) 
-41,708 (34%) 
Excluded based on Inclusion At least 2 HbA1c records within the prior 
280 days 
-48,281 (51%) 
-42,342 (51%) 
Excluded based on Inclusion At least 1 HbA1c record ≥ 7% within the 
prior 90 days 
-5,365 (12%) 
-4,644 (12%) 
Excluded based on Exclusion Use of any other anti-diabetes medications 
-893 (2%) 
-857 (2%) 
Excluded based on Exclusion Any insulin use 
-2,114 (5%) 
-1,881 (5%) 
Excluded based on Exclusion Pregnancy 
-3 (<1%) 
-2 (<1%) 
Excluded based on Exclusion Multiple Endocrine Neoplasia syndrome 
type 2 
-0 (<1%) 
-0 (<1%) 
Excluded based on Exclusion CKD stage 5, ESRD, dialysis or renal 
transplant 
-6 (<1%) 
-5 (<1%) 
Excluded based on Exclusion Nursing home admission 
-129 (<1%) 
-112 (<1%) 
Final cohort 
 
 
Appendix A: Attrition Table

Information from Trial
 
Trial Name: SEPRA  
https://clinicaltrials.gov/ct2/show/NCT03596450  
 
NCT: NCT03596450 
 
Therapeutic Area: Diabetes  
 
RCT Category:  
 
Sponsors and Collaborators:  
Novo Nordisk A/S 
 
Year: July 13, 2018 – June 9, 2023 
 
Measurable Endpoint: The primary outcome is Hemoglobin A1c (HbA1c) less than 7.0% (53 
mmol/mol).  
 
Active Comparators:  
Semaglutide 
Standard of care  
 
Population: Patients with type 2 diabetes who have previously been treated with metformin. 
 
No. of Patients: 1,387 
 
Power:  Without the SEPRA protocol, we were unable to ascertain the assumptions of the trial’s 
power calculation.  
 
Appendix A: Trial Information

Reference - NDC Generic name:
DPP-4 Inhibitors 
ALOGLIPTIN BENZOATE
DAPAGLIFLOZIN PROPANEDIOL/SAXAGLIPTIN HCL
ERTUGLIFLOZIN PIDOLATE/SITAGLIPTIN PHOSPHATE
SAXAGLIPTIN HCL/METFORMIN HCL
LINAGLIPTIN
ALOGLIPTIN BENZOATE/METFORMIN HCL
ALOGLIPTIN BENZOATE/PIOGLITAZONE HCL
EMPAGLIFLOZIN/LINAGLIPTIN
SAXAGLIPTIN HCL
SITAGLIPTIN PHOSPHATE/METFORMIN HCL
SITAGLIPTIN PHOSPHATE/SIMVASTATIN
SITAGLIPTIN PHOSPHATE
SGLT-2 Inhibitors
CANAGLIFLOZIN
CANAGLIFLOZIN/METFORMIN HCL
DAPAGLIFLOZIN PROPANEDIOL/SAXAGLIPTIN HCL
ERTUGLIFLOZIN PIDOLATE
ERTUGLIFLOZIN PIDOLATE/SITAGLIPTIN PHOSPHATE
DAPAGLIFLOZIN PROPANEDIOL/METFORMIN HCL
EMPAGLIFLOZIN/LINAGLIPTIN
EMPAGLIFLOZIN
DAPAGLIFLOZIN PROPANEDIOL
ERTUGLIFLOZIN PIDOLATE/METFORMIN HCL
EMPAGLIFLOZIN/METFORMIN HCL
2nd Generation Sus
GLIPIZIDE/METFORMIN HCL
GLYBURIDE,MICRONIZED
GLYBURIDE/METFORMIN HCL
GLYBURIDE
GLIPIZIDE
GLIMEPIRIDE
PIOGLITAZONE HCL/GLIMEPIRIDE
ROSIGLITAZONE MALEATE/GLIMEPIRIDE
GLP-1 RA (excluding semaglutide injection/subcutaneous)
ALBIGLUTIDE
DULAGLUTIDE
EXENATIDE
EXENATIDE MICROSPHERES
INSULIN GLARGINE,HUMAN RECOMBINANT ANALOG/LIXISENATIDE
LIXISENATIDE
LIRAGLUTIDE
INSULIN DEGLUDEC/LIRAGLUTIDE
SEMAGLUTIDE (route of adminitration: oral)
Appendix A: Codes

