Replication of the LEAD-2 Diabetes Trial in Healthcare Claims Data
Conditions: Diabetes
Sponsor: Brigham and Women's Hospital

 
 
 
 
 
 
 
 
 
 
Replication of the LEAD-2 Trial in Healthcare Claims 
 
RCT DUPLICATE – LEAD-2 
 
August 4, 2021 

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1. RCT Details 
This section provides a high-level overview of a published 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 
Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 
Diabetes. The LEAD (Liraglutide Effect and Action in Diabetes)-2 study (NCT00318461). 
 
1.2 Intended aim(s) 
To assess whether the glycemic control achieved by adding liraglutide to metformin was non-inferior to glimepiride and 
metformin combination therapy after 26 weeks of treatment, in subjects with type 2 diabetes and previously treated with 
oral antidiabetic therapy.  
 
1.3 Primary endpoint for replication  
Long-term glycemic control defined as change in HbA1c from baseline to the end of follow-up.  
 
1.4 Required power for primary endpoint and noninferiority margin (if applicable) 
The sample size calculation was based on both HbA1c and body weight endpoints. The assumed standard deviation for 
HbA1c and the coefficient of variance for body weight were 1.2% and 3%, respectively. The combined power (calculated as 
the product of the marginal powers for HbA1c and body weight) was at least 85%. Noninferiority of glycemic control with 
liraglutide versus glimepiride was concluded if the upper limit of the two-sided 95% CI for the treatment difference was < 
0.4%. 
With a standard deviation of 1.2% for HbA1c and a coefficient of variance of 3% for body weight, it was concluded that at 
least 168 subjects were required to complete the treatment in the liraglutide and in the glimepiride, respectively. Assuming 
a dropout rate of 25% after 26 weeks of treatment, the number of subjects to be randomized was calculated to be 228 in 
each of the liraglutide and glimepiride treatment groups.  
 
1.5 Secondary endpoint for replication (assay sensitivity) and RCT finding 
n/a 
 
1.6 Trial estimate 

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The HbA1c mean decreases of 1.0% (± 0.1) for both the 1.2 and 1.8 mg/day liraglutide groups and 1.0% (± 0.1) for 
glimepiride group. Treatment difference in HbA1c was 0.0% [95% CI: -0.2 to 0.2] for both comparisons liraglutide 1.2 
mg/day versus glimepiride and liraglutide 1.8 mg/day versus glimepiride (Nauck M et al. 2009). 
 
2. Person responsible for implementation of replication in Aetion 
Elvira D’Andrea, MD, MPH, 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. 
 
3. Data Source(s) 
Optum CDM 
 
4. Study Design Diagram 
The study design diagram visualizes key aspects of the longitudinal study design for expedited review. 
 
 
 

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Figure 1. Design Diagram – LEAD-2 TRIAL REPLICATION 
 

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5. Cohort Identification  
 
5.1 Cohort Summary 
This study will involve a new user, parallel group, propensity score-matched, retrospective cohort design comparing injectable 
subcutaneous liraglutide (1.2 or 1.8 mg/day) to oral glimepiride (4 mg once daily). Treatments in both arms are administered in 
combination with metformin (up to 2,000 mg/day). Patients will be required to have continuous enrollment during a baseline 
period of 180 days before initiation of liraglutide or glimepiride. The analyses will be restricted to individuals with type 2 diabetes 
mellitus who have been previously treated with antidiabetic drugs. In the replication, previous anti-diabetic treatment was 
defined as the presence of at least 2 prescriptions for metformin within 6 months before and including cohort entry. 
 
5.2 Important steps for cohort formation 
New use of liraglutide (exposure) is defined as no use of the exposure drug within 180 days prior to index date. New use of 
glimepiride (comparator) is defined as no use of the comparator drug within 180 days prior to index date. Eligible patients are 
required to be new users with respect to both exposure and comparator groups (i.e., no use of both exposure and comparator 
drugs) within 180 days prior to index date.  
 
5.2.1 Eligible cohort entry dates 
Liraglutide indication as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus 
was approved by FDA on Jan 25, 2010 (the approval of glimepiride for the same indication was antecedent to 2010).  
Thus, the initial eligible cohort entry date is the first date after the FDA approval available in the data.  
The last eligible date is June 30, 2020, three months before the end of all available data in Optum CDM. Since the effects 
of liraglutide and glimepiride on the outcome (i.e., change in HbA1c) will be estimated between 56 and 212 days after 
cohort entry (see Section 6.3), this will allow all eligible patients to contribute to the outcome. 
The database used is Optum CDM because lab results/values are available in this database for a subset of laboratory tests, 
including the A1C tests. The following eligible cohort entry dates were included:  
 
• Optum CDM: Jan 26, 2010 – Jun 30, 2020  
 
5.2.2 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.  

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Note. Patients who are censored between cohort entry and the beginning of the outcome assessment window (i.e., 0.x-56 
days after cohort entry) for the reasons reported in the Section 6.3.2 will not contribute to the unmatched or matched 
cohorts. Further details on the number of patients who are excluded from the study cohort are reported in the Section 7. 
 
5.3 Flowchart of the study cohort assembly 
For liraglutide vs. glimepiride: Aetion link: https://bwh-dope.aetion.com/cohorts/details/23482/1688/71700 
 
Optum 
Excluded 
Patients 
Remaining 
Patients 
All patients 
  
79,335,559 
Did not meet cohort entry criteria 
-78,554,666 (99%) 
780,893 
Excluded due to insufficient enrollment 
-119,528 (15%) 
661,365 
Excluded due to prior use of referent 
-424,186 (64%) 
237,179 
Excluded due to prior use of exposure 
-138,679 (58%) 
98,500 
Excluded because patient qualified in >1 exposure category 
-85 (<1%) 
98,415 
Excluded based on nursing home admission in the prior 180 days 
-3,784 (4%) 
94,631 
Excluded based on gender missing or unknown 
-10 (<1%) 
94,621 
Excluded based on Inclusion #1.1 - Type 2 diabetes mellitus 
-6,027 (6%) 
88,594 
Excluded based on Inclusion #1.2 - Metformin use (2 prescriptions within 183 days) 
-55,832 (63%) 
32,762 
Excluded based on Inclusion #1.3 - Concomitant initiation or concurrent use of metformin 
-3,670 (11%) 
29,092 
Excluded based on Inclusion #1.4 - No use of other anti-diabetic meds 
-9,861 (34%) 
19,231 
Excluded based on Inclusion #2.1 - 3 records of HbA1c 2-20% values/results within 365 days 
-13,962 (73%) 
5,269 
Excluded based on Inclusion #2.2 - At least 1 lab value HbA1c 7-11% recorded within 90 days 
-808 (15%) 
4,461 
Excluded based on Inclusion #3.1 - Age > 18 
-0 (<1%) 
4,461 
Excluded based on Inclusion #3.2 - Age < 80 
-87 (2%) 
4,374 
Excluded based on Exclusion #1 - Morbid Obesity BMI > 40 
-147 (3%) 
4,227 
Excluded based on Exclusion #2 - Any insulin use 
-234 (6%) 
3,993 
Excluded based on Exclusion #3 - End-stage liver disease 
-9 (<1%) 
3,984 
Excluded based on Exclusion #4 - Viral Hepatitis B and C 
-7 (<1%) 
3,977 
Excluded based on Exclusion #5 - CKD stage 5, End-stage renal disease, dialysis, or renal transplant 
-0 (<1%) 
3,977 

