Replication of the CARMELINA Diabetes Trial in Healthcare Claims
Conditions: Diabetes
Sponsor: Brigham and Women's Hospital

Replication of CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA trial)
NCT03936036
May 27, 2021

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
1 
 
1. RCT Details 
This section provides a high-level overview of the 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 
 
   CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA trial) 
 
1.2 Intended aim(s) 
 
The primary hypothesis was that treatment with linagliptin would be non-inferior with a hazard ratio of < 1.3 compared 
with placebo as assessed by the time to first occurrence of any of the 3P-MACE (primary endpoint) events.  
 
1.3 Primary endpoint for replication and RCT finding 
First occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. 
 
1.4 Required power for primary endpoint and noninferiority margin (if applicable) 
 
Power- 0.90. Assuming a HR of 1.0, to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified 
non-inferiority margin of 1.3 at a one-sided α-level of 2.5%. 
 
1.5 Primary trial estimate targeted for replication 
 
HR = 1.02 (95% CI 0.89-1.17) comparing linagliptin to placebo (Rosenstock et al.) 
 
2. Person responsible for implementation of replication in Aetion 
Ajinkya Pawar, Ph.D. implemented the study design in the Aetion Evidence Platform. S/he 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) 
United/Optum, MarketScan, Medicare  
 
 

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Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
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5. Cohort Identification  
 
5.1 Cohort Summary 
This study will involve a new user, parallel group, cohort study design comparing linagliptin to the 2nd generation sulfonylurea (SU) 
antidiabetic class as a proxy for placebo. 2nd generation SUs are not known to have an impact on the outcome of interest. In addition, 
SUs were the most frequent background treatment in CARMELINA (after metformin), and DPP4i and SUs are preferentially 
prescribed to similarly older patients in real world (Patorno et al., 2019). The patients will be required to have continuous enrollment 
during the baseline period of 180 days before initiation of linagliptin or a comparator drug (cohort entry date). Follow-up for the 
outcome (3P-MACE), begins the day after drug initiation. As in the trial, patients are allowed to take other antidiabetic medications 
during study follow-up. 
 
5.2 Important steps for cohort formation 
 
5.2.1 Eligible cohort entry dates 
Market availability of linagliptin in the U.S. started on May 2, 2011. 
• For Marketscan: May 2, 2011-Dec 31, 2017 (end of data availability).  
• For Medicare: Jan 1, 2012-Dec 31, 2017 (start- end of data availability).  
• For Optum: May 2, 2011-March 31, 2019 (end of data availability). 
 
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. 
 
5.3 Flowchart of the study cohort assembly 
 
  
Optum 
Marketscan 
Medicare* 
  
Less 
Excluded 
Patients 
Remaining 
Patients 
Less 
Excluded 
Patients 
Remaining 
Patients 
Less 
Excluded 
Patients 
Remaining 
Patients 

Effectiveness research with Real World Data to support FDA’s regulatory decision making: Protocol Template 
 
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All patients in the database 
  
74,864,884 
  
191,990,035 
  
23,466,175 
Patients who used exposure or a reference between 02 May 2011 to Dec 
2017 (for Marketscan)/March 2019 (for Optum) and 01 January 2012-
December 2017 for Medicare 
-73,493,670 
1,371,214 
-
190,287,730 
1,702,305 
-19,944,169 
3,522,006 
Patients who have continuous 6 months registration in the database  
-185,581 
1,185,633 
-171,524 
1,530,781 
-972,275 
2,549,731 
Patients without prior use of reference 
-877,495 
308,138 
-1,180,188 
350,593 
-1,838,491 
711,240 
Patients without prior use of exposure 
-68,637 
239,501 
-59,423 
291,170 
-133,733 
577,507 
Excluded because patient qualified in >1 exposure category 
-275 
239,226 
-211 
290,959 
-370 
577,137 
Patients who did not have missing age information 
-12 
239,214 
0 
290,959 
0 
577,137 
Patients who did not have missing gender information 
-19 
239,195 
0 
290,959 
0 
577,137 
Excluded based on Inclusion 1- DM Type 2 
-18,341 
220,854 
-37,618 
253,341 
-10,507 
566,630 
Excluded based on Inclusion 5- Age >= 18 
-19 
220,835 
-76 
253,265 
0 
566,630 
Excluded based on Inclusion 6- Body Mass Index (BMI) =< 45 kg/m2 at visit 
1 (as a proxy, excluding patients with morbid obesity) 
-9,096 
211,739 
-8,032 
245,233 
-13,155 
553,475 
Excluded based on Inclusion 8 - High risk of CV events 
-64,122 
147,617 
-98,434 
146,799 
-67,114 
486,361 
Excluded based on Exclusion 1- Type 1 DM with ICD10 CODES 
-2,983 
144,634 
-3,481 
143,318 
-12,175 
474,186 
Excluded based on Exclusion 2- Treatment (≥ 7 days) with GLP-1 RA, other 
DPP-4i or SGLT-2i 
-7,712 
136,922 
-9,388 
133,930 
-23,347 
450,839 
Excluded based on Exclusion 3- Liver disease 
-2,648 
134,274 
-1,931 
131,999 
-8,953 
441,886 
Excluded based on Exclusion 4- CKD Stage 5 (proxy for eGFR <15 
ml/min/1.73 m2)/Dialysis 
-707 
133,567 
-470 
131,529 
-3,368 
438,518 
Excluded based on Exclusion 5- Any history of or planned bariatric surgery 
0 
133,567 
0 
131,529 
0 
438,518 
Excluded based on Exclusion 6- Previous cardiac procedure (CABG or PTCA 
or Stent) ≤ 2 months 
-436 
133,131 
-569 
130,960 
-1101 
437,417 
Excluded based on Exclusion 8- Alcohol abuse/Drug abuse and Exclusion 
10- Pregnancy 
-1047 
132,081 
-501 
130,459 
-2,267 
435,149 
Excluded based on Exclusion 11 part 1- life expectancy less than 5 years 
[using combined comorbidity index as a proxy (365 days) 
-2,263 
129,818 
-1,125 
129,334 
-12,200 
422,949 
Excluded based on Exclusion 11 part 2- History of Malignant Neoplasm 
(within last 3 years) 
-4,153 
125,665 
-4,128 
125,206 
-14,241 
408,708 
Excluded based on Exclusion 12- ACS/unstable angina (≤ 2 months prior ) 
-374 
125,291 
-332 
124,874 
-788 
407,920 
Excluded based on Exclusion 13- Stroke or TIA (≤ 3 months prior) 
-2,292 
122,999 
-1,981 
122,893 
-7,081 
400,839 
Final cohort 
  
122,999 
  
122,893 
  
400,839 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
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* Medicare database includes only patients ³65 years of age with at least one diagnosis for diabetes, heart failure, or stroke. 
** Exclusion 8 and Exclusion 10 collapsed for adherence to CMS suppression guidelines. 
 
 
6. Variables  
 
6.1 Exposure-related variables:  
 
Study drug:  
The study exposure of interest is initiation of linagliptin. Initiation will be defined by no use of lingatliptin or a comparator in the 
prior 6 months before treatment initiation (washout period).  
 
Comparator agents: 
• Initiators of linagliptin will be compared to initiators of- 
o 2nd generation sulfonylureas 
 
Because linagliptin and comparators are frequently used as second or third line treatments of T2DM, we expect it to be unlikely that 
linagliptin and comparators are initiated in patients with substantially different baseline risk for proposed outcomes.  
 
6.2 Preliminary covariates: 
• Age 
• Sex 
• 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). These covariates are based on those used by 
Patorno et al. (2019). 
 
6.3 Outcome variables and study follow-up:  

Effectiveness research with Real World Data to support FDA’s regulatory decision making: Protocol Template 
 
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6.3.1 Outcome variables 
 
Effectiveness outcomes of interest (definitions provided in Appendix A):  
 
• Primary outcome: 3-point major adverse cardiovascular events (MACE), i.e., non-fatal myocardial infarction, non-fatal stroke, 
or CV mortality 
• Secondary outcomes: Individual MACE components: 
o Hospital admission for MI (for purposes of this individual component, fatal MI is included) 
o Hospital admission for stroke (for purposes of this individual component, fatal stroke is included) 
o All-cause mortality/CV mortality: 
§ All-cause inpatient mortality identified using discharge status codes will be used as a proxy for “CV mortality” 
in commercial databases 
§ Information on CV mortality through data linkage with the National Death Index (NDI) will only become 
available at a later date for Medicare and will be used in secondary analyses. 
 