1. Delivery Codes
Procedure Codes
Description
CPT-4 codes
1960
Anesthesia for vaginal delivery only
1961
Anesthesia for cesarean delivery only
1962
Anesthesia for urgent hysterectomy following delivery
1963
Anesthesia for cesarean hysterectomy w/o any labor analgesia/anesthesia care
1967
Neuraxial labor analgesia/anesthesia, planned vaginal delivery
1968
Anesthesia for cesarean delivery following neuraxial labor analgesia/anesthesia
1969
Anes for cesarean hysterectomy following neuraxial labor analgesia/anesthesia
59050
Fetal monitoring in labor, physician w/written report; s & i
59051
Fetal monitoring in labor, physician w/written report; intrepretation only
59400
ROUTINE TOTAL OBSTETRIC CARE including antepartum care, vaginal delivery (with or without episiotomy, and/or forceps) and postpartum care.
59409
Vaginal delivery only (w/wo episiotomy &/or forceps)
59410
Vaginal delivery only (w/wo episiotomy &/or forceps); w/postpartum care
59412
Ext cephalic version, w/wo tocolysis
59414
Delivery of placenta (separate  proc)
59430
Postpartum care only
59510
Routine obstetric care w/antepartum care, cesarean delivery, & postpartum care
59514
Cesarean delivery only
59515
Cesarean delivery only; w/postpartum care
59525
Subtotal/total hysterectomy after cesarean delivery
59610
Routine obstetric care including antepartum care, vaginal delivery (with or without episiotomy, and/or forceps) and postpartum care, after previous cesarean delivery
59612
Vaginal delivery only, after previous cesarean delivery (with or without episiotomy and/or forceps)
59614
Vaginal delivery only, previous cesarean delivery w/postpartum care
59618
Routine obstetric care including antepartum care, cesarean delivery, and postpartum care, following attempted vaginal delivery after previous cesarean delivery
59620
Cesarean delivery after failed vaginal delivery, previous cesarean delivery
59622
Cesarean delivery after failed vaginal delivery, previous cesarean delivery; w/postpartum care
99436
Attendance at delivery, at request of delivering physician, & stabilization of newborn
99440
Newborn resuscitation
ICD-9 procedure codes
72.xx
Forceps, vacuum, & breech
73.xx
Other including manual delivery
74xx
Cesarean section
75.4x
Manual removal of placenta
ICD-10 procedure codes
Normal Delivery
10E0XZZ 
Delivery of Products of Conception, External Approach
C-Section
10D00Z0 
Extraction of Products of Conception, High, Open Approach
10D00Z1 
Extraction of Products of Conception, Low, Open Approach
10D00Z2 
Extraction of Products of Conception, Extraperitoneal, Open Approach
Other assisted delivery (forceps, vacuum, internal version, other)
10D07Z3 
Extraction of Products of Conception, Low Forceps, Via Natural or Artificial Opening
10D07Z4 
Extraction of Products of Conception, Mid Forceps, Via Natural or Artificial Opening
10D07Z5 
Extraction of Products of Conception, High Forceps, Via Natural or Artificial Opening
10D07Z6 
Extraction of Products of Conception, Vacuum, Via Natural or Artificial Opening
10D07Z7 
Extraction of Products of Conception, Internal Version, Via Natural or Artificial Opening
10D07Z8 
Extraction of Products of Conception, Other, Via Natural or Artificial Opening
2.      Identify preterm births
a.       Codes that have a specific gestational age mentioned
ICD-9 code
Definition
765.21
Less than 24 completed weeks of gestation
765.22
24 completed weeks of gestation
765.23
25-26 completed weeks of gestation
765.24
27-28 completed weeks of gestation
765.25
29-30 completed weeks of gestation
765.26
31-32 completed weeks of gestation
765.27
33-34 completed weeks of gestation
765.28
35-36 completed weeks of gestation
ICD-10 code
Definition
P07.21
Extreme immaturity of newborn, gestational age less than 23 completed weeks
P07.22
Extreme immaturity of newborn, gestational age 23 completed weeks
P07.23
Extreme immaturity of newborn, gestational age 24 completed weeks
P07.24
Extreme immaturity of newborn, gestational age 25 completed weeks
P07.25
Extreme immaturity of newborn, gestational age 26 completed weeks
P07.26
Extreme immaturity of newborn, gestational age 27 completed weeks
P07.31
Preterm newborn, gestational age 28 completed weeks
P07.32
Preterm newborn, gestational age 29 completed weeks
P07.33
Preterm newborn, gestational age 30 completed weeks
P07.34
Preterm newborn, gestational age 31 completed weeks
P07.35
Preterm newborn, gestational age 32 completed weeks
P07.36
Preterm newborn, gestational age 33 completed weeks
P07.37
Preterm newborn, gestational age 34 completed weeks
P07.38
Preterm newborn, gestational age 35 completed weeks
P07.39
Preterm newborn, gestational age 36 completed weeks
ICD-9 code
Definition
765
Disorders relating to extreme immaturity of infant
765.00 
Extreme immaturity, unspecified [weight]
765.01 