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Excluded based on Exclusion #6.1 - Myocardial Infarction 
-1 (<1%) 
3,976 
Excluded based on Exclusion #6.2 - Heart Failure 
-1 (<1%) 
3,975 
Excluded based on Exclusion #7 - Anti-VEGFi OR Photocoagulation  
-5 (<1%) 
3,970 
Excluded based on Exclusion #8 - Uncontrolled hypertension 
-34 (<1%) 
3,936 
Excluded based on Exclusion #9 - Malignant neoplasm (except non-melanoma skin cancer) 
-79 (2%) 
3,857 
Excluded based on Exclusion #10 - Recurrent Hypoglycemia  
-8 (<1%) 
3,849 
Excluded based on Exclusion #11 - Systemic glucocorticoids use 
-48 (1%) 
3,801 
Excluded based on Exclusion #12 - Drug addiction or alcohol abuse and dependence 
-11 (<1%) 
3,790 
Excluded based on Exclusion #13 - Mental incapacity, unwillingness to comply 
-13 (<1%) 
3,777 
Excluded based on Exclusion #14 - Pregnancy 
-0 (<1%) 
3,777 
Excluded based on Exclusion #15.1 - Type 1 diabetes mellitus (contraindication glimepiride) 
-10 (<1%) 
3,767 
Excluded based on Exclusion #15.2 - Diabetic ketoacidosis (contraindication glimepiride) 
-2 (<1%) 
3,765 
Excluded based on Exclusion #15.3 - Other metabolic acidosis (contraindication glimepiride) 
-1 (<1%) 
3,764 
Excluded based on Exclusion #16 - Multiple endocrine neoplasia type 2 (MEN2) 
-0 (<1%) 
3,764 
Final cohort 
 
3,764 
 
6. Variables  
 
6.1 Exposure-related variables:  
 
Study drug:  
New initiation of injectable subcutaneous liraglutide (1.2 or 1.8 mg/day), a glucagon-like peptide-1 receptor agonist. New 
initiation is defined as no use of liraglutide within 180 days before treatment initiation (washout period). New users of liraglutide 
are not allowed to receive glimepiride within 180 days prior to treatment initiation. Concurrent use of metformin is required 
(2,000 mg/day). 
 
Comparator agent: 
New initiation of oral glimepiride (4 mg once daily). New initiation is defined as no use of glimepiride within 180 days before 
treatment initiation (washout period). New users of glimepiride are not allowed to receive liraglutide within 180 days prior to 
treatment initiation. Concurrent use of metformin is required (2,000 mg/day). 
 

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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): 
 
§ Primary outcome: Changes in HbA1c from baseline to 26 weeks of treatment (end of follow-up). 
 
Note. In the trial, HbA1c was also measured at 8, 12, 18 weeks (± 3 days) after randomization. Missing values of HbA1c at 
26 weeks were replaced using last observation carried forward (LOCF) in the intention-to-treat (ITT) analysis set. 
In the replication, HbA1c at baseline will be defined as the last recorded HbA1c value measured within 90 days before and 
including cohort entry date in both groups. HbA1c at the end of follow-up will be defined as a recorded HbA1c value closest 
to the end of the 26th week and measured between 56 and 212 days (8-30 weeks) after cohort entry.  
 
§ Secondary outcome: -- 
 
6.3.2 Primary analysis and study follow-up 
As-treated (AT) analysis will be performed as main analysis. The treatment drug will be defined as the index drug assigned on the 
day of cohort entry. Patients will be followed for about 30 weeks (212 days). Compared to the trial (Nauck M et al. 2009), we will 

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extend the follow-up and the outcome assessment periods of 4 weeks. The follow-up and outcome assessment window will start 56 
days after cohort entry date and will continue until the earliest date of the following events:  
§ The first occurrence of the outcome of interest (measured between 56 and 212 days after cohort entry), 
§ The date of end of continuous registration in the database (disenrollment or end of available data), 
§ End of the study period, 
§ Measured death event occurs, 
§ Index drugs discontinuation (liraglutide, glimepiride or metformin), 
§ Crossover or addition of drug from the other treatment group, 
§ Addition of any other anti-diabetic medications, 
§ Nursing home admission 
o Nursing home admissions are considered a censoring event because the data sources utilized typically provide little to 
no data on a patient, particularly on drug utilization, after admission. We will utilize this as an exclusion reason for 
cohorts for the same reason.   
 
Note. To decrease the incidence of missing values of the outcome (specifically, missing of HbA1c values measured between 56-212 
days after cohort entry), we required that the eligible patients had at least 3 HbA1c measurements recorded within 365 days before 
and including cohort entry. This will increase 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 outcome. Multiple imputation will be used to 
handle missing values in the primary analysis, while complete case analysis will be applied in a sensitivity analysis. 
 
7. Initial Feasibility Analysis  
Aetion report name: 
For liraglutide vs. glimepiride 
Optum CDM (continuous HbA1c outcome) https://bwh-dope.aetion.com/projects/details/1688/rwrs/71723 
Optum CDM (binary HbA1c outcome [flag: presence or absence of an HbA1c result within 56-212 days after cohort entry]) – calculated 
merging the databases from https://bwh-dope.aetion.com/projects/details/1688/rwrs/71715 and https://bwh-
dope.aetion.com/projects/details/1688/rwrs/71716 – see file LEAD-2_programming_steps and output of “STEP 1 - Initial FEASIBILITY 
Analysis (with study outcome) - Paragraph 7 of the protocol” 
 
 
Date conducted: 06/17/2021 

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Complete Aetion feasibility analysis using age and CCI as the only covariates and the primary endpoint (Section 6.3.1) as the 
outcome. 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 liraglutide vs. glimepiride 
 
  
Optum CDM 
 
Glimepiride - Comparator 
Liraglutide - Exposure 
Difference 
Number of patients * 
3,096 
378 
- (-, -) 
Age 
...mean (sd) 
64.24 (10.37) 
59.22 (10.94) 
5.02 (3.90, 6.13) 
...median [IQR] 
67.00 [58.00, 72.00] 
60.00 [51.00, 68.00] 
- (-, -) 
Gender 
 
 
 
...M = MALE; n (%) 
1,726 (55.7%) 
179 (47.4%) 
8.39% (3.08%, 13.7%) 
...F = FEMALE; n (%) 
1,370 (44.3%) 
199 (52.6%) 
-8.39% (-13.7%, -3.08%) 
Combined Comorbidity Score - CCI (180 days) 
...mean (sd) 
2.06 (1.56) 
1.86 (1.36) 
0.19 (0.03, 0.36) 
...median [IQR] 
2.00 [1.00, 3.00] 
2.00 [1.00, 2.00] 
- (-, -) 
* The overall n. of patients in the unmatched cohort is 3,470. Patients who were censored between cohort entry and the beginning of the outcome assessment 
window (n. 290 patients) are excluded from the Table reporting patient characteristics by groups because they will not contribute to the unmatched or matched 
cohorts. 
 