Control outcomes of interest (control outcomes only serve to assess aspects of study validity but are not further interpreted):  
1. End Stage Renal Disease (we expect to see no association; Rosenstock et al., 2019) 
Control outcome definitions 
Outcome 
Definition 
Comments 
Control Outcomes 
End Stage Renal Disease 
(ESRD) 
ESRD with dialysis, defined as:  
An ICD9 diagnosis (inpatient or outpatient) for ESRD: 
o 585.5x, Chronic kidney disease, Stage V (for ESRD with no mention of dialysis)  
o 585.6x, End stage renal disease (for ESRD with dialysis)  
AND an ICD9 procedural codes for dialysis (=index date): 
o 39.95, Hemodialysis 
o 54.98, Peritoneal dialysis 
AND an additional procedural code for dialysis or physician provider code indicating dialysis procedure or 
ESRD-related activity within two time windows 31-60 and 61-90 days from index date. For patients who die 
prior to 61 days (31 days), the second (second and first) confirmation requirement(s) can be dropped. This 
ensures the inclusion of patients with true ESRD outcomes who die early (high early mortality) as well as early 
withdrawals from dialysis (which lead to high fatality within days or weeks). 
Note- The  corresponding 
ICD-10 codes will  be used  
also 

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Additional procedural codes for dialysis or physician provider codes indicating dialysis procedure or ESRD-
related activity include: 
- ICD9 procedural codes:  
o 39.95, Hemodialysis 
o 54.98, Peritoneal dialysis 
- ICD9 diagnostic codes:  
o 585.6x, End stage renal disease (for ESRD with dialysis) 
o V56.0x, encounter for dialysis NOS 
o V56.8x, encounter for peritoneal dialysis 
- CPT4 codes:  
o 90957, 90960, ESRD related services monthly, for patients 12-19 and 20 years of age and older; with 4 
or more face-to-face physician visits per month 
o 90958, 90961, ESRD related services monthly, for patients 12-19 and 20 years of age and older; with 2-
3 face-to-face physician visits per month 
o 90959, 90962, ESRD related services monthly, for patients 12-19 and 20 years of age and older; with 1 
face-to-face physician visit per month 
o 90920, 90921, ESRD related services per full month; for patients 12-19 and twenty years of age and 
over 
o 90924, 90925, ESRD related services (less than full month), per day; for patients 12-19 and twenty 
years of age and over 
o 90935, Hemodialysis procedure with single physician evaluation 
o 90937, Hemodialysis procedure requiring repeated evaluation(s) with or without substantial revision of 
dialysis prescription 
o 90945, Dialysis procedure other than hemodialysis (eg, peritoneal dialysis, hemofiltration, or other 
continuous renal replacement therapies), with single physician evaluation 
o 90947, Dialysis procedure other than hemodialysis (eg, peritoneal dialysis, hemofiltration, or other 
continuous renal replacement therapies) requiring repeated physician evaluations, with or without 
substantial revision of dialysis prescription 
o 90965, 90966, ESRD related services for home dialysis per full month, for patients 12-19 and 20 years 
of age and older 
o 90969, 90970, ESRD related services for dialysis less than a full month of service, per day; for patients 
12-19 and 20 years of age and older 
o 90989, Dialysis training, patient, including helper where applicable, any mode, completed course 
o 90993, Dialysis training, patient, including helper where applicable, any mode, course not completed, 
per training session 
o 90999, Unlisted dialysis procedure, inpatient or outpatient 
o 99512, Home visit for hemodialysis 
- HCPCS codes: 
o G0257, Unscheduled or emergency dialysis treatment for ESRD patient in a hospital outpatient dept. 
that is not certified as an ESRD facility  
o G0314, G0317, ESRD related services during the course of treatment, for patients 12-19 and 20 yrs of 
age an over to include monitoring for the adequacy of nutrition, etc. w/4 or more physician visit per month 
o G0315, G0318, ESRD related services during the course of treatment, for patients 12-19 and 20yrs of 
age and over to include monitoring for the adequacy of nutrition, etc. w/2 or 3 physician visit per month 

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6.3.2 Study follow-up 
Both as-treated (AT) and intention-to-treat (ITT) analyses will be conducted with treatment defined as the index drug on the day of 
cohort entry. Because adherence in the real world databases is expected to be much worse than in the trial, the AT analysis is the 
primary analysis, as it targets the relative hazard of outcomes on treatment.  
 
For the AT analyses, the follow-up will start the day after initiation of linagliptin and comparator and will continue until the earliest 
date of the following events: 
• The first occurrence of the outcome of interest, unless otherwise specified for selected outcomes,  
• The date of end of continuous registration in the database, 
• End of the study period, 
• Measured death event occurs, 
• Nursing home admission 
o G0316, G0319, ESRD related services during the course of treatment, for patients 12-19 and 20 yrs of 
age and over to include monitoring for the adequacy of nutrition, etc. w/1 physician visit per month 
o G0322, G0323, ESRD related services for home dialysis patients per full month: for patients 12-19 and 
20 yrs of age and over to include monitoring for adequacy of nutrition and etc. 
o G0326, G0327, ESRD related services for home dialysis (less than full month), per day; for patients 12-
19 and 20 yrs of age and over 
o S9335, Home therapy, hemodialysis; administrative services, professional pharmacy services, care 
coordination, and all necessary supplies and equipment (drugs and nursing services coded separately), per 
diem 
o S9339, Home therapy, peritoneal dialysis, administrative services, care coordination and all necessary 
supplies and equipment, per diem 
OR 
 
Kidney transplant, defined as either 1 inpatient or 1 outpatient code 
Codes include: 
- ICD9 prox codes:  
o 55.6x, Transplant of kidney (Exclude 55.61) 
- CPT4 codes: 
o 50360, Renal allotransplantation, implantation, graft, w/o donor & recipient nephrectomy 
o 
50365, Renal allotransplantation, implantation, graft, w/ donor & recipient nephrectomy 

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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. 
• The date of drug discontinuation, defined as the date of the last continuous treatment episode of the index drug (linagliptin 
and comparator) plus a defined grace period (i.e., 30 days after the end of the last prescription’s days’ supply in main 
analyses). 
•  The date of augmentation or switching from an exposure to a comparator or any other agent in the comparator class and 
vice versa (e.g. switching from glimepiride to glipizide would be a censoring event); 
o A dosage change on the index treatment does not fulfill this criterion 
o An added treatment that is not part of the exposure or comparator group does not fulfill this criterion (e.g. if a 
linagliptin user adds insulin, he or she does not get censored at the time of insulin augmentation) 
 
For the ITT analyses, the censoring based on the augmentation/switching and treatment discontinuation will be replaced with a 
maximum allowed follow-up time of 365 days.  
 
7. Initial Feasibility Analysis  
 
Aetion report links: 
Optum: https://bwh-dope.aetion.com/#/projects/details/702/results/30636/result/0  
Marketscan: https://bwh-dope.aetion.com/#/projects/details/701/results/30634/result/0  
Medicare: https://bwh-dope.aetion.com/#/projects/details/703/results/30635/result/0  
 
Date conducted: rerun on January 28, 2019 
 
Complete Aetion feasibility analysis using age, sex, 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 incidence rates stratified by treatment group.  
 
• Report patient characteristics by treatment group 
• Report summary parameters of the overall study population 
• Report median follow-up time by treatment group 
• Report reasons for censoring in the overall study population 

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8. Initial Power Assessment 
 
Aetion report links: 
Optum: https://bwh-dope.aetion.com/#/projects/details/702/results/30639/result/1  
Marketscan: https://bwh-dope.aetion.com/#/projects/details/701/results/30637/result/1  
Medicare: https://bwh-dope.aetion.com/#/projects/details/703/results/30638/result/1  
 
Date conducted: rerun on January 28, 2019 
 
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, sex, and combined 
comorbidity index. Power calculations are based on the formulas from Chow 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. 
Reviewed by PI: 
Jessica M. Franklin 
Date reviewed: 
10/26/18 
Reviewed by FDA: 
Ken Quinto 
Date reviewed: 
12/19/18 
Reasons for stopping 
analysis (if required): 
 
 
 
9. Balance Assessment after PS matching 
 
Aetion report name: 
Optum: https://bwh-dope.aetion.com/projects/details/702/results/44872/result/0 
Marketscan: https://bwh-dope.aetion.com/projects/details/701/results/44873/result/0 
Medicare: https://bwh-dope.aetion.com/projects/details/703/results/45415/result/0 
 
Date conducted: 11/18/2019 (Medicare 11/30/2019) 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
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After review of initial feasibility and power analyses, complete creation of the remaining covariates (see Table 1 below for list of 
covariates). 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 (excluding laboratory values, which are missing in some patients). 
 