Extreme immaturity, less than 500 grams
765.02 
Extreme immaturity, 500-749 grams
PREGNANCY DEFINITION
b.       Codes indicating extreme prematurity
Appendix A: Codes

765.03 
Extreme immaturity, 750-999 grams
765.04 
Extreme immaturity, 1,000-1,249 grams
765.05 
Extreme immaturity, 1,250-1,499 grams
765.06 
Extreme immaturity, 1,500-1,749 grams
765.07 
Extreme immaturity, 1,750-1,999 grams
765.08 
Extreme immaturity, 2,000-2,499 grams
ICD-10 code
Definition
P07.2
Extreme immaturity of newborn
P07.20
Extreme immaturity of newborn, unspecified weeks of gestation
O42.012
Preterm premature rupture of membranes, onset of labor within 24 hours of rupture, second trimester
ICD-9 code
Definition
765.1
Disorders relating to other preterm infants
765.10 
Other preterm infants, unspecified [weight]
765.11 
Other preterm infants, less than 500 grams
765.12 
Other preterm infants, 500-749 grams
765.13 
Other preterm infants, 750-999 grams
765.14 
Other preterm infants, 1,000-1,249 grams
765.15 
Other preterm infants, 1,250-1,499 grams
765.16 
Other preterm infants, 1,500-1,749 grams
765.17 
Other preterm infants, 1,750-1,999 grams
765.18 
Other preterm infants, 2,000-2,499 grams
644.21
Onset of delivery before 37 completed weeks of gestation
ICD-10 code
Definition
P05.01 
Disorders of newborn related to slow fetal growth and fetal malnutrition less than 500 grams
P05.02
Disorders of newborn related to slow fetal growth and fetal malnutrition, 500-749 grams
P05.03
Disorders of newborn related to slow fetal growth and fetal malnutrition, 750-999 grams
P05.04
Disorders of newborn related to slow fetal growth and fetal malnutrition, 1000-1249 grams
P05.05
Disorders of newborn related to slow fetal growth and fetal malnutrition, 1250-1499 grams
P05.06
Disorders of newborn related to slow fetal growth and fetal malnutrition, 1500-1749 grams
P05.11
Newborn small for gestational age, less than 500 grams
P05.12
Newborn small for gestational age, 500-749 grams
P05.13
Newborn small for gestational age, 750-999 grams
P05.14
Newborn small for gestational age, 1000-1249 grams
P05.15
Newborn small for gestational age, 1250-1499 grams
P05.16
Newborn small for gestational age, 1500-1749 grams
P07.01
Extremely low birth weight newborn, less than 500 grams
P07.02
Extremely low birth weight newborn, 500-749 grams
P07.03
Extremely low birth weight newborn, 750-999 grams
P07.14
Other low birth weight newborn,1000-1249 grams
P07.15
Other low birth weight newborn,1250-1499 grams
P07.16
Other low birth weight newborn,1500-1749 grams
P07.3
Preterm [premature] newborn [other]
P07.30 
Preterm newborn, unspecified weeks of gestation
O60.1 
Preterm labor with preterm delivery
O42.01
Preterm premature rupture of membranes, onset of labor within 24 hours of rupture
O42.019
Preterm premature rupture of membranes, onset of labor within 24 hours of rupture, unspecified trimester
O42.013
Preterm premature rupture of membranes, onset of labor within 24 hours of rupture, third trimester
Other Codes
Description
ICD-9
644.2
early onset of delivery
644.2
Early onset of delivery, unspecified as to episode of care or not applicable
644.21
Early onset of delivery, delivered, with or without mention of antepartum condition
776.6
anemia of prematurity
362.2
retinopathy of prematurity, unspecified
362.22
retinopathy of prematurity, stage 0
362.23
retinopathy of prematurity, stage 1
362.24
retinopathy of prematurity, stage 2
362.25
retinopathy of prematurity, stage 3
362.26
retinopathy of prematurity, stage 4
362.27
retinopathy of prematurity, stage 5
CPT
49491
repair, initial inguinal hernia, preterm infant (younger than 37 weeks gestation at birth), performed from birth up to 50 weeks postconception
49492
repair, initial inguinal hernia, preterm infant (younger than 37 weeks gestation at birth), performed from birth up to 50 weeks postconception
67229
treatment of extensive or progressive retinopathy, 1 or more sessions; preterm infant (less than 37 weeks gestation at birth), performed from
836
anesthesia for hernia repairs in the lower abdomen not otherwise specified, infants younger than 37 weeks gestational age at birth
ICD-10 code
Definition
H35.1
Retinopathy of prematurity
P61.2
Anemia of prematurity
2.      Multiple Gestation (V for ICD-9 and Z for ICD-10 codes excluded)
ICD9 Code 
Description
V27.2
Twins both liveborn
V27.3
Mother with twins one liveborn and one stillborn 
V27.4
Mother with twins both stillborn
V27.5 
Other multiple birth, all liveborn
V27.6
Other multiple birth, some liveborn
V31
Twin, mate liveborn
V32
Twin birth mate stillborn 
V33
Twin, unspecified
V34
Other multiple, mates all liveborn
V35
Other multiple birth (three or more) mates all stillborn 
V36
Other multiple, mates live- and stillborn
V37
Other multiple, unspecified
c.       Other preterm codes
Appendix A: Codes