• Report summary parameters of study population FEASIBILITY- FOR STUDY OUTCOME 
For liraglutide vs. glimepiride 
 

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Optum CDM 
Number of patients in full cohort 
3,764 
Number of patients that did not begin follow-up * 
290 
Number of patients 
3,474 
Number of person-years of patients that did begin the follow-up 
1,118.53 
Number of patients in group: Glimepiride 
3,096 
Number of patients in group: Liraglutide 
378 
Outcome - Lab value HbA1c 
...mean (sd) 
7.24 (1.01) 
...median [IQR] 
7.00 [6.60, 7.70] 
...minimum 
4.1 
...maximum 
13.4 
Number of patients with zero value 
0 
Non-zero mean value (SD) 
7.24 (1.01) 
Non-zero median value [IQR] 
7.00 [6.60, 7.70] 
* patients who were censored between cohort entry and the beginning of the outcome assessment window/follow-up (i.e., 0.5-56 days after cohort entry) will 
not contribute to the unmatched and matched cohorts. 
 
 
• Report median follow-up time by treatment group 
For liraglutide vs. glimepiride 
 
Median Follow-Up Time (Days) [IQR] – AT analysis 
Patient Group 
Optum CDM 
Overall Patient Population 
99 [84, 148] 
Referent 
101 [84, 148] 
Exposure 
88 [79, 130] 
 
• Report reasons for censoring in the overall study population 

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§ 
For liraglutide vs. glimepiride 
 
Overall (n. 3,470) 
Liraglutide (n. 378) 
Glimepiride (n. 3,092) 
Outcome * 
2,262 (65.2%) 
233 (61.6%) 
2,029 (65.6%) 
Death 
2 (0.1%) 
0 (0%) 
2 (0.1%) 
Start of an additional exposure 
8 (0.2%) 
3 (0.8%) 
5 (0.2%) 
End of index exposure 
368 (10.6%) 
74 (19.6%) 
294 (9.5%) 
Maximum follow-up time 
336 (9.7%) 
22 (5.8%) 
314 (10.2%) 
End of patient data 
37 (1.0%) 
3 (0.8%) 
34 (1.1%) 
End of patient enrollment 
108 (3.1%) 
12 (3.2%) 
96 (3.1%) 
Start of additional antidiabetic drugs + Nursing home + Metformin 
discontinuation with allowed 60 days gap  
349 (10.1%) 
22 (5.82%) 
314 (10.2%) 
* patients with outcome recorded between 56-212 days after cohort entry.  
 
• Report overall mean (sd) of the primary outcome. 
 
  
Optum CDM 
Outcome – Lab value HbA1c ...mean (sd) 
7.24 (1.01) 
 
 
8. Initial Power Assessment 
 
Analysis report name: 
For liraglutide vs. glimepiride 
Optum CDM – see file LEAD-2_programming_steps and output of “STEP 2 - INITIAL POWER Assessment - PS matching on age, gender, CCI 
(with dummy outcome) - Paragraphs 8 of the protocol” 
 
Date conducted:  06/16/2021 
 
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. 

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Complete a 1:1 PS-matched comparative analysis using this outcome. PS should include only 3 covariates: age, gender and combined 
comorbidity index. Power calculations are based on the formulas from Julios et al. (2008). 
 
• 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. 
 
o Optum CDM 
 
Non-inferiority Analysis 
 
Standard deviation of outcome 
1.01 
Non-inferiority limit 
0.4 
Alpha (2-sided) 
0.05 
Power (1-beta) 
90% 
Sample size required per group 
110 
Total sample size required 
220 
 
 
Number of patients matched 
752 
Reference 
376 
Exposed 
376 
 
 
• Stop analyses until feasibility and power are reviewed by primary investigators, FDA, and assigned members of advisory board. 
Reviewed by PI: 
Shirley Wang 
Date reviewed: 
07/16/2021 
Reviewed by FDA: 
Ken Quinto 
Date reviewed: 
08/2/2021 
Reasons for stopping 
analysis (if required): 
 
 

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9. Balance Assessment 
For liraglutide vs. glimepiride 
Optum CDM: see file LEAD-2_programming_steps and output of “STEP 3 - BALANCE Assessment (with dummy outcome) - Paragraphs 9-
10 of the protocol” 
 
Date conducted: 06/16/2021 
 
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. 
 
• 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 reasons for censoring by treatment group. 
 

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Overall 
(n. 746) 
Liraglutide – exposure 
(n. 373) 
Glimepiride – comparator 
(n. 373) 
Outcome (dummy) 
0 (0%) 
0 (0%) 
0 (0%) 
Death 
0 (0%) 
0 (0%) 
0 (0%) 
Start of an additional exposure 
9 (1.2%) 
6 (0.8%) 
3 (0.4%) 
End of index exposure 
194 (26.0%) 
137 (18.4%) 
57 (7.6%) 
Maximum follow-up time 
340 (45.6%) 
137 (18.4%) 
203 (27.2 %) 
End of patient data 
5 (0.7%) 
3 (0.4%) 
2 (0.3%) 
End of patient enrollment 
61 (6.3%) 
25 (3.4%) 
36 (4.8%) 
Start of additional antidiabetic drugs + Nursing home + Metformin 
discontinuation with allowed 60 days gap  
137 (18.4%) 
65 (8.7%) 
72 (9.7%) 
 
• Report follow-up time by treatment group. 
 
Median Follow-Up Time (Days) [IQR] 
Patient Group 
Overall (n. 746) 
Liraglutide (n. 373) 
Glimepiride (n. 373) 
Overall Patient Population 
188 [97 - 212] 
150 [89 - 212] 
212 [119 -212] 
 
• Report overall mean (sd) of the primary outcome (from initial feasibility analysis). 
 
  
Optum CDM 
Outcome – Lab value HbA1c ...mean (sd) 
7.24 (1.01) 
 
 
10. Final Power Assessment 
 
Date conducted:  
 
• Re-calculate power in the appropriate excel table, using the revised number of matched patients from the PS-match in Section 9. 
All other parameters in the table should be the same as in Section 8. 

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Non-inferiority Analysis 
 
Standard deviation of outcome 
1.01 
Non-inferiority limit 
0.4 
Alpha (2-sided) 
0.05 
Power (1-beta) 
90% 
Sample size required per group 
110 
Total sample size required 
220 
 
 
Number of patients matched 
746 
Reference 
373 
Exposed 
373 
 
 
• Stop analyses until balance and final power assessment are reviewed by primary investigators, FDA, and assigned members of 
advisory board. 
Reviewed by PI: 
Shirley Wang 
Date reviewed: 
07/16/2021 
Reviewed by FDA: 
Ken Quinto 
Date reviewed: 
08/2/2021 
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 

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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. 
 
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 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 

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14.2 
Table 2: Follow-up time 
 
Patient Group 
Median Follow-Up Time (Days) [IQR] 
Overall Patient Population 
 
Referent 
 
Exposure 
 
 
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. 

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15. References 
 
 
Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, Düring M, Matthews DR; LEAD-2 Study Group. Efficacy 
and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD 
(liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009 Jan;32(1):84-90. doi: 10.2337/dc08-1355.  
Julious SA. Sample sizes for clinical trials with Normal data. Statist. Med. 2004; 23:1921-1986. Sealed Envelope Ltd. 2012. Power 
calculator for continuous outcome non-inferiority trial. [Online] Available from: 
https://www.sealedenvelope.com/power/continuous-noninferior/ [Accessed Fri May 07, 2021]. 
 