• 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. 
  
Overall 
Referent 
Exposure 
Dummy Outcome 
0 (0.00%) 
0 (0.00%) 
0 (0.00%) 
Death 
1,704 (1.67%) 
929 (1.82%) 
775 (1.52%) 
Start of an additional exposure 
4,752 (4.67%) 
746 (1.47%) 
4,006 (7.87%) 
End of index exposure 
58,792 (57.74%) 
29,602 (58.14%) 
29,190 (57.33%) 
Specified date reached 
18,168 (17.84%) 
9,825 (19.30%) 
8,343 (16.39%) 
End of patient enrollment 
9,190 (9.02%) 
4,583 (9.00%) 
4,607 (9.05%) 
Switch to other SUs (for censoring) + nursing home admission 
9,224 (9.06%) 
5,230 (10.27%) 
3,994 (7.84%) 
 
• Report follow-up time by treatment group. 
 
Median Follow-Up Time (Days) [IQR] 
Patient Group 
Optum 
Marketscan 
Medicare 
Overall Patient Population 
118 [58-286] 
128 [63-304] 
137 [65-323] 
Referent 
122 [65-304] 
148 [86-344] 
148 [86-344] 
Exposure 
118 [58-269] 
127 [58-303] 
127 [58-303] 
 
• Report overall risk of the primary outcome. 

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12 
  
Optum 
Marketscan 
Medicare 
Risk per 1,000 patients 
16.55 
18.7 
42.47 
 
10. Final Power Assessment 
 
Date conducted: 12/01/2019 
 
• 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. If the study is to be implemented in more than one 
database, copy and paste excel sheet to report power for each database separately and for the pooled analysis that uses data 
from all databases together. Power calculations are based on the formulas from Chow et al. (2008). 
 
o Pooled 
 
 
o Optum 
Non-inferiority Analysis
Number of patients matched
Reference
50,915
Exposed
50,915
Risk per 1,000 patients
25.91
Assumed HR from RCT
1
Alpha (2-sided)
0.05
Non-inferiority margin
1.3
Number of events expected
2638.4153
Power
0.999999116

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o Marketscan 
 
 
o Medicare 
Non-inferiority Analysis
Number of patients matched
Reference
8,880
Exposed
8,880
Risk per 1,000 patients
16.55
Assumed HR from RCT
1
Alpha (2-sided)
0.05
Non-inferiority margin
1.3
Number of events expected
293.928
Power
0.613734405
Non-inferiority Analysis
Number of patients matched
Reference
8,716
Exposed
8,716
Risk per 1,000 patients
18.7
Assumed HR from RCT
1
Alpha (2-sided)
0.05
Non-inferiority margin
1.3
Number of events expected
325.9784
Power
0.658551313

Effectiveness research with Real World Data to support FDA’s regulatory decision making: Protocol Template 
 
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• Stop analyses until balance and final power assessment are reviewed by primary investigators, FDA, and assigned members of 
advisory board. Reviewers evaluate the results of the analyses described above in Sections 9 and 10, including numbers of 
patients, balance in patient characteristics, follow-up time, and reasons for censoring by treatment group, as well as overall rates 
of outcomes and study power.  
Reviewed by PI: 
Jessica Franklin 
Date reviewed: 
12/9/19 
Reviewed by FDA: 
Ken Quinto 
Date reviewed: 
12/20/19 
Reasons for stopping 
analysis (if required): 
 
 
11. Study Confidence and Concerns 
 
Deadline for voting on study confidence and listing concerns: 12/20/19 
 
• 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 
Non-inferiority Analysis
Number of patients matched
Reference
33,319
Exposed
33,319
Risk per 1,000 patients
42.47
Assumed HR from RCT
1
Alpha (2-sided)
0.05
Non-inferiority margin
1.3
Number of events expected
2830.11586
Power
0.99999974

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15 
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. 
 
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:  
 
• In the PS-matched cohort from Section 9, calculate the HR for each outcome for linagliptin versus referent patients using a Cox 
proportional hazards model.  
 
13.2 
For secondary analyses: 
 
• In the pre-matched cohort, perform asymmetrical trimming to remove patients with PS values below the 2.5th percentile of 
treated patients and above the 97.5th percentile of untreated patients. In the trimmed cohort, calculate the HR for canagliflozin 
versus referent patients using a Cox proportional hazards model, adjusting for deciles of the PS. 
 
14.  Requested Results  
 
 
14.1 
Results from primary and secondary analyses: 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making: Protocol Template 
 
16 
Separately for each endpoint: 
Analysis 
No. exposed events 
No. referent events 
Exposed rate 
Referent rate 
HR (95% CI) 
Crude 
 
 
 
 
 
Primary analysis 
 
 
 
 
 
Analysis 2 
 
 
 
 
 
... 
 
 
 
 
 
HR, Hazard Ratio; CI, Confidence Interval. 
 
15. References 
 
Chow S, Shao J, Wang H. 2008.  Sample Size Calculations in Clinical Research. 2nd Ed. Chapman & Hall/CRC Biostatistics Series. page 
177 
 
Patorno E, Pawar A, Franklin JM, et al. Empagliflozin and the Risk of Heart Failure Hospitalization in Routine Clinical Care: A First 
Analysis from the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) Study. Circulation. 2019; in press. 
(https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.118.039177)  
 
Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, Alexander JH, Pencina M, Toto RD, Wanner C, Zinman B, Woerle 
HJ, Baanstra D, Pfarr E, Schnaidt S, Meinicke T, George JT, von Eynatten M, McGuire DK, CARMELINA Investigators. Effect of Linagliptin 
vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA 
Randomized Clinical Trial. JAMA. 2019; 321(1):69-79. 
 
 
 

# 
CARMELINA trial definitions
Implementation in routine care
References/Rationale
Color coding
Please see the following Google Drive for further details or any missing information: 
https://drive.google.com/open?id=1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV
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
Linagliptin 5mg/day vs. placebo
linagliptin vs. 2nd generation sulfonylureas
Intermediate mapping in claims
Poor mapping or cannot be measured in claims 
The primary outcome is the time to the first occurrence
of CV death, non-fatal myocardial infarction (MI) or
non-fatal stroke—the so-called 3-point major adverse CV
events (3P-MACE) composite outcome.
Measured 1 days after drug initiation in diagnosis position specified below and inpatient care 
setting:
Inpatient mortality/MI/Stroke --
For MI
Any diagnosis position in inpatient care setting
ICD-9 Dx 410.X (acute myocardial infarction) excluding 410.x2 (subsequent episode of care)
For stroke
Primary diagnosis position in inpatient care setting 
ICD-9 discharge diagnosis:
430.xx  Subarachnoid hemorrhage (SAH)
431.xx  Intracerebral hemorrhage (ICH)
433.x1  Occlusion and stenosis of precerebral arteries with cerebral infarction
434.xx (excluding 434.x0)  Occlusion and stenosis of cerebral arteries with cerebral infarction
436.x  Acute, but ill-defined cerebrovascular events
Mortality- See Mortality Sheet.
For MI: 
PPV 94% in Medicare claims data [Kiyota Y, Schneeweiss S, Glynn RJ, Cannuscio CC, 
Avorn J, Solomon DH. Accuracy of Medicare claims-based diagnosis of acute myocardial 
infarction: estimating positive predictive value on the basis of review of hospital records. 
American heart journal 2004;148:99-104.]
PPV 88.4% in commercially-insured population [Wahl PM, Rodgers K, Schneeweiss S, 
et al. Validation of claims-based diagnostic and procedure codes for cardiovascular and 
gastrointestinal serious adverse events in a commercially-insured population. 
Pharmacoepidemiology and Drug Safety 2010;19:596-603.]
For stroke:
PPV of 85% or higher for ischemic stroke
PPV ranging from 80% to 98% for hemorrhagic stroke
[Andrade SE, Harrold LR, Tjia J, et al. A systematic review of validated methods for 
identifying cerebrovascular accident or transient ischemic attack using administrative 
data. Pharmacoepidemiology and Drug Safety 2012;21 Suppl 1:100-28.]
[Tirschwell DL, Longstreth WT, Jr. Validating administrative data in stroke research. 
Stroke; a journal of cerebral circulation 2002;33:2465-70.]
[Roumie CL, Mitchel E, Gideon PS, Varas-Lorenzo C, Castellsague J, Griffin MR. 
Validation of ICD-9 codes with a high positive predictive value for incident strokes 
resulting in hospitalization using Medicaid health data. Pharmacoepidemiology and 
drug safety 2008;17:20-6.]
Can't be measured in claims but not important for the 
analysis
1)  Documented diagnosis of T2DM before visit 1 (screening).
Measured 180 days prior to drug initiation any diagnosis position in inpatient or outpatient care 
settings:
Patients with a diagnosis of T2DM (ICD-9 Dx code of 250.x0 or 250.x2; ICD-10 Dx code of E11.x) in 
the 6 months prior to drug initiation
Patorno, Elisabetta et al. "Cardiovascular outcomes associated with canagliflozin versus 
other non-gliflozin antidiabetic drugs: population based cohort study." BMJ 
2018;360:k119 http://dx.doi.org/10.1136/bmj.k119
Patorno, Elisabetta et al. "Empagliflozin and the Risk of Heart Failure Hospitalization in 
Routine Clinical Care: A First Analysis from the Empagliflozin Comparative Effectiveness 
and Safety (EMPRISE) Study."  Circulation. 2019 Apr 8. doi: 
10.1161/CIRCULATIONAHA.118.039177
2)  Male or female patients who are drug-naïve or pre-treated with any antidiabetic background 
therapy, excluding treatment with GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 inhibitors if ≥ 
7 consecutive days.
This is basically everyone except for those with treatment with GLP-1 receptor agonists, DPP-4 
inhibitors or SGLT-2 inhibitors if ≥ 7 consecutive days. One of the exclusion criteria below is 
exclusion based on ≥ 7 consecutive days use of GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 
inhibitors, so ignoring this inclusion criteria.
3)  Ssheetle antidiabetic background medication (unchanged daily dose) for at least 8 weeks prior to 
randomization.  If insulin is part of the background therapy, the average daily insulin dose should not 
have been changed by more than 10% within the 8 weeks prior to randomization compared with the 
daily insulin dose at randomization.
N/A
-
4)  HbA1c of ≥ 6.5% and ≤ 10.0% at visit 1 (screening).
N/A
-
5)  Age ≥ 18 years at visit 1 (screening). For Japan only: Age ≥ 20 years at Visit 1.
Measured 180 days prior to drug initiation
Age ≥18 years
PRIMARY OUTCOME
5a- Successful NI with label change
EXPOSURE vs. COMPARISON
INCLUSION CRITERIA
Appendix A