651
Multiple gestation
651.0x
Twin Pregnancy
651.1x
Triplet pregnancy
651.2x
Quadruplet pregnancy
651.3x
Twin pregnancy with fetal loss and retention of one fetus 
651.4x
Triplet pregnancy with fetal loss and retention of one or more fetus(es)
651.5x
Quadruplet pregnancy with fetal loss and retention of one or more fetus(es)
651.6x
Other multiple pregnancy with fetal loss and retention of one or more fetus(es)
651.7x
Multiple gestation following (elective) fetal reduction
651.8x
Other specified multiple gestation
651.9x
Unspecified multiple gestation
652.6x
Multiple gestation with malpresentation of one fetus or more
660.5x
Locked Twins
662.3x
Delayed delivery of second twin, triplet, etc.
761.5x
Multiple pregnancy
ICD10 Code 
Description
O30xxxx 
Multiple gestation
O31xxxx 
Complications specific to multiple gestation
O43.02 
Fetus-to-fetus placental transfusion syndrome
O63.2 
Delayed delivery of second twin, triplet, etc.
Z37.2 
Twins, both liveborn
Z37.3 
Twins, one liveborn and one stillborn
Z37.5 
Other multiple births, all liveborn
Z37.50 
Multiple births, unspecified, all liveborn
Z37.51 
Triplets, all liveborn
Z37.52 
Quadruplets, all liveborn
Z37.53 
Quintuplets, all liveborn
Z37.54 
Sextuplets, all liveborn
Z37.59 
Other multiple births, all liveborn
Z37.6 
Other multiple births, some liveborn
Z37.60 
Multiple births, unspecified, some liveborn
Z37.61 
Triplets, some liveborn
Z37.62 
Quadruplets, some liveborn
Z37.63 
Quintuplets, some liveborn
Z37.64 
Sextuplets, some liveborn
Z37.69 
Other multiple births, some liveborn
Z38.3 
Twin liveborn infant, born in hospital
Z38.30 
Twin liveborn infant, delivered vaginally
Z38.31 
Twin liveborn infant, delivered by cesarean
Z38.4 
Twin liveborn infant, born outside hospital
Z38.5 
Twin liveborn infant, unspecified as to place of birth
Z38.6 
Other multiple liveborn infant, born in hospital
Z38.61 
Triplet liveborn infant, delivered vaginally
Z38.62 
Triplet liveborn infant, delivered by cesarean
Z38.63 
Quadruplet liveborn infant, delivered vaginally
Z38.64 
Quadruplet liveborn infant, delivered by cesarean
Z38.65 
Quintuplet liveborn infant, delivered vaginally
Z38.66 
Quintuplet liveborn infant, delivered by cesarean
Z38.68 
Other multiple liveborn infant, delivered vaginally
Z38.69 
Other multiple liveborn infant, delivered by cesarean
Z38.7 
Other multiple liveborn infant, born outside hospital
Z38.8 
Other multiple liveborn infant, unspecified as to place of birth
P01.5 
Newborn affected by multiple pregnancy
3.      Post-Term Codes
ICD-9 code
Definition
645
Late Pregnancy
645.1
Post term pregnancy
645.1
Post term pregnancy, unspecified as to episode of care or not applicable
645.11
Post term pregnancy, delivered, with or without mention of antepartum condition
645.13
Post term pregnancy, antepartum condition or complication
645.2
Prolonged pregnancy
645.2
Prolonged pregnancy, unspecified as to episode of care or not applicable
645.21
Prolonged pregnancy, delivered, with or without mention of antepartum condition
645.23
Prolonged pregnancy, antepartum condition or complication
766.2
Late infant, not 'heavy-for-dates'
766.21
Post-term infant
766.22
Prolonged gestation of infant
ICD-10 code
Definition
O48 
Late pregnancy
O48.0 
Post-term pregnancy
O48.1 
Prolonged pregnancy
P08.2 
Late newborn, not heavy for gestational age
P08.21 
Post-term newborn
P08.22 
Prolonged gestation of newborn
Z3A.41 
41 weeks gestation of pregnancy
Z3A.42 
42 weeks gestation of pregnancy
Z3A.49 
Greater than 42 weeks gestation of pregnancy
4.      Codes indicating a prenatal care visit:
ICD-9: V220x, V221x, V23xx
ICD-10: O0900, O0901, O0902, O0903, O0910, O0911, O0912, O0913, O09211, O09212, O09213, O09219, O09291, O09292, O09293, O09299, O0930, O0931, O0932, O0933, O0940, O0941, O0942, 
O0943, O09511, O09512, O09513, O09519, O09521, O09522, O09523, O09529, O09611, O09612, O09613, O09619, O09621, O09622, O09623, O09629, O0970, O0971, O0972, O0973, O09811, O09812, 
O09813, O09819, O09821, O09822, O09823, O09829, O09891, O09892, O09893, O09899, O0990, O0991, O0992, O0993, O09A0, O09A1, O09A2, O09A3, O3680X0, O3680X1, O3680X2, O3680X3, 
O3680X4, O3680X5, O3680X9, Z3400, Z3401, Z3402, Z3403, Z3480, Z3481, Z3482, Z3483, Z3490, Z3491, Z3492, Z3493, Z362
Appendix A: Codes