 

#
LEAD-2 trial definitions
Implementation in routine care
References/Rationale
Color coding
Exposure: Liraglutide s.c. 0.6 mg/day, 1.2 mg/day and 1.8 mg/day in combination with metformin (1500-
2000 mg/day) for 26 weeks
Reference for non-inferiority: Glimepiride (4 mg/day) in combination with metformin (1500-2000 
mg/day)
Reference for superiority: Metformin monotherapy (1500-2000 mg/day)
Aim: To evaluate whether the effect on glycaemic control (as measured by change in HbA1c) of 
treatment with 0.6 mg/day, 1.2 mg/day and 1.8 mg/day of liraglutide in combination with metformin was 
superior to metformin monotherapy and non-inferior to metformin and glimepiride combination therapy 
after 26 weeks of treatment.
Exposure: new-use of Liraglutide (washout 180 days) in combination with metformin 
NDC Generic Name:
LIRAGLUTIDE
NDC Brand name:
Viktoza (FlexPen)
Reference: new use of Glimepiride (washout 180 days) in combination with metformin
NDC Generic Name:
GLIMEPIRIDE
NDC Brand name:
GLIMEPIRIDE
AMARYL
Criteria
Adequate mapping in claims
Change in HbA1c from baseline to week 26
Note: in the trial missing values are replaced with last value carried forward [LVCF]
Measured as change in HbA1c from baseline to the last recorded HbA1c value between 56 and 212 days after drug 
initiation: 
Loinc codes:
17855-8, 17856-6, 41995-2, 43150-2, 4548-4, 4549-2, 55454-3, 71875-9, 74246-0
Intermediate mapping in claims
Poor mapping or cannot be measured in claims 
0
Informed consent obtained before any trial-related activities (trial-related activities are any procedure that 
would not have been performed during normal management of the subject).
N/A
Can't be measured in claims but not important for the analysis
1
(1.1) Subjects diagnosed with type 2 diabetes and (1.2) treated with OAD(s) for at least three months.
1.1 Selecting patients with a diagnosis of type 2 diabetes measured from the time of enrollment to the day of drug 
initiation inpatient (any position), outpatient (any position):
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
1.2 Selecting patients with at least two prescriptions of metformin within 183 days before cohort entry (OADs 
treatment ≥ 3 months), and 
1.3 Concomitant or current use of metformin at cohort entry date in both treatment groups:
Generic name:
Metformin Hcl
1.4  Selecting patients with no other anti-diabetic treatments within the 180 days before cohort entry:
Please refer to Anti-diabetic treatments (other than insulin) in "Anti-diabetic treatment"
2
HbA1c:
− 7.0-10.0% (both incl.) in subjects on OAD combination therapy
− 7.0-11.0% (both incl.) in subjects on OAD monotherapy.
2.1 Selecting patients with 3 measurements of HbA1c values (between 2-20%) recorded within 365 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 AND Result value 2-20%
2.2 Selecting patients with at least one measurement of HbA1c value (between and included 7-11%) 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 AND Result value 7-11%
3
Age 18-80 years, both inclusive (as allowed according to local guidelines for metformin and glimepiride 
treatment). This inclusion criterion has been modified for Site 344 in Australia according to Substantial 
Protocol Amendment No. 1-AU, see Section 9.8.1.
Female and male, 18-80 years at the time of drug initiation
EXCLUSION CRITERIA
Please see the following Google Drive for further details or any missing information: 
https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV?usp=sharing
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
Trial details - clinicaltrial.gov NCT00318461
EXPOSURE vs. COMPARISON
PRIMARY OUTCOME
INCLUSION CRITERIA
Appendix A

1
Body mass index (BMI) >= 40.0 kg/m2.
Measured 180 days prior to and including the day of drug initiation inpatient (any position), outpatient (any 
position):
Morbid obesity diagnosis or BMI >= 40 kg/m2:
ICD 9 diagnosis:: 278.01, 278.03, V85.4x
ICD 10 diagnosis: E66.01, E66.2, Z68.4x
NB. Codes for bariatric surgey, complications of bariatric surgery and prescriptions of drugs for weight loss were not 
included in the measure since this exclusion criterion aims to exclude specifically patients with morbid obesity. Codes for 
obesity during pregnancy were not included because of the exclusion criterion #17.  
2
Treatment with insulin within the last three months prior to trial (except for short-term treatment
due to intercurrent illness at the discretion of the investigator).
Measured 180 days prior to and including the day of drug initiation:
NDC Generic Name:
Please refer to Insulin  in "Anti-diabetic treatments"
NB. Although the trial excluded patients in treatment with insulin within the 90 days before drug initiation, with real-
world data we are required to be more conservative and to extend the washout period to 180 days. In fact, a 90-day 
washout applied in real world does not  garantee the exclusion of prevalent users (i.e. patients on active insulin therapy) 
from the cohort.
3
Impaired liver function, defined as alanine aminotransferase (ALAT) >= 2.5 times upper limit of
normal (one retest analysed at the central laboratory within a week is permitted with the result
of the last sample being conclusive).
Measured 180 days prior to and including the day of drug initiation in any diagnosis position and inpatient or 
outpatient care setting:
Cirrhosis: 
ICD-9 Diagnosis: 571.2, 571.5, 571.6
ICD-10 Diagnosis: K70.11, K70.2, K70.3x, K70.4x, K74.x
Hepatic decompensation: 
ICD-9 Diagnosis: 456.0, 456.20, 456.1, 456.21, 789.5, 789.59, 572.2, 567.0, 567.2, 567.21, 567.22, 567.29, 567.8, 
567.89, 567.9, 572.4 
ICD-10 Diagnosis: R18.x, I85.x, K72.x, K65.x, K66.x, K67
HCC is already excluded with exclusion criterion 9
4
Subjects known to be Hepatitis B antigen or Hepatitis C antibody positive.
Measured 180 days prior to and including the day of drug initiation  in any diagnosis position and inpatient or 
outpatient care setting:
Viral hepatitis B or C:
ICD-9 diagnosis: 070.2x, 070.3x, 070.4x, 070.51, 070.54, 070.71, 070.74, V02.61, V02.62
ICD-10 diagnosis: B16.x, B17.0, B17.1x, B18.0-B18.2, B19.1x, B19.2x, Z22.51, Z22.52
5
Impaired renal function defined as serum creatinine >= 135 µmol/L (>= 1.5 mg/dL) for males and
>= 110 µmol/L (>= 1.3 mg/dL) for females (one retest analysed at the central laboratory within a
week is permitted with the result of the last sample being conclusive)
Measured 180 days prior to and including the 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
6
Clinically significant active cardiovascular disease including history of myocardial infarction within the 
past 6 months and/or heart failure (New York Heart Association class III and IV) at the discretion of the 
investigator.
Measured 180 days prior to and including the day of drug initiation in inpatient care setting, any position:
Myocardial Infarction:
ICD-9 DX: 410.xx 
ICD-10 DX: I21.xx, I22.xx
Measured 180 days prior to and including the day of drug initiation in inpatient care setting, primary position:
Heart Failure:
ICD-9 DX: 428.xx, 398.91, 402.x1, 404.x1, 404.x3
ICD-10 DX: I09.81, I11.0, I13.0, I13.2, I50.xxx, I97.13x
NB. HF is included only if inpatient / primary position to detect the most severe cases as specified in the exclusion 
criterion of the trial
Appendix A