6)  Body Mass Index (BMI) £ 45 kg/m2 at visit 1 (screening).
Measured 180 days prior to drug initiation any diagnosis position in inpatient or outpatient care 
setting:
Excluding patients with
ICD-9 Diagnosis Code (any position) is any of: { “278.01” }
278.01 - MORBID OBESITY
7)  Signed and dated written informed consent by date of visit 1 (screening) in accordance with GCP 
and local legislation prior to any study related procedure.
N/A
-
8)  High risk of CV events (I and/or II):
I. Albuminuria (UACR ≥ 30 mg/g creatinine or ≥ 30 µg/min [microgram albumin per minute] or ≥ 30 
mg/24 h [milligram albumin per 24 hours] in two out of three unrelated spot urine or timed samples 
in the last 24 months prior to randomization)* 
AND previous macrovascular disease, defined as either one or more:
Ia
Confirmed history of MI (> 2 months prior to Visit 1)
Ib
Advanced coronary artery disease, defined by any one of the following:
• ≥ 50% narrowing of the luminal diameter in 2 or more major coronary arteries by coronary 
angiography, MRI angiography or CT angiography;
Definition of major coronary arteries: LAD (Left Anterior Descending). CX (Circumflex) or RCA (right 
coronary artery)
• Left main stem coronary artery with ≥ 50% narrowing of the luminal diameter by coronary 
angiography, MRI angiography or CT angiography;
• Prior percutaneous or surgical revascularization of ≥ 2 major coronary arteries at least 2 months 
prior to Visit 1 (screening);
• The combination of prior percutaneous or surgical revascularization of 1 major coronary artery at 
least 2 months prior to visit 1 (screening), and ≥ 50% narrowing of the luminal diameter by coronary 
angiography, MRI angiography or CT angiography of at least 1 additional major coronary artery.
Ic
High-risk single-vessel coronary artery disease, defined as the presence of ≥ 50%
narrowing of the luminal diameter of one major coronary artery by coronary angiography, MRI 
angiography or CT angiography in patients not revascularized:
AND at least one of the following:
• A positive non invasive stress test, confirmed by either:
o a positive ECG exercise tolerance test in patients without left bundle branch block, Wolff-Parkinson-
White syndrome, left ventricular hypertrophy with repolarization abnormality, or paced ventricular 
rhythm, atrial fibrillation in case of abnormal ST-T segments;
o a positive stress echocardiogram showing induced regional systolic wall motion abnormalities;
o a positive nuclear myocardial perfusion imaging stress test showing stress- induced reversible 
perfusion abnormality;
o a positive cardiac stress perfusion MRI showing a stress induced perfusion defect;
• Patient discharged from hospital with a documented diagnosis of unstable angina pectoris between 
2 and 12 months prior to visit 1 (screening).
Id
History of ischemic or haemorrhagic stroke (>3 months prior to visit 1)
Measured from the start of all available data to on the date of drug initiation in any diagnosis 
position and procedure position in inpatient or outpatient care setting:
Any stroke ICD-9 Dx: 430.xx, 431.xx, 433.xx, 434.xx, 436.xx
We including anytime prior to drug initiation here, but then any patients with any 
stroke within last 3 months are excluded due to the last exclusion criteria.
Ie
Presence of carotid artery disease (symptomatic or not) documented by either:
o imaging techniques with at least one lesion estimated to be ≥50%
narrowing of the luminal diameter;
o prior percutaneous or surgical carotid revascularization.
Measured from the start of all available data to on the date of drug initiation in any diagnosis 
position and procedure position in inpatient or outpatient care setting:
Carotid artery disease
ICD-9  433.10 : Occlusion and stenosis of carotid artery without mention of cerebral infarction.
 ICD-10-CM I65.29 Occlusion and stenosis of unspecified carotid artery
Patorno, Elisabetta et al. "Cardiovascular outcomes associated with canagliflozin versus 
other non-gliflozin antidiabetic drugs: population based cohort study." BMJ 
2018;360:k119 http://dx.doi.org/10.1136/bmj.k119
Patorno, Elisabetta et al. "Empagliflozin and the Risk of Heart Failure Hospitalization in 
Routine Clinical Care: A First Analysis from the Empagliflozin Comparative Effectiveness 
and Safety (EMPRISE) Study."  Circulation. 2019 Apr 8. doi: 
10.1161/CIRCULATIONAHA.118.039177
Patorno, Elisabetta et al. "Cardiovascular outcomes associated with canagliflozin versus 
other non-gliflozin antidiabetic drugs: population based cohort study." BMJ 
2018;360:k119 http://dx.doi.org/10.1136/bmj.k119
Patorno, Elisabetta et al. "Empagliflozin and the Risk of Heart Failure Hospitalization in 
Routine Clinical Care: A First Analysis from the Empagliflozin Comparative Effectiveness 
and Safety (EMPRISE) Study."  Circulation. 2019 Apr 8. doi: 
10.1161/CIRCULATIONAHA.118.039177
Measured from the start of all available data to on the date of drug initiation with 
diagnosis/procedure position and care setting as noted below:
Ischemic heart disease in any diagnosis position and inpatient or outpatient care setting: ICD-9 
410.xx-414.xx
OR 
Previous cardiac procedure (CABG or PTCA or Stent) in any procedure position and care setting 
defined below:
PTCA:
 Inpatient CPT-4: 92973, 92982, 92984, 92995, 92996, 92920 – 92921, 92924 – 92925, 92937, 
92938, 92941, 92943, 92944
OR –
Inpatient or outpatient ICD-9 procedure: 00.66, 36.01, 36.02, 36.03, 36.05, 36.09
Stenting:
Inpatient CPT-4:  92980, 92981, 92928 – 92929, 92933 - 92934
OR –
Inpatient or outpatient ICD-9 procedure: 36.06, 36.07
CABG:
Inpatient CPT-4: 33510 – 33536, 33545, 33572. 
       OR – 
Inpatient or outpatient ICD-9 procedure: 36.1x, 36.2x
Transmyocardial revascularization: Inpatient or Outpatient CPT-4: 33140, 33141 OR - Inpatient or 
outpatient ICD-9 procedure: 36.31-36.34
Appendix A