Other anti-diabetic treatments (other than insulin)
1st Generation SUs
ACETOHEXAMIDE
TOLBUTAMIDE
TOLAZAMIDE
CHLORPROPAMIDE
AGIs
ACARBOSE
MIGLITOL
Glitazones
ALOGLIPTIN BENZOATE/PIOGLITAZONE HCL
PIOGLITAZONE HCL
PIOGLITAZONE HCL/GLIMEPIRIDE
PIOGLITAZONE HCL/METFORMIN HCL
ROSIGLITAZONE MALEATE
ROSIGLITAZONE MALEATE/GLIMEPIRIDE
ROSIGLITAZONE MALEATE/METFORMIN HCL
Meglitinides
NATEGLINIDE
REPAGLINIDE
REPAGLINIDE/METFORMIN HCL
GLP-1 RA
SEMAGLUTIDE (admin.: oral)
Insulin
Bolus insulins
INSULIN GLULISINE
INSULIN REGULAR,BEEF-PORK
INSULIN ASPART (NIACINAMIDE)
INSULIN REGULAR, HUMAN/INSULIN RELEASE UNIT
INSULIN REGULAR,HUMAN BUFFERED
INSULIN REGULAR, HUMAN/INSULIN RELEASE UNIT/CHAMBER/INHALER
INSULIN ASPART
INSULIN ASPART PROTAMINE HUMAN/INSULIN ASPART
INSULIN LISPRO PROTAMINE AND INSULIN LISPRO
INSULIN LISPRO
INSULIN REGULAR, HUMAN
Intermediate and Long-acting Insulins
INSULIN DEGLUDEC
INSULIN DETEMIR
INSULIN DEGLUDEC/LIRAGLUTIDE
INSULIN NPH HUMAN AND INSULIN REGULAR HUMAN SEMI-SYNTHETIC
INSULIN NPH HUMAN SEMI-SYNTHETIC
INSULIN ISOPHANE NPH,BF-PK
INSULIN GLARGINE,HUMAN RECOMBINANT ANALOG/LIXISENATIDE
INSULIN GLARGINE,HUMAN RECOMBINANT ANALOG
INSULIN NPH HUMAN ISOPHANE
INSULIN NPH HUMAN ISOPHANE/INSULIN REGULAR, HUMAN
Appendix A: Codes

Baseline characteristics
Standard care (DPP-4i, 
SGLT-2i, SU)
Semaglutide
St. Diff
Standard care (DPP-4i, 
SGLT-2i, SU)
Semaglutide
St. Diff
Standard care (DPP-4i, 
SGLT-2i, SU)
Semaglutide
St. Diff Standard care (DPP-4i, 
SGLT-2i, SU)
Semaglutide
St. Diff
Number of patients
26,541
635
633
633
18,706
682
678
678
Demographics
Year of Cohort Entry Date
...5 Dec 2017 - 31 Dec 2018; n (%)
10,159 (38.3%)
8 (1.3%)
1.05
36 (5.7%)
8 (1.3%)
0.00
6,145 (32.9%)
5 (0.7%)
0.95
4 (0.6%)
5 (0.7%)
0.00
...1 Jan 2019 - 31 Dec 2019; n (%)
9,948 (37.5%)
307 (48.3%)
-0.22
228 (36.0%)
306 (48.3%)
-0.25
6,058 (32.4%)
253 (37.1%)
-0.10
262 (38.6%)
252 (37.2%)
0.03
...1 Jan 2020 - 31 Dec 2020; n (%)
6,434 (24.2%)
320 (50.4%)
-0.56
369 (58.3%)
319 (50.4%)
0.16
5,978 (32.0%)
384 (56.3%)
-0.50
382 (56.3%)
382 (56.3%)
0.00
…1 Jan 2021 -30  Jun 2021; n (%)
0 (0.0%)
0 (0.0%)
0.00
0 (0.0%)
0 (0.0%)
0.00
525 (2.8%)
40 (5.9%)
-0.15
30 (4.4%)
39 (5.8%)
-0.06
Quarter Calendar Time Score
...mean (sd)
4.39 (2.32)
6.35 (1.36)
-1.03
6.41 (1.66)
6.34 (1.36)
0.05
4.34 (2.67)
6.30 (1.70)
-0.88
6.16 (1.77)
6.30 (1.70)
-0.08
...median [IQR]
4.00 [2.00, 6.00]
7.00 [5.00, 7.00]
 --
7.00 [5.00, 8.00]
7.00 [5.00, 7.00]
 --
4.35 [1.86, 6.62]
6.46 [5.00, 7.66]
 --
6.33 [4.63, 7.62]
6.45 [5.00, 7.66]
 --
Age*
...mean (sd)
64.75 (11.55)
56.80 (11.95)
0.68
56.59 (11.98)
56.85 (11.94)
-0.02
65.27 (11.34)
56.87 (11.91)
0.72
56.40 (11.71)
56.95 (11.87)
-0.05
...median [IQR]
67.00 [58.00, 73.00]
57.00 [48.00, 67.00]
 --
57.00 [48.00, 66.00]
57.00 [48.00, 
67.00]
 --
67.00 [59.00, 73.00]
57.00 [48.00, 66.00]
 --
57.00 [48.00, 66.00]
57.00 [48.00, 
66.00]
 --
Age squared*
...mean (sd)
777,625.01 (255,648.88)
603,932.18 
(240,773.04)
0.70
595,923.84 (245,993.22)
604,345.50 
(240,737.59)
-0.03
788,645.31 
(252,226.56)
605,313.19 
(240,904.21)
0.74
595,304.40 
(232,661.95)
606,900.52 
(240,515.39)
-0.05
...median [IQR]
812,509.00 [591,116.50, 
938,739.00]
588,069.00 
[407,524.00, 
794,155.00]
 --
579,198.50 [401,895.25, 
788,436.00]
588,069.00 
[414,649.00, 
794,254.75]
 --
812,509.00 
[617,776.00, 
951,934.00]
587,165.00 
[417,024.00, 
788,436.00]
 --
586,035.00 
[417,024.00, 
771,045.75]
588,069.00 
[417,024.00, 
788,436.00]
 --
Age Categories
...18 - 40; n (%)
931 (3.5%)
66 (10.4%)
-0.27
62 (9.8%)
65 (10.3%)
-0.02
624 (3.3%)
66 (9.7%)
-0.26
73 (10.8%)
64 (9.4%)
0.05
...41 - 50; n (%)
2,528 (9.5%)
131 (20.6%)
-0.31
143 (22.6%)
130 (20.5%)
0.05
1,618 (8.6%)
138 (20.2%)
-0.34
134 (19.8%)
138 (20.4%)
-0.01
...51 - 60; n (%)
4,784 (18.0%)
192 (30.2%)
-0.29
174 (27.5%)
192 (30.3%)
-0.06
3,113 (16.6%)
207 (30.4%)
-0.33
191 (28.2%)
205 (30.2%)
-0.04
...61 - 70; n (%)
9,434 (35.5%)
159 (25.0%)
0.23
169 (26.7%)
159 (25.1%)
0.04
6,907 (36.9%)
180 (26.4%)
0.23
205 (30.2%)
180 (26.5%)
0.08
...71 - 80; n (%)
8,864 (33.4%)
87 (13.7%)
0.48
85 (13.4%)
87 (13.7%)
-0.01
6,444 (34.4%)
91 (13.3%)
0.51
75 (11.1%)
91 (13.4%)
-0.07
Sex*
...Male; n (%)
14,310 (53.9%)
302 (47.6%)
0.13
305 (48.2%)
301 (47.6%)
0.01
10,545 (56.4%)
331 (48.5%)
0.16
316 (46.6%)
330 (48.7%)
-0.04
...Female; n (%)
12,231 (46.1%)
333 (52.4%)
-0.13
328 (51.8%)
332 (52.4%)
-0.01
8,161 (43.6%)
351 (51.5%)
-0.16
362 (53.4%)
348 (51.3%)
0.04
Race categories*
...White; n (%)
13,684 (51.6%)
384 (60.5%)
-0.18
381 (60.2%)
382 (60.3%)
0.00
9,817 (52.5%)
437 (64.1%)
-0.24
435 (64.2%)
433 (63.9%)
0.01
…Not White; n (%)
12,857 (48.4%)
251 (39.5%)
0.18
252 (39.8%)
251 (39.7%)
0.00
8,889 (47.5%)
245 (35.9%)
0.24
243 (35.8%)
245 (36.1%)
-0.01
Combined comorbidity score, 180 days*
...mean (sd)
2.64 (1.89)
2.30 (1.59)
0.19
2.25 (1.63)
2.29 (1.59)
-0.02
2.59 (1.88)
2.28 (1.62)
0.18
2.30 (1.76)
2.26 (1.62)
0.02
...median [IQR]
2.00 [1.00, 4.00]
2.00 [1.00, 3.00]
 --
2.00 [1.00, 3.00]
2.00 [1.00, 3.00]
 --
2.00 [1.00, 4.00]
2.00 [1.00, 3.00]
 --
2.00 [1.00, 3.00]
2.00 [1.00, 3.00]
 --
Frailty score*
…Robust; n (%)
6,605 (24.9%)
195 (30.7%)
-0.13
205 (32.4%)
195 (30.8%)
0.03
4,934 (26.4%)
191 (28.0%)
-0.04
184 (27.1%)
190 (28.0%)
-0.02
…Pre-frail; n (%)
9,985 (37.6%)
233 (36.7%)
0.02
235 (37.1%)
232 (36.7%)
0.01
7,092 (37.9%)
260 (38.1%)
0.00
246 (36.3%)
258 (38.1%)
-0.04
…Frail; n (%)
9,951 (37.5%)
207 (32.6%)
0.10
193 (30.5%)
206 (32.5%)
-0.04
6,680 (35.7%)
231 (33.9%)
0.04
248 (36.6%)
230 (33.9%)
0.06
HbA1c test order (Number of tests)*
Semaglutide vs Standard - Cohort ITT (12m +/- 90 days)
Semaglutide vs Standard - Cohort AT 12-30w
UNMATCHED
MATCHED
UNMATCHED
MATCHED
Appendix B: Table 1