7
Proliferative retinopathy or maculopathy requiring acute treatment as judged by the investigator.
Measured 180 days prior to and including the day of drug initiation:
Anti-VEGFi
CPT: 67028 (Intravitreal injection for pharmacologic agent)
AND
HCPCS: J9035 OR C9257 OR Q5107 (Bevacizumab 10 mg injection)  OR
HCPCS: J2778 (Ranibizumab 0.1 mg) OR
HCPCS: C9291 OR Q2046 OR J0178 OR C9296 OR J9400 (Aflibercept 2 mg injection)
Photocoagulation:
CPT: 67228 (Panretinal photocoagulation) OR
CPT: 67220 (Focal/Grid photocoagulation) OR
CPT: 67028 (Intravitreal injection for pharmacologic agent) 
8
Uncontrolled treated/untreated hypertension (systolic blood pressure >= 180 mmHg and/or diastolic 
blood pressure >= 100 mmHg).
Measured 180 days prior to and including the day of drug initiation in any diagnosis position in the inpatient and 
outpatient and emergency care setting:
 
Hypertensive crisis
ICD-10 diagnosis: I16.x (includes hypertensive urgency, emergency, crisis, unspecified)
 
OR
 
Measured 180 days prior to and including the day of drug initiation in primary diagnosis position for inpatient or 
any position for emergency care setting:
 
Uncontrolled hypertension:
ICD-9 diagnosis:
401.9 (unspecified essential hypertension)
401.0 (malignant essential hypertension)
402.0x (malignant hypertensive heart disease)
403.0x (malignant hypertensive kidney disease)
404.0x (malignant hypertensive heart and kidney disease)
405.0x (malignant secondary hypertension)
403.9x (unspecified hypertensive kidney disease)
796.2 (elevated BP reading without Dx of HTN)
9
Cancer (except basal cell skin cancer or squamous cell skin cancer) or any clinically significant
disease or disorder, except for conditions associated to type 2 diabetes, which in the
investigator’s opinion could interfere with the results of the trial.
Measured 1825 prior to and including the day of drug initiation in any diagnosis position and inpatient or outpatient 
care setting:
Cancer:
ICD 9 diagnosis: 140.x-209.x (except 173.x, non-melanoma skin cancer and 209.4x, 209.5x, 209.6x)
ICD 10 diagnosis: C00.x-C96, D45 (except C44.x, non-melanoma skin cancer) 
10
Recurrent major hypoglycaemia as judged by the investigator.
At least two measurements in the 180 days prior to and including the day of drug initiation inpatient or emergency 
department settings:
Hypoglycemia:
ICD-9  diagnosis: 251.0, 251.1, 251.2, 962.3, or 270.3 (primary position) or 250.8 without co-existence of 259.8, 272.7, 
681.x,682.x, 686.9, 707.1–707.9, 730.0–730.2, or 731.8 (any position)
ICD-10 diagnosis: E10.641, E11.641, E13.641, E10.649, E11.649, E13.649, E16.0, E16.1, E16.2 (primary position) or 
E11.69, E13.69, E10.69 without coexistence of E34.1, E34.8, E35, E75.2, E75.3, E77, L01, L02, L03, L97, M86, M90
N/A
Known or suspected allergy to trial product(s) or related products.
N/A
11
Use of any drug (except for OADs), which in the investigator’s opinion could interfere with glucose 
levels (e.g. systemic corticosteroids).
Measured 90 days prior to and including the day of drug initiation:
Injectable (IV) or (IM): 
NDC Generic Name:
methylprednisolone, hydrocortisone, dexamethasone
CPT/HCPCS Procedure Code:
J1020, J1030, J1040, J1720, J2920, J2930
Oral:
NDC Generic Name: 
Cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, dexamethasone 
N/A
Receipt of any investigational drug within the four weeks prior to this trial.
N/A
N/A
Previous participation in the randomised phase of this trial. Re-screening is allowed once within
the recruitment period.
N/A
Appendix A

12
Known or suspected abuse of alcohol or narcotics.
Measured 180 days prior to and including the day of drug initiation in any diagnosis position in inpatient or 
outpatient care setting:
Alcohol Abuse or Dependence
ICD-9 diagnosis: 291.x, 303.xx, 305.9x, 357.5, 425.5, 535.30, 535.31, 571.0 - 571.3, 760.71, 790.3, 980.0, E860.0, 
E860.1, E860.8, E860.9, V11.3, V79.1
ICD-10 diagnosis: E24.4, F10.1xx (excluding F10.13x), F10.2xx, F10.9xx (excluding F10.93x), G31.2, G62.1, G72.1, 
I42.6, K29.2x, K70.xx, K85.2x, K86.0, O35.4, P04.3, Q86.0, R78.0, T51.0X1x, Z50.2, Z71.4, Z72.1
OR
Drug Abuse or Dependence 
ICD-9 diagnosis: 292.xx, 304.xx, 305.xx (excluding 305.0x and 305.1), 648.3x, 779.5, 965.0x, 967.x, 969.xx, 970.xx, 
V65.42
ICD-10 diagnosis: F11.xxx, F12.xxx, F13.xxx, F14.xxx, F15.xxx, F16.xxx, F18.xxx, F19.xxx, O99.32x, P96.1, 
T40 xxxx (excluding T40 xx6x) T43 xxxx (excluding T43 xx6x) Z71 51
13
Mental incapacity, unwillingness or language barrier precluding adequate understanding or
cooperation.
Measured 180 days prior to and including the day of drug initiation in any diagnosis position in inpatient or 
outpatient care setting:
Dementia and brain damages:
ICD-9 diagnosis: 290.x, 294.x, 330.x, 331.x
ICD-10 diagnosis: F01.50, F01.51, F02.80, F02.81, F03.90, F03.91, F04, F05, F06.x, F84.2, G13.2, G13.8, G30.x, 
G31.x, G91.x, G93.x, G94, E750, E751, E752, E754
NDC generic names: RIVASTIGMINE, DONEPEZIL HCL, ERGOLOID MESYLATES, GALANTAMINE HBR, 
MEMANTINE HCL, MEMANTINE HCL/DONEPEZIL HCL, RIVASTIGMINE TARTRATE, TACRINE HCL
OR
Non-compliance: 
ICD-9 diagnosis: V45.12, V15.81
14
Females of childbearing potential who are pregnant, breast-feeding or intend to become
pregnant or are not using adequate contraceptive methods (adequate contraceptive measures as
required by local law or practice). This exclusion criterion has been modified in Germany
according to Substantial Protocol Amendment No. 2-DE, see Section 9.8.1.
Measured 180 days prior to and including the day of drug initiation in any diagnosis position and inpatient or 
outpatient care setting:
Please refer to "Pregnancy definition"
15
Any contraindications to metformin or glimepiride (according to local requirements).
Measured 180 days prior to and including day of drug initiation in any diagnosis position and inpatient or outpatient 
care setting:
Contraindications to Glimepiride:
Type 1 diabetes:
ICD 9 diagnosis: 250.01, 250.03, 250.11, 250.13, 250.21, 250.23, 250.31, 250.33, 250.41, 250.43, 250.51, 250.53, 
250.61, 250.63, 250.71, 250.73, 250.81, 250.83, 250.91, 250.93
ICD 10 diagnosis: E10.x
Diabetic ketoacidosis (DKA):
ICD9 diagnosis: 250.1x
ICD10 diagnosis: E10.1x, E11.1x, E13.1x, E08.1x, E09.1x
Other metabolic acidosis:
ICD9 diagnosis: 276.2 
ICD10 diagnosis: E87.2
NB. All patients no treated with metformin at cohort entry have been excluded from the eligible cohort, assuming that all 
incl ded patients ha e not conraindications for this dr g
16
Subjects with medical history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary 
thyroid carcinoma (FMTC) if total thyroidectomy has not been performed or cannot be ensured (i.e. 
posterior capsule of the thyroid gland not removed). This exclusion criterion has been added only in 
Germany according to Substantial Protocol Amendment No. 2-DE, see Section 9.8.1.
Measured 1825 days prior to and including day of drug initiation in any diagnosis position and inpatient or 
outpatient care setting:
ICD-9 diagnosis: 258.02, 258.03
ICD-10 diagnosis: E31.22, E31.23
NB. Thyroid carcinoma is already excluded with exclusion criterion 9
Appendix A