If
Presence of peripheral artery disease documented by either:
o previous limb angioplasty, stenting or bypass surgery;
o previous limb or foot amputation due to macrocirculatory insufficiency;
o angiographic evidence of peripheral artery stenosis ≥ 50% narrowing of the luminal diameter in at 
least one limb (definition of peripheral artery: common iliac artery, internal iliac artery, external iliac 
artery, femoral artery, popliteal artery).
Measured from the start of all available data to on the date of drug initiation in any diagnosis 
position and procedure position in inpatient or outpatient care setting
Carotid bypass: 
ICD9 procedure: 39.28 
ICD 10 procedure:
031H09G Bypass Right Common Carotid Artery to Intracranial Artery with Autologous Venous 
Tissue, Open Approach
031H0AG Bypass Right Common Carotid Artery to Intracranial Artery with Autologous Arterial 
Tissue, Open Approach
031H0JG Bypass Right Common Carotid Artery to Intracranial Artery with Synthetic Substitute, 
Open Approach
031H0KG Bypass Right Common Carotid Artery to Intracranial Artery with Nonautologous Tissue 
Substitute, Open Approach
031H0ZG Bypass Right Common Carotid Artery to Intracranial Artery, Open Approach
031J09G Bypass Left Common Carotid Artery to Intracranial Artery with Autologous Venous Tissue, 
Open Approach
031J0AG Bypass Left Common Carotid Artery to Intracranial Artery with Autologous Arterial 
Tissue, Open Approach
031J0JG Bypass Left Common Carotid Artery to Intracranial Artery with Synthetic Substitute, Open 
Approach
031J0KG Bypass Left Common Carotid Artery to Intracranial Artery with Nonautologous Tissue 
Substitute, Open Approach
031J0ZG Bypass Left Common Carotid Artery to Intracranial Artery, Open Approach
Evidence of impaired renal function with predefined UACR, with or without CV co- morbidities, 
defined as follows (and/or criteria):
· Impaired renal function (as defined by MDRD formula) with an eGFR:  15- <45 mL/min/1.73 m2 at 
visit 1 (screening) with any UACR.
· Impaired renal function (as defined by MDRD formula) with an eGFR ≥ 45-75 mL/min/1.73 m2 at 
visit 1 (screening) with an UACR > 200 mg/g creatinine or
> 200 µg/min (microgram albumin per minute) or > 200 mg/24 h [milligram albumin per 24 hours] 
demonstrated in two out of three unrelated spot urine or timed samples in the last 24 months prior 
to randomization.
N/A
1)  Type 1 diabetes mellitus.
Measured 180 days prior to drug initiation in any diagnosis position in inpatient or outpatient 
care setting:
DM type 1- At least 1 inpatient or outpatient ICD-9 Dx code of 250.x1 or 250.x3 or ICD-10 Dx code 
of E10.x in the 12 months prior to drug initiation. 6-months prior
2)  Treatment (≥ 7 consecutive days) with GLP-1 receptor agonists, other DPP-4 inhibitors or
SGLT-2 inhibitors prior to informed consent. Note: This also includes clinical trials where these 
antidiabetic drugs have been provided to the patient.
Measured 180 days prior to drug initiation as a dispensing for one of the following:
Treatment (≥ 7 days) with GLP-1 receptor agonists (lixisenatide, dulaglutide, albiglutide, 
liraglutide, exenatide), other DPP-4 inhibitors (alogliptin, sitagliptin, saxagliptin) or SGLT-2 
inhibitors (canagliflozin, dapagliflozin, empagliflozin) prior to CED
3)  Active liver disease or impaired hepatic function, defined by serum levels of either ALT (SGPT), AST 
(SGOT), or alkaline phosphatase (AP) ≥3 x upper limit of normal (ULN) as determined at Visit 1.
Measured 180 days prior to drug initiation in any diagnosis/procedure position in inpatient or 
outpatient care setting:
Liver disease- ICD-9 diagnosis:
070.xx, 570.xx- 573.xx 
456.0x-456.2x, 576.8x, 782.4x, 789.5x 
ICD-9 procedure codes:
39.1x, 42.91 
Patorno, Elisabetta et al. "Cardiovascular outcomes associated with canagliflozin versus 
other non-gliflozin antidiabetic drugs: population based cohort study." BMJ 
2018;360:k119 http://dx.doi.org/10.1136/bmj.k119
Patorno, Elisabetta et al. "Empagliflozin and the Risk of Heart Failure Hospitalization in 
Routine Clinical Care: A First Analysis from the Empagliflozin Comparative Effectiveness 
and Safety (EMPRISE) Study."  Circulation. 2019 Apr 8. doi: 
10.1161/CIRCULATIONAHA.118.039177
4)  eGFR <15 ml/min/1.73 m2 (severe renal impairment or ESRD, MDRD formula), as determined 
during screening at Visit 1 and/or the need for maintenance dialysis.
Measured 180 days prior to drug initiation : 
CKD stage 5 in any diagnosis/procedure position in inpatient or outpatient care setting- 585.5x
OR
Dialysis in any diagnosis/procedure position and inpatient care setting: 
Codes are in the sheet 'Dialysis' Sheet
II.
EXCLUSION CRITERIA
Measured 180 days prior to drug initiation in any diagnosis position in inpatient or outpatient 
filters:
CKD stage 3 and stage 4
585.3x-585.4x
CKD stage 1: GFR >90
CKD stage 2: GFR 60 to 89
CKD stage 3a: GFR 45 to 59
CKD stage 3b: GFR 30 to 44
CKD stage 4: GFR 15 to 29
CKD stage 5: GFR <15
Appendix A

5)  Any previous (or planned within next 12 months) bariatric surgery (open or laparoscopic)
or intervention (gastric sleeve).
Measured 180 days prior to drug initiation in any procedure position in inpatient or outpatient 
care setting:
Any history
CPT -Code- Abbreviation Procedure
43644 -LRYBG -Laparoscopic Roux-en-Y gastric bypass (Roux limb 150 cm or less)
43645 -LRYGBX-
Laparoscopic gastric bypass with small intestine reconstruction to
limit absorption
43770 -LAGB- Laparoscopic adjustable gastric band
43846 -ORYGB- Open Roux-en-Y gastric bypass (Roux limb 150 cm or less)
43847 -ORYGBX- Open gastric bypass with small intestine reconstruction to limit
absorption
Patorno, Elisabetta et al. "Cardiovascular outcomes associated with canagliflozin versus 
other non-gliflozin antidiabetic drugs: population based cohort study." BMJ 
2018;360:k119 http://dx.doi.org/10.1136/bmj.k119
Patorno, Elisabetta et al. "Empagliflozin and the Risk of Heart Failure Hospitalization in 
Routine Clinical Care: A First Analysis from the Empagliflozin Comparative Effectiveness 
and Safety (EMPRISE) Study."  Circulation. 2019 Apr 8. doi: 
10.1161/CIRCULATIONAHA.118.039177
6)  Pre-planned coronary artery re-vascularization (PCI, CABG) or any previous PCI and/or
CABG ≤ 2 months prior informed consent
Measured 60 days prior to drug initiation in any diagnosis position and procedure position in 
care settings indicated below:
(≤ 2 months)
PTCA:
Inpatient CPT-4: 92973, 92982, 92984, 92995, 92996, 92920 – 92921, 92924 – 92925, 92937, 
92938, 92941, 92943, 92944
OR –
Inpatient or outpatient: ICD-9 procedure: 00.66, 36.01, 36.02, 36.03, 36.05, 36.09
Stenting:
Inpatient CPT-4:  92980, 92981, 92928 – 92929, 92933 - 92934
OR –
Inpatient  or outpatient ICD-9 procedure: 36.06, 36.07
CABG:
Inpatient CPT-4: 33510 – 33536, 33545, 33572. 
       OR – 
Inpatient or outpatient ICD-9 procedure: 36.1x, 36.2x
Patorno, Elisabetta et al. "Cardiovascular outcomes associated with canagliflozin versus 
other non-gliflozin antidiabetic drugs: population based cohort study." BMJ 
2018;360:k119 http://dx.doi.org/10.1136/bmj.k119
Patorno, Elisabetta et al. "Empagliflozin and the Risk of Heart Failure Hospitalization in 
Routine Clinical Care: A First Analysis from the Empagliflozin Comparative Effectiveness 
and Safety (EMPRISE) Study."  Circulation. 2019 Apr 8. doi: 
10.1161/CIRCULATIONAHA.118.039177
7)  Known hypersensitivity or allergy to the investigational products or its excipients.
N/A
-
8)  Any previous or current alcohol or drug abuse that would interfere with trial participation in the 
opinion of the investigator.
Measured 180 days prior to drug initiation in any diagnosis position in inpatient or outpatient 
care setting:
Alcohol abuse or dependence 291.xx, 303.xx, 305.0x, 571.0x, 571.1x, 571.2x, 571.3x, 357.5x, 
425.5x, E860.0x, V11.3x
Drug abuse or dependence 292.xx, 304.xx, 305.2x-305.9x, 648.3x
Patorno, Elisabetta et al. "Cardiovascular outcomes associated with canagliflozin versus 
other non-gliflozin antidiabetic drugs: population based cohort study." BMJ 
2018;360:k119 http://dx.doi.org/10.1136/bmj.k119
Patorno, Elisabetta et al. "Empagliflozin and the Risk of Heart Failure Hospitalization in 
Routine Clinical Care: A First Analysis from the Empagliflozin Comparative Effectiveness 
and Safety (EMPRISE) Study."  Circulation. 2019 Apr 8. doi: 
10.1161/CIRCULATIONAHA.118.039177
9)  Participation in another trial with an investigational drug ongoing or within 2 months prior to 
visit 1 (screening)*.
N/A
-
9)  Participation in another trial with an investigational drug ongoing or within 2 months prior to 
visit 1 (screening)*.
Measured 180 days prior to drug initiation in any diagnosis/procedure position in inpatient or 
outpatient care setting:
Please see Pregnancy codes sheet.
11) Patients considered unreliable by the investigator concerning the requirements for follow- up 
during the study and/or compliance with study drug administration, have a life expectancy less than 
5 years for non-CV causes, 
or have cancer other than non-melanoma skin cancer within last 3 years, 
or has any other condition than mentioned which in the opinion of the investigator, would not allow 
safe participation in the study.
Measured over 365 days prior to drug initiation:
CCI >=10  
OR
Measured 1095 days prior to drug initiation in any diagnosis position in inpatient and outpatient 
care setting: 
History of malignant neoplasm ICD-9: 140.xx-208.xx (except 173.xx, non-melanoma skin cancer)- 
in prior 3 years
"Gagne, Josh J et. al. ""A combined comorbidity score predicted mortality in elderly 
patients better than existing scores."" J Clin Epidemiol. 2011 Jul;64(7):749-59. doi: 
10.1016/j.jclinepi.2010.10.004.
Sun, Jenny W et. al. ""Validation of the Combined Comorbidity Index of Charlson and 
Elixhauser to Predict 30-Day Mortality Across ICD-9 and ICD-10."" Med Care. 2018 
Sep;56(9):812. doi: 10.1097/MLR.0000000000000954."
12) Acute coronary syndrome (ACS), diagnosed ≤ 2 months prior to visit 1 (screening).
Measured 60 days prior to drug initiation in any diagnosis position in inpatient and outpatient 
care setting:
ACS/unstable angina 411.xx
Patorno, Elisabetta et al. "Cardiovascular outcomes associated with canagliflozin versus 
other non-gliflozin antidiabetic drugs: population based cohort study." BMJ 
2018;360:k119 http://dx.doi.org/10.1136/bmj.k119
Patorno, Elisabetta et al. "Empagliflozin and the Risk of Heart Failure Hospitalization in 
Routine Clinical Care: A First Analysis from the Empagliflozin Comparative Effectiveness 
and Safety (EMPRISE) Study."  Circulation. 2019 Apr 8. doi: 
10.1161/CIRCULATIONAHA.118.039177
Appendix A