...mean (sd)
8.61 (1.49)
8.67 (1.59)
-0.04
8.77 (1.60)
8.67 (1.59)
0.06
8.53 (1.43)
8.62 (1.51)
-0.06
8.63 (1.46)
8.63 (1.51)
0.00
...median [IQR]
8.20 [7.50, 9.30]
8.10 [7.50, 9.50]
 --
8.30 [7.60, 9.60]
8.10 [7.50, 9.50]
 --
8.10 [7.50, 9.10]
8.20 [7.50, 9.40]
 --
8.20 [7.60, 9.20]
8.20 [7.50, 9.40]
 --
Smoking; n (%)*
3,381 (12.7%)
80 (12.6%)
0.00
73 (11.5%)
78 (12.3%)
-0.02
2,379 (12.7%)
89 (13.0%)
-0.01
99 (14.6%)
88 (13.0%)
0.05
Obesity or overweight; n (%)*
10,389 (39.1%)
325 (51.2%)
-0.24
309 (48.8%)
323 (51.0%)
-0.04
7,030 (37.6%)
334 (49.0%)
-0.23
323 (47.6%)
331 (48.8%)
-0.02
Overweight; n (%)
8,087 (30.5%)
279 (43.9%)
-0.28
256 (40.4%)
277 (43.8%)
-0.07
5,420 (29.0%)
294 (43.1%)
-0.30
264 (38.9%)
291 (42.9%)
-0.08
Obesity; n (%)
2,798 (10.5%)
55 (8.7%)
0.06
64 (10.1%)
55 (8.7%)
0.05
1,930 (10.3%)
53 (7.8%)
0.09
67 (9.9%)
53 (7.8%)
0.07
Cardiovascular Comorbidities
Hypertension; n (%)*
5,002 (18.8%)
153 (24.1%)
-0.13
138 (21.8%)
151 (23.9%)
-0.05
3,743 (20.0%)
159 (23.3%)
-0.08
154 (22.7%)
158 (23.3%)
-0.01
Hyperlipidemia; n (%)*
18,366 (69.2%)
451 (71.0%)
-0.04
435 (68.7%)
450 (71.1%)
-0.05
12,913 (69.0%)
467 (68.5%)
0.01
450 (66.4%)
465 (68.6%)
-0.05
Atherosclerosis Cardiovascular Disease; n (%)*
5,336 (20.1%)
93 (14.6%)
0.15
82 (13.0%)
92 (14.5%)
-0.04
3,696 (19.8%)
95 (13.9%)
0.16
90 (13.3%)
94 (13.9%)
-0.02
    Old MI; n (%)
608 (2.3%)
8 (1.3%)
0.08
13 (2.1%)
8 (1.3%)
0.06
432 (2.3%)
13 (1.9%)
0.03
11 (1.6%)
13 (1.9%)
-0.02
    Acute MI ; n (%)
195 (0.7%)
8 (1.3%)
-0.06
5 (0.8%)
8 (1.3%)
-0.05
126 (0.7%)
5 (0.7%)
0.00
2 (0.3%)
5 (0.7%)
-0.06
    ACS/unstable angina; n (%)
269 (1.0%)
7 (1.1%)
-0.01
6 (0.9%)
7 (1.1%)
-0.02
172 (0.9%)
5 (0.7%)
0.02
6 (0.9%)
5 (0.7%)
0.02
    Stable angina; n (%)
934 (3.5%)
24 (3.8%)
-0.02
18 (2.8%)
24 (3.8%)
-0.06
611 (3.3%)
22 (3.2%)
0.01
22 (3.2%)
22 (3.2%)
0.00
    CAD and other forms of chronic ischemic 
heart disease; n (%)
3,768 (14.2%)
61 (9.6%)
0.14
57 (9.0%)
61 (9.6%)
-0.02
2,628 (14.0%)
68 (10.0%)
0.12
67 (9.9%)
68 (10.0%)
0.00
    History of CABG or PTCA ; n (%)
1,086 (4.1%)
18 (2.8%)
0.07
16 (2.5%)
18 (2.8%)
-0.02
746 (4.0%)
21 (3.1%)
0.05
18 (2.7%)
21 (3.1%)
-0.02
    PAD or PAD surgery; n (%)
1,792 (6.8%)
33 (5.2%)
0.07
21 (3.3%)
32 (5.1%)
-0.09
1,200 (6.4%)
29 (4.3%)
0.09
23 (3.4%)
28 (4.1%)
-0.04
Cerebrovascular disease; n (%)*
723 (2.7%)
11 (1.7%)
0.07
6 (0.9%)
11 (1.7%)
-0.07
517 (2.8%)
15 (2.2%)
0.04
12 (1.8%)
15 (2.2%)
-0.03
    Stroke (Ischemic or hemorrhagic); n (%)
433 (1.6%)
8 (1.3%)
0.03
2 (0.3%)
8 (1.19%)
-0.10
300 (1.6%)
9 (1.3%)
0.03
9 (1.3%)
9 (1.3%)
0.00
    TIA; n (%)
255 (1.0%)
3 (0.5%)
0.06
2 (0.3%)
3 (0.5%)
-0.03
171 (0.9%)
7 (1.0%)
-0.01
3 (0.4%)
7 (1.0%)
-0.07
    Late effects of cerebrovascular disease; n 
(%)
252 (0.9%)
4 (0.6%)
0.03
3 (0.5%)
4 (0.6%)
-0.01
175 (0.9%)
5 (0.7%)
0.02
3 (0.4%)
5 (0.7%)
-0.04
Heart Failure; n (%)*
1,508 (5.7%)
21 (3.3%)
0.12
14 (2.2%)
20 (3.2%)
-0.06
1,033 (5.5%)
24 (3.5%)
0.10
24 (3.5%)
22 (3.2%)
0.02
Atrial fibrillation; n (%)*
1,541 (5.8%)
22 (3.5%)
0.11
24 (3.8%)
21 (3.3%)
0.03
1,132 (6.1%)
27 (4.0%)
0.10
26 (3.8%)
25 (3.7%)
0.01
Other cardiac dysrhythmia; n (%)
2,486 (9.4%)
38 (6.0%)
0.13
39 (6.2%)
37 (5.8%)
0.02
1,760 (9.4%)
48 (7.0%)
0.09
48 (7.1%)
46 (6.8%)
0.01
Diabetes Mellitus Comorbidities
Diabetic nephropathy; n (%)*
4,503 (17.0%)
68 (10.7%)
0.18
60 (9.5%)
68 (10.7%)
-0.04
2,999 (16.0%)
78 (11.4%)
0.13
74 (10.9%)
78 (11.5%)
-0.02
Diabetic neuropathy; n (%)*
5,402 (20.4%)
95 (15.0%)
0.14
86 (13.6%)
95 (15.0%)
-0.04
3,492 (18.7%)
107 (15.7%)
0.08
103 (15.2%)
107 (15.8%)
-0.02
Diabetic retinopathy ; n (%)*
1,550 (5.8%)
38 (6.0%)
-0.01
44 (7.0%)
38 (6.0%)
0.04
949 (5.1%)
33 (4.8%)
0.01
30 (4.4%)
33 (4.9%)
-0.02
Diabetes with unspecified complications; n 
(%)*
1,628 (6.1%)
41 (6.5%)
-0.02
45 (7.1%)
40 (6.3%)
0.03
1,088 (5.8%)
46 (6.7%)
-0.04
39 (5.8%)
46 (6.8%)
-0.04
Diabetes with peripheral circulatory disorders, 
amputations, and diabetic foot; n (%)*
413 (1.6%)
10 (1.6%)
0.00
10 (1.6%)
9 (1.4%)
0.02
303 (1.6%)
10 (1.5%)
0.01
11 (1.6%)
10 (1.5%)
0.01
    Diabetes with peripheral circulatory 
disorders; n (%)
47 (0.2%)
1 (0.2%)
0.00
2 (0.3%)
1 (0.2%)
0.02
34 (0.2%)
1 (0.1%)
0.03
1 (0.1%)
1 (0.1%)
0.00
    Lower-limb amputations; n (%)
106 (0.4%)
1 (0.2%)
0.04
2 (0.3%)
1 (0.2%)
0.02
71 (0.4%)
1 (0.1%)
0.06
0 (0.0%)
1 (0.1%)
-0.04
    Diabetic Foot; n (%)
303 (1.1%)
9 (1.4%)
-0.03
7 (1.1%)
8 (1.3%)
-0.02
224 (1.2%)
9 (1.3%)
-0.01
10 (1.5%)
9 (1.3%)
0.02
Renal Comorbidities
Chronic kidney disease (CKD); n (%)
3,910 (14.7%)
64 (10.1%)
0.14
62 (9.8%)
64 (10.1%)
-0.01
2,581 (13.8%)
64 (9.4%)
0.14
57 (8.4%)
64 (9.4%)
-0.04
    CKD Stage 1-2; n (%)*
1,558 (5.9%)
20 (3.1%)
0.14
13 (2.1%)
20 (3.2%)
-0.07
1,040 (5.6%)
18 (2.6%)
0.15
18 (2.7%)
18 (2.7%)
0.00
    CKD Stage 3-4; n (%)*
2,363 (8.9%)
46 (7.2%)
0.06
49 (7.7%)
46 (7.3%)
0.02
1,560 (8.3%)
47 (6.9%)
0.05
41 (6.0%)
47 (6.9%)
-0.04
    CKD unspecified ; n (%)*
484 (1.8%)
7 (1.1%)
0.06
10 (1.6%)
7 (1.1%)
0.04
311 (1.7%)
8 (1.2%)
0.04
9 (1.3%)
8 (1.2%)
0.01
Miscellaneous renal disease; n (%)
1,100 (4.1%)
22 (3.5%)
0.03
21 (3.3%)
22 (3.5%)
-0.01
764 (4.1%)
25 (3.7%)
0.02
17 (2.5%)
25 (3.7%)
-0.07
Other Comorbidities
Mood disorders; n (%)*
3,392 (12.8%)
90 (14.2%)
-0.04
79 (12.5%)
90 (14.2%)
-0.05
2,272 (12.1%)
105 (15.4%)
-0.10
107 (15.8%)
105 (15.5%)
0.01
Appendix B: Table 1