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
PREGNANCY DEFINITION
Appendix A

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
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
b.       Codes indicating extreme prematurity
c.       Other preterm codes
Appendix A

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
Appendix A

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
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
Appendix A

 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

Anti-diabetic treatments (other than insulin)
1st and 2nd Generation Sus (excluding glimepiride)
GLIPIZIDE/METFORMIN HCL
ACETOHEXAMIDE
GLYBURIDE,MICRONIZED
TOLBUTAMIDE
GLYBURIDE/METFORMIN HCL
TOLAZAMIDE
CHLORPROPAMIDE
GLYBURIDE
GLIPIZIDE
AGIs
ACARBOSE
MIGLITOL
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
Glitazones
ALOGLIPTIN BENZOATE/PIOGLITAZONE HCL
PIOGLITAZONE HCL
PIOGLITAZONE HCL/GLIMEPIRIDE
PIOGLITAZONE HCL/METFORMIN HCL
ROSIGLITAZONE MALEATE
ROSIGLITAZONE MALEATE/GLIMEPIRIDE
ROSIGLITAZONE MALEATE/METFORMIN HCL
Appendix A

GLP-1 RA (excluding liraglutide monotherapy)
ALBIGLUTIDE
DULAGLUTIDE
EXENATIDE
EXENATIDE MICROSPHERES
INSULIN DEGLUDEC/LIRAGLUTIDE
INSULIN GLARGINE,HUMAN RECOMBINANT ANALOG/LIXISENATIDE
LIXISENATIDE
SEMAGLUTIDE
Meglitinides
NATEGLINIDE
REPAGLINIDE
REPAGLINIDE/METFORMIN HCL
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
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
Appendix A

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

Optum
BEFORE PS MATCHING
AFTER PS MATCHING
The c-statistics for the propensity score model, pre-matching was 0.722
The c-statistics for the propensity score model, post-matching was 0.576
Appendix B