13) Stroke or TIA ≤ 3 months prior to visit 1 (screening).
Measured 90 days prior to drug initiation in any diagnosis position in inpatient and outpatient 
care setting:
Any stroke 
ICD-9 Dx: 430.xx, 431.xx, 433.xx, 434.xx, 436.xx
TIA
435.xx
Patorno, Elisabetta et al. "Cardiovascular outcomes associated with canagliflozin versus 
other non-gliflozin antidiabetic drugs: population based cohort study." BMJ 
2018;360:k119 http://dx.doi.org/10.1136/bmj.k119
Patorno, Elisabetta et al. "Empagliflozin and the Risk of Heart Failure Hospitalization in 
Routine Clinical Care: A First Analysis from the Empagliflozin Comparative Effectiveness 
and Safety (EMPRISE) Study."  Circulation. 2019 Apr 8. doi: 
10.1161/CIRCULATIONAHA.118.039177
Appendix A

Trial ID 
Trial Name (with web links)
CARMELINA
NCT
NCT01897532
Trial category
5a- Successful NI with label change
Therapeutic Area
Endocrinology
RCT Category  
Secondary indication
Brand Name
Generic Name
Linagliptin
Sponsor
Boehringer Ingelheim
Year
2019
Measurable endpoint
Composite of Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-
fatal Stroke
Exposure
Linagliptin
Comparator
Placebo
Population
Trial finding
1.02 (95% CI 0.89-1.17) 
No. of Patients
6979 
Non-inferiority margin
1.3
Assay Sens. Endpoint
Assay Sens. Finding
Power
Power- 0.90. Assuming a HR of 1.0, to demonstrate non-inferiority of linagliptin 
versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-
sided α-level of 2.5%.
Blinding
Statistical Method
Appendix A

Mortality- Dependent on data source. 
1. All-cause mortality / inpatient mortality
Identified using the vital status file-
Medicare
Identified using the discharge status codes-
Optum-
• 20 = EXPIRED
• 21 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 22 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 23 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 24 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 25 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 26 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 27 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 28 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 29 = EXPIRED TO BE DEFINED AT STATE LEVEL       
• 40 = EXPIRED AT HOME (HOSPICE)
• 41 = EXPIRED IN A MEDICAL FACILITY (HOSPICE)
• 42 = EXPIRED - PLACE UNKNOWN (HOSPICE)
Truven-       
• 20 - Died
• 22 - Died
• 23 - Died
• 24 - Died
• 25 - Died
• 26 - Died
• 27 - Died
• 28 - Died
• 29 - Died
• 40 - Other died status or Expired at home (Hospice claims only) (depends on year)
• 41 - Other died status or Expired in medical facility (Hospice claims only) (depends on year)
Appendix A

• 42 - Other died status or Expired - place unknown (Hospice claims only) (depends on year)
• 21 - Died or Disch./Transf. to court/law enforcement (depends on year)
2. CV mortality
Information on CV mortality through data linkage with the National Death Index (NDI) will be 
available for Medicare at a later date. We will conduct secondary analyses using CV mortality at 
that time.
Appendix A

Antidiabetic class
Specific agent
Notes
Canagliflozin
Approved 3/29/2013
Dapagliflozin
Empagliflozin
Ertugliflozin
Approved Dec 21, 2017
Glimepiride
Glipizide
Glyburide 
Alogliptin
Linagliptin
Saxagliptin
Sitagliptin
Exenatide
Liraglutide
Albiglutide
Approved April 15, 2014 and 
discontinued July 26, 2017
Dulaglutide
Approved Sep 18, 2014
Lixisenatide
Approved July 28, 2016
Semaglutide
Approved Dec 5, 2017
Insulin Aspart
Insulin Aspart/Insulin Aspart 
Protamine
Insulin Degludec
Insulin Detemir
Insulin Glargine
Insulin Glulisine
Insulin human isophane (NPH)
Insulin human regular (search with 
NPH, don't want bf-pk)
Insulin human regular/ Insulin 
human isophane (NPH)
Insulin Lispro
SGLT2-inhibitors
2nd generation sulfonylureas
DPP-4 inhibitors
GLP-1 receptor agonist (GLP1-RA)
Insulin
Appendix A

Insulin Lispro/Insulin Lispro 
Protamine
Pioglitazone
Rosiglitazone
Nateglinide
Repaglinide
Acarbose
Miglitol
Pramlintide
Pramlintide
Acetohexamide
Chlorpropamide
Tolazamide 
Tolbutamide
Meglitinides
Alpha-glucosidase inhibitors
1st generation sulfonylureas
Glitazones
Appendix A