    Anxiety; n (%)
2,497 (9.4%)
68 (10.7%)
-0.04
61 (9.6%)
68 (10.7%)
-0.04
1,681 (9.0%)
74 (10.9%)
-0.06
85 (12.5%)
74 (10.9%)
0.05
    Depression; n (%)
1,505 (5.7%)
41 (6.5%)
-0.03
35 (5.5%)
41 (6.5%)
-0.04
1,002 (5.4%)
54 (7.9%)
-0.10
50 (7.4%)
54 (8.0%)
-0.02
Obstructive sleep apnea; n (%)*
3,293 (12.4%)
125 (19.7%)
-0.20
116 (18.3%)
124 (19.6%)
-0.03
2,238 (12.0%)
138 (20.2%)
-0.22
139 (20.5%)
137 (20.2%)
0.01
COPD; n (%)*
2,166 (8.2%)
38 (6.0%)
0.09
39 (6.2%)
38 (6.0%)
0.01
1,525 (8.2%)
39 (5.7%)
0.10
44 (6.5%)
39 (5.8%)
0.03
Asthma; n (%)*
1,496 (5.6%)
48 (7.6%)
-0.08
47 (7.4%)
48 (7.6%)
-0.01
1,018 (5.4%)
58 (8.5%)
-0.12
58 (8.6%)
57 (8.4%)
0.01
Osteoarthrosis; n (%)*
3,851 (14.5%)
100 (15.7%)
-0.03
102 (16.1%)
99 (15.6%)
0.01
2,674 (14.3%)
109 (16.0%)
-0.05
106 (15.6%)
109 (16.1%)
-0.01
NASH/NAFLD; n (%)*
1,418 (5.3%)
48 (7.6%)
-0.09
49 (7.7%)
48 (7.6%)
0.00
952 (5.1%)
50 (7.3%)
-0.09
58 (8.6%)
50 (7.4%)
0.04
Medications use
Antihypertensive medications; n (%)*
21,939 (82.7%)
491 (77.3%)
0.14
471 (74.4%)
489 (77.3%)
-0.07
15,621 (83.5%)
532 (78.0%)
0.14
519 (76.5%)
529 (78.0%)
-0.04
    ACEi/ARBs; n (%)
18,865 (71.1%)
421 (66.3%)
0.10
407 (64.3%)
420 (66.4%)
-0.04
13,406 (71.7%)
454 (66.6%)
0.11
450 (66.4%)
451 (66.5%)
0.00
    Beta blockers; n (%)
8,403 (31.7%)
168 (26.5%)
0.11
168 (26.5%)
167 (26.4%)
0.00
6,077 (32.5%)
197 (28.9%)
0.08
177 (26.1%)
195 (28.8%)
-0.06
    Calcium channel blockers; n (%)
7,033 (26.5%)
149 (23.5%)
0.07
143 (22.6%)
147 (23.2%)
-0.01
5,063 (27.1%)
165 (24.2%)
0.07
128 (18.9%)
164 (24.2%)
-0.13
    Thiazide; n (%)
3,407 (12.8%)
79 (12.4%)
0.01
76 (12.0%)
79 (12.5%)
-0.02
2,554 (13.7%)
90 (13.2%)
0.01
102 (15.0%)
90 (13.3%)
0.05
    Diuretics; n (%)
9,567 (36.0%)
213 (33.5%)
0.05
203 (32.1%)
212 (33.5%)
-0.03
6,838 (36.6%)
241 (35.3%)
0.03
234 (34.5%)
240 (35.4%)
-0.02
Statins Other lipid-lowering drugs; n (%)*
20,202 (76.1%)
467 (73.5%)
0.06
460 (72.7%)
466 (73.6%)
-0.02
14,641 (78.3%)
487 (71.4%)
0.16
466 (68.7%)
485 (71.5%)
-0.06
    Statins; n (%)
19,449 (73.3%)
454 (71.5%)
0.04
445 (70.3%)
453 (71.6%)
-0.03
14,094 (75.3%)
473 (69.4%)
0.13
453 (66.8%)
471 (69.5%)
-0.06
    Other lipid-lowering drugs; n (%)
2,441 (9.2%)
56 (8.8%)
0.01
60 (9.5%)
56 (8.8%)
0.02
1,749 (9.3%)
54 (7.9%)
0.05
68 (10.0%)
54 (8.0%)
0.07
Opioids; n (%)*
4,279 (16.1%)
104 (16.4%)
-0.01
110 (17.4%)
104 (16.4%)
0.03
2,813 (15.0%)
110 (16.1%)
-0.03
119 (17.6%)
109 (16.1%)
0.04
Mood Stabilizing Medications; n (%)*
7,564 (28.5%)
232 (36.5%)
-0.17
219 (34.6%)
231 (36.5%)
-0.04
5,192 (27.8%)
258 (37.8%)
-0.21
257 (37.9%)
258 (38.1%)
0.00
    Antidepressants; n (%)
6,079 (22.9%)
202 (31.8%)
-0.20
181 (28.6%)
201 (31.8%)
-0.07
4,180 (22.3%)
219 (32.1%)
-0.22
211 (31.1%)
219 (32.3%)
-0.03
    Anxiolytics/hypnotics; n (%)
1,244 (4.7%)
26 (4.1%)
0.03
34 (5.4%)
26 (4.1%)
0.06
848 (4.5%)
39 (5.7%)
-0.05
54 (8.0%)
39 (5.8%)
0.09
    Benzodiazepine; n (%)
2,202 (8.3%)
49 (7.7%)
0.02
54 (8.5%)
49 (7.7%)
0.03
1,487 (7.9%)
59 (8.7%)
-0.03
76 (11.2%)
59 (8.7%)
0.08
Gabapentinoids; n (%)*
3,592 (13.5%)
74 (11.7%)
0.05
73 (11.5%)
73 (11.5%)
0.00
2,426 (13.0%)
89 (13.0%)
0.00
80 (11.8%)
89 (13.1%)
-0.04
Health care utilization indicators
Number of medication claims*
...mean (sd)
11.01 (7.05)
12.03 (7.40)
-0.14
11.54 (7.20)
12.00 (7.38)
-0.06
10.98 (6.96)
12.34 (7.31)
-0.19
12.70 (8.53)
12.32 (7.31)
0.05
...median [IQR]
9.00 [6.00, 14.00]
10.00 [7.00, 15.00]
 --
10.00 [6.00, 15.00]
10.00 [7.00, 15.00]
 --
9.00 [6.00, 14.00]
11.00 [7.00, 16.00]
 --
11.00 [7.00, 16.00]
11.00 [7.00, 16.00]
 --
Number of office visits*
...mean (sd)
5.63 (4.61)
5.78 (4.53)
-0.03
5.76 (4.81)
5.76 (4.51)
0.00
5.47 (4.67)
5.75 (4.25)
-0.06
5.89 (5.06)
5.71 (4.24)
0.04
...median [IQR]
4.00 [3.00, 7.00]
5.00 [3.00, 7.00]
--
5.00 [3.00, 7.00]
5.00 [3.00, 7.00]
 --
4.00 [3.00, 7.00]
5.00 [3.00, 7.00]
--
4.00 [3.00, 7.00]
5.00 [3.00, 7.00]
 --
Number of hospitalizations/ED visit (binary)*
...mean (sd)
0.39 (1.24)
0.35 (1.00)
0.04
0.36 (1.11)
0.35 (1.00)
0.01
0.36 (1.35)
0.34 (1.00)
0.02
0.40 (1.16)
0.34 (1.00)
0.06
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
--
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
 --
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
--
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
 --
Brand name prescription - unique value*
...mean (sd)
9.19 (4.36)
9.62 (4.70)
-0.09
9.41 (4.69)
9.60 (4.69)
-0.04
9.11 (4.31)
9.53 (4.67)
-0.09
9.53 (5.13)
9.50 (4.65)
0.01
...median [IQR]
8.00 [6.00, 11.00]
9.00 [6.00, 12.00]
--
8.00 [6.00, 12.00]
9.00 [6.00, 12.00]
 --
8.00 [6.00, 11.00]
9.00 [6.00, 12.00]
--
9.00 [6.00, 12.00]
9.00 [6.00, 12.00]
 --
Generic name prescription - unique value*
...mean (sd)
0.99 (0.03)
0.99 (0.04)
0.00
9.30 (4.64)
9.49 (4.61)
-0.04
9.04 (4.25)
9.41 (4.56)
-0.08
9.41 (5.03)
9.39 (4.55)
0.00
...median [IQR]
1.00 [1.00, 1.00]
1.00 [1.00, 1.00]
--
8.00 [6.00, 11.00]
9.00 [6.00, 12.00]
 --
8.00 [6.00, 11.00]
8.00 [6.00, 12.00]
--
8.00 [6.00, 12.00]
8.00 [6.00, 12.00]
 --
Generic/Brand unique prescriptions
...mean (sd)
0.99 (0.03)
0.99 (0.04)
0.00
0.99 (0.04)
0.99 (0.04)
0.00
0.99 (0.03)
0.99 (0.04)
0.00
0.99 (0.03)
0.99 (0.04)
0.00
...median [IQR]
1.00 [1.00, 1.00]
1.00 [1.00, 1.00]
--
1.00 [1.00, 1.00]
1.00 [1.00, 1.00]
 --
1.00 [1.00, 1.00]
1.00 [1.00, 1.00]
--
1.00 [1.00, 1.00]
1.00 [1.00, 1.00]
 --
Number of Endocrinologist visits*
...mean (sd)
0.12 (0.50)
0.28 (0.74)
-0.25
0.26 (0.77)
0.27 (0.72)
-0.01
0.08 (0.42)
0.27 (0.74)
-0.32
0.23 (0.77)
0.24 (0.62)
-0.01
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
--
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
 --
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
--
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
 --
Appendix B: Table 1