Variable
Glimpiride
Liraglutide
St. Diff
Variable
Glimepiride 
Liraglutide 
St. Diff
Number of patients
3,096
378
Number of patients
373
373
Age squared
Age squared*
...mean (sd)
761406 (223830.2)
651214 (225218.8)
0.491
...mean (sd)
631746.5 (235037.9)
653328.8 (225529.3)
-0.094
Age (continuous)
Age (continuous)
...mean (sd)
64.24 (10.37)
59.22 (10.94)
0.471
...mean (sd)
58.19 (11.58)
59.31 (10.96)
-0.099
Age (categories)
Age (categories)
...18 - 40; n (%)
95 (3.1%)
20 (5.3%)
-0.110
...18 - 40; n (%)
32 (8.6%)
20 (5.4%)
0.126
...41 - 50; n (%)
266 (8.6%)
64 (16.9%)
-0.251
...41 - 50; n (%)
63 (16.9%)
62 (16.6%)
0.008
...51 - 60; n (%)
602 (19.4%)
106 (28.0%)
-0.203
...51 - 60; n (%)
104 (27.9%)
104 (27.9%)
0.000
...61 - 70; n (%)
1187 (38.3%)
133 (35.2%)
0.064
...61 - 70; n (%)
127 (34.0%)
132 (35.4%)
-0.029
...71 - 80; n (%)
946 (30.6%)
55 (14.6%)
0.390
...71 - 80; n (%)
47 (12.6%)
55 (14.7%)
-0.061
Gender
Gender*
...M = MALE; n (%)
1726 (55.7%)
179 (47.4%)
0.167
...M = MALE; n (%)
188 (50.4%)
194 (52.0%)
-0.032
...F = FEMALE; n (%)
1370 (44.3%)
199 (52.6%)
-0.167
...F = FEMALE; n (%)
185 (49.6%)
179 (48.0%)
0.032
Race
Race*
...White; n (%)
1492 (48.2%)
220 (58.2%)
-0.201
...White; n (%)
202 (54.2%)
217 (58.2%)
-0.081
…Not white; n (%)
1604 (51.8%)
158 (41.8%)
0.201
…Not white; n (%)
171 (45.8%)
156 (41.8%)
0.081
Calendar time years (Jan 2010 - Jun 2020)
Calendar time years (Jan 2010 - Jun 2020)*
...Jan 26, 2010 - Dec 31, 2017; n (%)
1850 (59.8%)
255 (67.5%)
-0.161
...Jan 26, 2010 - Dec 31, 2011; n (%)
254 (68.1%)
251 (67.3%)
0.017
...Jan 1, 2018 - Jun 30, 2020; n (%)
1246 (40.2%)
123 (32.5%)
0.161
...Jul 1, 2018 - Dec 31, 2018; n (%)
119 (31.9%)
122 (32.7%)
-0.017
General Health 
General Health 
Smoking; n (%)
296 (9.6%)
30 (7.9%)
0.060
Smoking; n (%)*
22 (5.9%)
30 (8.0%)
-0.083
Obesity or Overweight; n (%)
760 (24.5%)
93 (24.6%)
-0.002
Obesity or Overweight; n (%)*
89 (23.9%)
91 (24.4%)
-0.012
    Obesity; n (%)
554 (17.9%)
79 (20.9%)
-0.076
    Obesity; n (%)
72 (19.3%)
77 (20.6%)
-0.033
    Overweight; n (%)
247 (8.0%)
16 (4.2%)
0.159
    Overweight; n (%)
21 (5.6%)
16 (4.3%)
0.060
Combined comorbidity score, 180 days
Combined comorbidity score, 180 days
...mean (sd)
2.06 (1.56)
1.86 (1.36)
0.137
...mean (sd)
1.92 (1.35)
1.86 (1.37)
0.044
Frailty Score: Empirical Version 180 days
Frailty Score: Empirical Version 180 days*
...mean (sd)
0.99 (0.77)
1.03 (0.73)
-0.053
...mean (sd)
1.05 (0.73)
1.02 (0.72)
0.041
Lab value HbA1c
Lab value HbA1c*
...mean (sd)
8.16 (0.96)
8.18 (0.99)
-0.021
...mean (sd)
8.16 (0.98)
8.18 (0.99)
-0.020
Cardiovascular Comorbidities
Cardiovascular Disorders
Hypertension; n (%)
391 (12.6%)
66 (17.5%)
-0.137
Hypertension; n (%)*
69 (18.5%)
63 (16.9%)
0.042
Hyperlipidemia; n (%)
2296 (74.2%)
299 (79.1%)
-0.116
Hyperlipidemia; n (%)*
297 (79.6%)
296 (79.4%)
0.005
Atherosclerosis Disease (MI, angina, CAD and other forms of chronic ischemic 
heart disease, History of CABG or PTCA); n (%)
566 (18.3%)
43 (11.4%)
0.195
Atherosclerosis Disease (MI, angina, CAD and other forms of chronic ischemic 
heart disease, History of CABG or PTCA); n (%)*
43 (11.5%)
42 (11.3%)
0.006
    Old MI; n (%)
64 (2.1%)
3 (0.8%)
0.109
    Old MI; n (%)
6 (1.6%)
3 (0.8%)
0.074
    Acute MI ; n (%)
10 (0.3%)
1 (0.3%)
0.000
    Acute MI ; n (%)
0 (0.0%)
1 (0.3%)
-0.078
    ACS/unstable angina; n (%)
18 (0.6%)
1 (0.3%)
0.045
    ACS/unstable angina; n (%)
0 (0.0%)
1 (0.3%)
-0.078
    Stable angina; n (%)
80 (2.6%)
6 (1.6%)
0.070
    Stable angina; n (%)
3 (0.8%)
6 (1.6%)
-0.074
    CAD and other forms of chronic ischemic heart disease; n (%)
415 (13.4%)
30 (7.9%)
0.179
    CAD and other forms of chronic ischemic heart disease; n (%)
33 (8.8%)
29 (7.8%)
0.036
    History of CABG or PTCA ; n (%)
107 (3.5%)
9 (2.4%)
0.065
    History of CABG or PTCA ; n (%)
5 (1.3%)
9 (2.4%)
-0.082
    PAD or PAD surgery; n (%)
166 (5.4%)
11 (2.9%)
0.126
    PAD or PAD surgery; n (%)
9 (2.4%)
11 (2.9%)
-0.031
Cerebrovascular disease (Stroke, TIA, Late effects); n (%)
77 (2.5%)
2 (0.5%)
0.165
Cerebrovascular disease (Stroke, TIA, Late effects); n (%)*
1 (0.3%)
2 (0.5%)
-0.032
    Stroke (Ischemic or hemorrhagic); n (%)
40 (1.3%)
1 (0.3%)
0.112
    Stroke (Ischemic or hemorrhagic); n (%)
1 (0.3%)
1 (0.3%)
0.000
    TIA; n (%)
27 (0.9%)
1 (0.3%)
0.078
    TIA; n (%)
1 (0.3%)
1 (0.3%)
0.000
    Late effects of cerebrovascular disease; n (%)
28 (0.9%)
0 (0.0%)
0.135
    Late effects of cerebrovascular disease; n (%)
1 (0.3%)
0 (0.0%)
0.078
Heart Failure; n (%)
103 (3.3%)
10 (2.6%)
0.041
Heart Failure; n (%)*
10 (2.7%)
10 (2.7%)
0.000
Atrial fibrillation; n (%)
121 (3.9%)
14 (3.7%)
0.010
Atrial fibrillation; n (%)*
13 (3.5%)
14 (3.8%)
-0.016
Other cardiac dysrhythmia; n (%)
190 (6.1%)
18 (4.8%)
0.057
Other cardiac dysrhythmia; n (%)
25 (6.7%)
17 (4.6%)
0.091
Diabetes Mellitus Comorbidities
Diabetes Mellitus Complications
Hypoglycemia; n (%)
20 (0.6%)
4 (1.1%)
-0.054
Hypoglycemia; n (%)*
6 (1.6%)
4 (1.1%)
0.043
Diabetic nephropathy; n (%)
434 (14.0%)
48 (12.7%)
0.038
Diabetic Nephropathy; n (%)*
39 (10.5%)
46 (12.3%)
-0.057
Diabetic Neuropathy; n (%)
495 (16.0%)
60 (15.9%)
0.003
Diabetic Neuropathy; n (%)*
61 (16.4%)
59 (15.8%)
0.016
Diabetic Retinopathy ; n (%)
134 (4.3%)
20 (5.3%)
-0.047
Diabetic Retinopathy ; n (%)*
15 (4.0%)
20 (5.4%)
-0.066
 Diabetes with unspecified complications; n (%)
122 (3.9%)
14 (3.7%)
0.010
Diabetes with unspecified complications; n (%)
14 (3.8%)
13 (3.5%)
0.016
Diabetes with peripheral circulatory disorders and amputations, DF; n (%)*
70 (2.3%)
9 (2.4%)
-0.007
Diabetes with peripheral circulatory disorders and amputations, DF; n (%)*
7 (1.9%)
9 (2.4%)
-0.034
    Diabetes with peripheral circulatory disorders; n (%)
38 (1.2%)
5 (1.3%)
-0.009
    Diabetes with peripheral circulatory disorders; n (%)
3 (0.8%)
5 (1.3%)
-0.049
    Lower-limb amputations; n (%)
4 (0.1%)