Pregnancy 
Dx codes 
650   NORMAL DELIVERY
660   OBSTRUCTED LABOR
661   ABNORMALITY OF FORCES OF LABOR
662   LONG LABOR
663   UMBILICAL CORD COMPLICATIONS DURING LABOR AND DELIVERY
664   TRAUMA TO PERINEUM AND VULVA DURING DELIVERY
665   OTHER OBSTETRICAL TRAUMA
667   RETAINED PLACENTA OR MEMBRANES WITHOUT HEMORRHAGE
668   COMPLICATIONS OF THE ADMINISTRATION OF ANESTHETIC OR OTHER SEDATION IN LABOR AND 
DELIVERY
669.94   UNSPECIFIED COMPLICATION OF LABOR AND DELIVERY POSTPARTUM CONDITION OR 
COMPLICATION
V24   POSTPARTUM CARE AND EXAMINATION
V24.0   POSTPARTUM CARE AND EXAMINATION IMMEDIATELY AFTER DELIVERY
V24.1   POSTPARTUM CARE AND EXAMINATION OF LACTATING MOTHER
V24.2   ROUTINE POSTPARTUM FOLLOW
V27   OUTCOME OF DELIVERY
V27.0   MOTHER WITH SINGLE LIVEBORN
V27.1   MOTHER WITH SINGLE STILLBORN
V27.2   MOTHER WITH TWINS BOTH LIVEBORN
V27.3   MOTHER WITH TWINS ONE LIVEBORN AND ONE STILLBORN
V27.4   MOTHER WITH TWINS BOTH STILLBORN
V27.5   MOTHER WITH OTHER MULTIPLE BIRTH ALL LIVEBORN
V27.6   MOTHER WITH OTHER MULTIPLE BIRTH SOME LIVEBORN
V27.7   MOTHER WITH OTHER MULTIPLE BIRTH ALL STILLBORN
V27.9   MOTHER WITH UNSPECIFIED OUTCOME OF DELIVERY
Procedure codes 
72.0   LOW FORCEPS OPERATION
72.1   LOW FORCEPS OPERATION WITH EPISIOTOMY
72.2   MID FORCEPS OPERATION
72.21   MID FORCEPS OPERATION WITH EPISIOTOMY
72.29   OTHER MID FORCEPS OPERATION
72.3 HIGH FORCEPS OPERATION
Appendix A

7 .3 HIGH FORC PS OP RATION
72.31   HIGH FORCEPS OPERATION WITH EPISIOTOMY
72.39   OTHER HIGH FORCEPS OPERATION
72.4   FORCEPS ROTATION OF FETAL HEAD
72.5   BREECH EXTRACTION
72.51   PARTIAL BREECH EXTRACTION WITH FORCEPS TO AFTERCOMING HEAD
72.52   OTHER PARTIAL BREECH EXTRACTION
72.53   TOTAL BREECH EXTRACTION WITH FORCEPS TO AFTERCOMING HEAD
72.54   OTHER TOTAL BREECH EXTRACTION
72.6   FORCEPS APPLICATION TO AFTERCOMING HEAD
72.7   VACUUM EXTRACTION
72.71   VACUUM EXTRACTION WITH EPISIOTOMY
72.79   OTHER VACUUM EXTRACTION
72.8   OTHER SPECIFIED INSTRUMENTAL DELIVERY
72.9   UNSPECIFIED INSTRUMENTAL DELIVERY
73.0   ARTIFICIAL RUPTURE OF MEMBRANES
73.01   INDUCTION OF LABOR BY ARTIFICIAL RUPTURE OF MEMBRANES
73.09   OTHER ARTIFICIAL RUPTURE OF MEMBRANES
73.1   OTHER SURGICAL INDUCTION OF LABOR
73.2   INTERNAL AND COMBINED VERSION AND EXTRACTION
73.21   INTERNAL AND COMBINED VERSION WITHOUT EXTRACTION
73.22   INTERNAL AND COMBINED VERSION WITH EXTRACTION
73.3   FAILED FORCEPS
73.4   MEDICAL INDUCTION OF LABOR
73.5   MANUALLY ASSISTED DELIVERY
73.51   MANUAL ROTATION OF FETAL HEAD
73.59   OTHER MANUALLY ASSISTED DELIVERY
73.6   EPISIOTOMY
73.8   OPERATIONS ON FETUS TO FACILITATE DELIVERY
73.9   OTHER OPERATIONS ASSISTING DELIVERY
73.91   EXTERNAL VERSION ASSISTING DELIVERY
73.92   REPLACEMENT OF PROLAPSED UMBILICAL CORD
73.93   INCISION OF CERVIX TO ASSIST DELIVERY
73.94   PUBIOTOMY TO ASSIST DELIVERY
73.99   OTHER OPERATIONS ASSISTING DELIVERY
74.0 CLASSICAL CESAREAN SECTION
Appendix A

74.0 C ASSICA C SAR AN S CTION
74.1   LOW CERVICAL CESAREAN SECTION
74.2   EXTRAPERITONEAL CESAREAN SECTION
74.3   REMOVAL OF EXTRATUBAL ECTOPIC PREGNANCY
74.4   CESAREAN SECTION OF OTHER SPECIFIED TYPE
74.9   CESAREAN SECTION OF UNSPECIFIED TYPE
74.91   HYSTEROTOMY TO TERMINATE PREGNANCY
74.99   OTHER CESAREAN SECTION OF UNSPECIFIED TYPE
75.4   MANUAL REMOVAL OF RETAINED PLACENTA
75.5   REPAIR OF CURRENT OBSTETRIC LACERATION OF UTERUS
75.6   REPAIR OF OTHER CURRENT OBSTETRIC LACERATION
75.7   MANUAL EXPLORATION OF UTERINE CAVITY, POSTPARTUM
75.9   OTHER OBSTETRIC OPERATIONS
Appendix A

Dialysis
Dialysis
Codes include:
- ICD9 prox codes: 
39.95, Hemodialysis
54.98, Peritoneal dialysis
- ICD9 dx codes: 
V56.0x, encounter for dialysis NOS
V56.8x, encounter for peritoneal dialysis
V45.1x, renal dialysis status
- CPT4 codes: 
90957, 90960, ESRD related services monthly, for patients 12-19 and 20 years of age and older; with 4 or more face-to-face 
physician visits per month
90958, 90961, ESRD related services monthly, for patients 12-19 and 20 years of age and older; with 2-3 face-to-face physician 
visits per month
90959, 90962, ESRD related services monthly, for patients 12-19 and 20 years of age and older; with 1 face-to-face physician visit 
per month
90920, 90921, ESRD related services per full month; for patients 12-19 and twenty years of age and over
90924, 90925, ESRD related services (less than full month), per day; for patients 12-19 and twenty years of age and over
90935, Hemodialysis procedure with single physician evaluation
90937, Hemodialysis procedure requiring repeated evaluation(s) with or without substantial revision of dialysis prescription
90945, Dialysis procedure other than hemodialysis (eg, peritoneal dialysis, hemofiltration, or other continuous renal replacement 
therapies), with single physician evaluation
90947, Dialysis procedure other than hemodialysis (eg, peritoneal dialysis, hemofiltration, or other continuous renal replacement 
therapies) requiring repeated physician evaluations, with or without substantial revision of dialysis prescription
90965, 90966, ESRD related services for home dialysis per full month, for patients 12-19 and 20 years of age and older
90969, 90970, ESRD related services for dialysis less than a full month of service, per day; for patients 12-19 and 20 years of age 
and older
90989, Dialysis training, patient, including helper where applicable, any mode, completed course
90993, Dialysis training, patient, including helper where applicable, any mode, course not completed, per training session
90999, Unlisted dialysis procedure, inpatient or outpatient
99512, Home visit for hemodialysis
- HCPCS codes:
G0257, Unscheduled or emergency dialysis treatment for ESRD patient in a hospital outpatient dept. that is not certified as an ESRD 
facility 
G0314, G0317, ESRD related services during the course of treatment, for patients 12-19 and 20 yrs of age an over to include 
monitoring for the adequacy of nutrition, etc. w/4 or more physician visit per month
G0315, G0318, ESRD related services during the course of treatment, for patients 12-19 and 20yrs of age and over to include 
monitoring for the adequacy of nutrition, etc. w/2 or 3 physician visit per month
G0316, G0319, ESRD related services during the course of treatment, for patients 12-19 and 20 yrs of age and over to include 
Appendix A

monitoring for the adequacy of nutrition, etc. w/1 physician visit per month
G0322, G0323, ESRD related services for home dialysis patients per full month: for patients 12-19 and 20 yrs of age and over to 
include monitoring for adequacy of nutrition and etc.
G0326, G0327, ESRD related services for home dialysis (less than full month), per day; for patients 12-19 and 20 yrs of age and 
over
S9335, Home therapy, hemodialysis; administrative services, professional pharmacy services, care coordination, and all necessary 
supplies and equipment (drugs and nursing services coded separately), per diem
S9339, Home therapy, peritoneal dialysis, administrative services, care coordination and all necessary supplies and equipment, per 
diem
Appendix A

AFTER PS MATCHING
Optum
MarketScan
Medicare
BEFORE PS MATCHING
The c-statistics for the propensity score model, pre-matching was 0.728. The post-matching c-statistic 
was 0.535.
The c-statistics for the propensity score model, pre-matching was 0.724. The post-matching 
c-statistic was 0.531.
The c-statistics for the propensity score model, pre-matching was 0.732. The post-matching c-statistic 
was 0.519.
Appendix B