Number of HbA1c*
...mean (sd)
1.58 (0.72)
1.62 (0.72)
-0.06
1.64 (0.67)
1.61 (0.72)
0.04
1.57 (0.70)
1.59 (0.69)
-0.03
1.55 (0.69)
1.59 (0.69)
-0.06
...median [IQR]
2.00 [1.00, 2.00]
2.00 [1.00, 2.00]
--
2.00 [1.00, 2.00]
2.00 [1.00, 2.00]
 --
2.00 [1.00, 2.00]
2.00 [1.00, 2.00]
--
2.00 [1.00, 2.00]
2.00 [1.00, 2.00]
 --
Basic or comprehensive metabolic blood 
chemistry test; n (%)*
22,174 (83.5%)
500 (78.7%)
0.12
499 (78.8%)
498 (78.7%)
0.00
15,699 (83.9%)
546 (80.1%)
0.10
537 (79.2%)
542 (79.9%)
-0.02
Number of bone density tests; n (%)*
1,038 (3.9%)
24 (3.8%)
0.01
17 (2.7%)
24 (3.8%)
-0.06
716 (3.8%)
24 (3.5%)
0.02
28 (4.1%)
23 (3.4%)
0.04
PSA test or Prostate exam for DRE; n (%)*
5,109 (19.2%)
117 (18.4%)
0.02
113 (17.9%)
117 (18.5%)
-0.02
3,755 (20.1%)
124 (18.2%)
0.05
111 (16.4%)
124 (18.3%)
-0.05
Flexible Sigmoidoscopy or colonoscopy or CT 
virtual colonoscopy; n (%)
1,245 (4.7%)
36 (5.7%)
-0.05
36 (5.7%)
36 (5.7%)
0.00
887 (4.7%)
43 (6.3%)
-0.07
40 (5.9%)
43 (6.3%)
-0.02
Number of Mammograms (Breast cancer 
screening); n (%)
3,308 (12.5%)
99 (15.6%)
-0.09
94 (14.8%)
99 (15.6%)
-0.02
2,180 (11.7%)
100 (14.7%)
-0.09
96 (14.2%)
99 (14.6%)
-0.01
Number of Pap smear (Cervical cancer 
screening); n (%)*
856 (3.2%)
38 (6.0%)
-0.13
37 (5.8%)
37 (5.8%)
0.00
533 (2.8%)
36 (5.3%)
-0.13
38 (5.6%)
35 (5.2%)
0.02
Flu vaccine; n (%)
4,932 (18.6%)
110 (17.3%)
0.03
90 (14.2%)
110 (17.4%)
-0.09
3,625 (19.4%)
136 (19.9%)
-0.01
124 (18.3%)
136 (20.1%)
-0.05
Pneumococcal vaccine; n (%)
6,982 (26.3%)
155 (24.4%)
0.04
150 (23.7%)
155 (24.5%)
-0.02
5,093 (27.2%)
189 (27.7%)
-0.01
191 (28.2%)
189 (27.9%)
0.01
Copay for pharmacy cost (charges in U.S. $)*
...mean (sd)
200.93 (403.50)
296.02 (350.92)
-0.25
227.65 (399.41)
295.75 (351.08)
-0.18
189.00 (322.50)
280.00 (299.36)
-0.29
244.73 (382.68)
280.00 (299.65)
-0.10
...median [IQR]
119.08 [44.36, 256.47]
207.17 [101.87, 
381.05]
 --
134.85 [47.08, 298.01]
207.17 [101.91, 
379.84]
 --
107.26 [37.51, 239.55]
204.83 [99.90, 
371.72]
 --
141.41 [54.32, 289.05]
204.83 [99.90, 
371.72]
 --
Business type*
...Commercial; n (%)
8,101 (30.5%)
374 (58.9%)
-0.60
372 (58.8%)
373 (58.9%)
0.00
5,441 (29.1%)
408 (59.8%)
-0.65
419 (61.8%)
404 (59.6%)
0.05
...Medicare; n (%)
18,440 (69.5%)
261 (41.1%)
0.60
261 (41.2%)
260 (41.1%)
0.00
13,265 (70.9%)
274 (40.2%)
0.65
259 (38.2%)
274 (40.4%)
-0.05
Low income indicator; n (%)*
3,690 (13.9%)
54 (8.5%)
0.17
64 (10.1%)
53 (8.4%)
0.06
2,769 (14.3%)
70 (9.4%)
0.15
58 (8.6%)
61 (9.0%)
-0.01
*variables included in the PS model
Appendix B: Table 1

OPTUM
Semaglutide vs Standard - Cohort ITT (12m +/- 90 days) 
BEFORE PS MATCHING
 
 
AFTER PS MATCHING
 
 
 
 
Appendix B: Propensity 

Semaglutide vs Standard - Cohort AT 12-30w 
BEFORE PS MATCHING
 
 
AFTER PS MATCHING
 
 
 
 
Appendix B: Propensity