1 (0.3%)
-0.045
    Lower-limb amputations; n (%)
0 (0.0%)
1 (0.3%)
-0.078
    Diabetic Foot; n (%)
32 (1.0%)
3 (0.8%)
0.021
    Diabetic Foot; n (%)
5 (1.3%)
3 (0.8%)
0.049
Renal Comorbidities
Renal Disorders
Chronic kidney disease stages I-IV and NOS; n (%)
381 (12.3%)
40 (10.6%)
0.053
Chronic kidney disease stages I-IV and NOS; n (%)*
36 (9.7%)
40 (10.7%)
-0.033
Miscellaneous renal disease; n (%)
109 (3.5%)
10 (2.6%)
0.052
Miscellaneous renal disease; n (%)
10 (2.7%)
10 (2.7%)
0.000
Mood disorders (Anxiety and Depression); n (%)
332 (10.7%)
47 (12.4%)
-0.053
Mood disorders (Anxiety and Depression); n (%)*
47 (12.6%)
47 (12.6%)
0.000
    Anxiety; n (%)
211 (6.8%)
27 (7.1%)
-0.012
    Anxiety; n (%)
28 (7.5%)
27 (7.2%)
0.011
    Depression; n (%)
162 (5.2%)
28 (7.4%)
-0.091
    Depression; n (%)
26 (7.0%)
28 (7.5%)
-0.019
Other Comorbidities
Other Disorders
Obstructive sleep apnea; n (%)
259 (8.4%)
41 (10.8%)
-0.082
Obstructive sleep apnea; n (%)*
38 (10.2%)
39 (10.5%)
-0.010
COPD; n (%)
207 (6.7%)
9 (2.4%)
0.207
COPD; n (%)*
15 (4.0%)
9 (2.4%)
0.091
Asthma; n (%)
96 (3.1%)
14 (3.7%)
-0.033
Asthma; n (%)
19 (5.1%)
13 (3.5%)
0.079
Osteoarthrosis; n (%)
363 (11.7%)
49 (13.0%)
-0.040
Osteoarthrosis; n (%)
50 (13.4%)
48 (12.9%)
0.015
NASH/NAFLD; n (%)
98 (3.2%)
16 (4.2%)
-0.053
NASH/NAFLD; n (%)
14 (3.8%)
15 (4.0%)
-0.010
Medications
Medications
Antihypertensive medications; n (%)
2585 (83.5%)
324 (85.7%)
-0.061
Antihypertensive medications; n (%)*
318 (85.3%)
320 (85.8%)
-0.014
    ACEi/ARBs; n (%)
2257 (72.9%)
285 (75.4%)
-0.057
    ACEi/ARBs; n (%)
282 (75.6%)
281 (75.3%)
0.007
    Beta blockers; n (%)
971 (31.4%)
94 (24.9%)
0.145
    Beta blockers; n (%)
98 (26.3%)
94 (25.2%)
0.025
    Calcium channel blockers; n (%)
795 (25.7%)
83 (22.0%)
0.087
    Calcium channel blockers; n (%)
91 (24.4%)
81 (21.7%)
0.064
    Thiazide; n (%)
369 (11.9%)
52 (13.8%)
-0.057
    Thiazide; n (%)
54 (14.5%)
51 (13.7%)
0.023
    Diuretics; n (%)
1108 (35.8%)
133 (35.2%)
0.013
    Diuretics; n (%)
137 (36.7%)
129 (34.6%)
0.044
Statins Other lipid-lowering drugs; n (%)
2402 (77.6%)
291 (77.0%)
0.014
Statins Other lipid-lowering drugs; n (%)*
299 (80.2%)
287 (76.9%)
0.080
    Statins; n (%)
2285 (73.8%)
273 (72.2%)
0.036
    Statins; n (%)
281 (75.3%)
269 (72.1%)
0.025
    Other lipid-lowering drugs; n (%)
370 (12.0%)
49 (13.0%)
-0.030
    Other lipid-lowering drugs; n (%)
50 (13.4%)
48 (12.9%)
0.015
Opioids; n (%)
507 (16.4%)
72 (19.0%)
-0.068
Opioids; n (%)*
74 (19.8%)
69 (18.5%)
0.033
Mood Stabilizing Medications; n (%)
719 (23.2%)
129 (34.1%)
-0.243
Mood Stabilizing Medications; n (%)*
127 (34.0%)
125 (33.5%)
-0.041
    Antidepressants; n (%)
540 (17.4%)
105 (27.8%)
-0.251
    Antidepressants; n (%)
98 (26.3%)
101 (27.1%)
-0.018
    Anxiolytics/hypnotics; n (%)
114 (3.7%)
25 (6.6%)
-0.131
    Anxiolytics/hypnotics; n (%)
23 (6.2%)
24 (6.4%)
-0.008
    Benzodiazepine; n (%)
256 (8.3%)
42 (11.1%)
-0.095
    Benzodiazepine; n (%)
47 (12.6%)
40 (10.7%)
0.059
Gabapentinoids; n (%)
319 (10.3%)
49 (13.0%)
-0.084
Gabapentinoids; n (%)*
47 (12.6%)
47 (12.6%)
0.000
Healthcare Utlization 
Healthcare Utlization 
Number of medication claims
Number of medication claims*
...mean (sd)
11.47 (6.60)
12.82 (6.94)
-0.199
...mean (sd)
12.76 (7.08)
12.73 (6.89)
0.004
Number of office visits
Number of office visits*
...mean (sd)
4.76 (3.58)
5.24 (3.72)
-0.131
...mean (sd)
4.91 (3.59)
5.19 (3.66)
-0.071
Number of hospitalizations or ED visits
Number of hospitalizations or ED visits* 
...mean (sd)
0.24 (0.87)
0.20 (0.66)
0.052
...mean (sd)
0.25 (0.91)
0.20 (0.67)
0.025
Number of Endocrinologist visits
Number of Endocrinologist visits*
...mean (sd)
0.13 (0.55)
0.27 (0.85)
-0.196
...mean (sd)
0.25 (0.75)
0.24 (0.73)
0.013
Number of HbA1c test orders
Number of HbA1c test orders
...mean (sd)
1.77 (0.68)
1.79 (0.78)
-0.012
...mean (sd)
1.84 (0.64)
1.78 (0.78)
0.083
Number of lexible Sigmoidoscopy or colonoscopy or CT virtual colonoscopy (CRC 
screening); n (%)
149 (4.8%)
17 (4.5%)
0.014
Number of flexible Sigmoidoscopy or colonoscopy or CT virtual colonoscopy 
(CRC screening); n (%)
57 (15.3%)
54 (14.5%)
0.022
 Number of Mammograms (Breast cancer screening); n (%)
400 (12.9%)
59 (15.6%)
-0.077
Number of Mammograms (Breast cancer screening); n (%)
15 (4.0%)
16 (4.3%)
-0.015
Number of Pap smear (Cervical cancer screening); n (%)
120 (3.9%)
16 (4.2%)
-0.015
Number of Pap smear (Cervical cancer screening); n (%)
48 (12.9%)
59 (15.8%)
-0.083
Flu vaccine; n (%)
659 (21.3%)
93 (24.6%)
-0.079
Flu vaccine; n (%)
20 (5.4%)
15 (4.0%)
0.066
Pneumococcal vaccine; n (%)
671 (21.7%)
82 (21.7%)
0.000
Pneumococcal vaccine; n (%)
87 (23.3%)
93 (24.9%)
-0.037
Number of DXA tests
Number of DXA tests
76 (20.4%)
82 (22.0%)
-0.039
...mean (sd)
0.04 (0.19)
0.03 (0.18)
0.002
...mean (sd)
0.03 (0.18)
0.03 (0.18)
0.000
 Copay for pharmacy cost (charges in U.S. $)
Copay for pharmacy cost (charges in U.S. $)*# 
...mean (sd)
180.68 (259.85)
280.36 (336.80)
-0.331
...mean (sd)
268.00 (356.42)
269.85 (316.10)
-0.005
 Business type
 Business type*
...Commercial; n (%)
1016 (32.8%)
201 (53.2%)
-0.421
...Commercial; n (%)
201 (53.9%)
196 (52.5%)
0.028
...Medicare; n (%)
2080 (67.2%)
177 (46.8%)
0.421
...Medicare; n (%)
172 (46.1%)
177 (47.5%)
-0.028
Generic/Brand unique prescriptions
Generic/Brand unique prescriptions
...mean (sd)
0.99 (0.04)
0.99 (0.04)
0.000
...mean (sd)
0.99 (0.04)
0.99 (0.04)
0.000
Brand name prescription - unique value
Brand name prescription - unique value*
...mean (sd)
8.55 (3.69)
9.35 (3.85)
-0.212
...mean (sd)
9.32 (4.11)
9.25 (3.70)
0.018
Generic name prescription - unique value
Generic name prescription - unique value*
...mean (sd)
8.47 (3.64)
9.23 (3.76)
-0.205
...mean (sd)
9.20 (4.05)
9.13 (3.62)
0.018
* variables included in the PS model
# copay of index drugs is not included
MATCHED
UNMATCHED
Optum
Optum
Appendix B