Variable
Reference- 2nd 
Generation SUs
Exposure- Linagliptin
Reference- 2nd 
Generation SUs
Exposure- Linagliptin
Reference- 2nd 
Generation SUs
Exposure- 
Linagliptin
Reference- 2nd 
Generation SUs
Exposure- Linagliptin
St. Diff.
Number of patients
                                       113,991                                              8,904 
114,025
                                      
8,736
                                            
366,136
                                    
33,401
                       
                                       594,152                                           51,041 
Age
...mean (sd)
69.66 (10.39)
66.94 (11.64)
65.35 (11.87)
63.75 (11.53)
75.67 (7.35)
75.97 (7.44)
72.54 (9.00)
72.30 (9.09)
0.03
...median [IQR]
70.00 [64.00, 77.00]
67.00 [59.00, 76.00]
64.00 [57.00, 74.00]
62.00 [56.00, 71.00]
75.00 [70.00, 81.00]5.00 [70.00, 81.00]
71.93 (9.00)
71.38 (9.09)
0.06
Age categories 
...18 - 54; n (%)
10,233 (9.0%)
1,320 (14.8%)
19,802 (17.4%)
1,718 (19.7%)
0 (0.0%)
0 (0.0%)
30,035 (5.1%)
3,038 (6.0%)
-0.04
...55 - 64; n (%)
20,561 (18.0%)
2,441 (27.4%)
40,305 (35.3%)
3,535 (40.5%)
4,429 (1.2%)
340 (1.0%)
65,295 (11.0%)
6,316 (12.4%)
-0.04
...65 - 74; n (%)
44,396 (38.9%)
2,639 (29.6%)
26,643 (23.4%)
1,785 (20.4%)
177,715 (48.5%)
15,653 (46.9%)
248,754 (41.9%)
20,077 (39.3%)
0.05
...>= 75; n (%)
38,801 (34.0%)
2,504 (28.1%)
27,275 (23.9%)
1,698 (19.4%)
183,992 (50.3%)
17,408 (52.1%)
250,068 (42.1%)
21,610 (42.3%)
0.00
Gender 
...Males; n (%)
63,640 (55.8%)
4,680 (52.6%)
68,352 (59.9%)
5,051 (57.8%)
175,512 (47.9%)
14,152 (42.4%)
307,504 (51.8%)
23,883 (46.8%)
0.10
...Females; n (%)
50,351 (44.2%)
4,224 (47.4%)
45,673 (40.1%)
3,685 (42.2%)
190,624 (52.1%)
19,249 (57.6%)
286,648 (48.2%)
27,158 (53.2%)
-0.10
Race 
...White; n (%)
N/A
N/A
N/A
N/A
288,259 (78.7%)
23,448 (70.2%)
288,259 (78.7%)
23,448 (70.2%)
0.20
...Black; n (%)
N/A
N/A
N/A
N/A
40,279 (11.0%)
4,263 (12.8%)
40,279 (11.0%)
4,263 (12.8%)
-0.06
...Asian; n (%)
N/A
N/A
N/A
N/A
11,760 (3.2%)
2,180 (6.5%)
11,760 (3.2%)
2,180 (6.5%)
-0.15
...Hispanic; n (%)
N/A
N/A
N/A
N/A
13,446 (3.7%)
1,876 (5.6%)
13,446 (3.7%)
1,876 (5.6%)
-0.09
...North American Native; n (%)
N/A
N/A
N/A
N/A
2,376 (0.6%)
270 (0.8%)
2,376 (0.6%)
270 (0.8%)
-0.02
...Other/Unknown; n (%)
N/A
N/A
N/A
N/A
10,016 (2.7%)
1,364 (4.1%)
10,016 (2.7%)
1,364 (4.1%)
-0.08
Region   (lumping missing&other category with West)
...Northeast; n (%)
11,593 (10.2%)
1,146 (12.9%)
18,556 (16.3%)
1,945 (22.3%)
59,526 (16.3%)
6,826 (20.4%)
89,675 (15.1%)
9,917 (19.4%)
-0.11
...South; n (%)
54,025 (47.4%)
4,626 (52.0%)
33,925 (29.8%)
1,644 (18.8%)
159,156 (43.5%)
14,335 (42.9%)
247,106 (41.6%)
20,605 (40.4%)
0.02
...Midwest; n (%)
22,555 (19.8%)
1,593 (17.9%)
45,492 (39.9%)
4,155 (47.6%)
89,214 (24.4%)
5,801 (17.4%)
157,261 (26.5%)
11,549 (22.6%)
0.09
...West; n (%)
25,818 (22.6%)
1,539 (17.3%)
15,054 (13.2%)
897 (10.3%)
58,240 (15.9%)
6,439 (19.3%)
99,112 (16.7%)
8,875 (17.4%)
-0.02
...Unknown+missing; n (%)
N/A
N/A
998 (0.9%)
95 (1.1%)
N/A
N/A
998 (0.9%)
95 (1.1%)
-0.02
CV Covariates
Ischemic heart disease; n (%)
45,790 (40.2%)
3,476 (39.0%)
41,586 (36.5%)
3,037 (34.8%)
159,800 (43.6%)
13,793 (41.3%)
247,176 (41.6%)
20,306 (39.8%)
0.04
Acute MI; n (%)
2,328 (2.0%)
211 (2.4%)
2,429 (2.1%)
164 (1.9%)
7,206 (2.0%)
572 (1.7%)
11,963 (2.0%)
947 (1.9%)
0.01
ACS/unstable angina; n (%)
1,604 (1.4%)
117 (1.3%)
1,705 (1.5%)
125 (1.4%)
4,863 (1.3%)
443 (1.3%)
8,172 (1.4%)
685 (1.3%)
0.01
Old MI; n (%)
6,271 (5.5%)
428 (4.8%)
3,486 (3.1%)
243 (2.8%)
19,590 (5.4%)
1,572 (4.7%)
29,347 (4.9%)
2,243 (4.4%)
0.02
Stable angina; n (%)
6,380 (5.6%)
540 (6.1%)
4,778 (4.2%)
382 (4.4%)
17,135 (4.7%)
1,710 (5.1%)
28,293 (4.8%)
2,632 (5.2%)
-0.02
Coronary atherosclerosis and other forms of chronic 
ischemic heart disease; n (%)
42,037 (36.9%)
3,219 (36.2%)
38,319 (33.6%)
2,842 (32.5%)
151,932 (41.5%)
13,061 (39.1%)
232,288 (39.1%)
19,122 (37.5%)
0.03
Other atherosclerosis with ICD10  ; n (%)
1,534 (1.3%)
114 (1.3%)
1,423 (1.2%)
107 (1.2%)
7,853 (2.1%)
681 (2.0%)
10,810 (1.8%)
902 (1.8%)
0.00
Previous cardiac procedure (CABG or PTCA or Stent) ; n (%)
720 (0.6%)
56 (0.6%)
919 (0.8%)
80 (0.9%)
2,049 (0.6%)
170 (0.5%)
3,688 (0.6%)
306 (0.6%)
0.00
History of CABG or PTCA; n (%)
9,769 (8.6%)
778 (8.7%)
4,953 (4.3%)
382 (4.4%)
40,597 (11.1%)
3,417 (10.2%)
55,319 (9.3%)
4,577 (9.0%)
0.01
Any stroke; n (%)
5,024 (4.4%)
347 (3.9%)
4,490 (3.9%)
355 (4.1%)
20,639 (5.6%)
1,835 (5.5%)
30,153 (5.1%)
2,537 (5.0%)
0.00
Ischemic stroke (w and w/o mention of cerebral 
infarction); n (%)
4,945 (4.3%)
339 (3.8%)
4,425 (3.9%)
349 (4.0%)
20,378 (5.6%)
1,815 (5.4%)
29,748 (5.0%)
2,503 (4.9%)
0.00
Hemorrhagic stroke; n (%)
114 (0.1%)
13 (0.1%)
100 (0.1%)
10 (0.1%)
431 (0.1%)
32 (0.1%)
645 (0.1%)
55 (0.1%)
0.00
TIA; n (%)
847 (0.7%)
56 (0.6%)
801 (0.7%)
63 (0.7%)
3,716 (1.0%)
337 (1.0%)
5,364 (0.9%)
456 (0.9%)
0.00
Other cerebrovascular disease; n (%)
2,079 (1.8%)
179 (2.0%)
1,489 (1.3%)
112 (1.3%)
9,408 (2.6%)
949 (2.8%)
12,976 (2.2%)
1,240 (2.4%)
-0.01
Late effects of cerebrovascular disease; n (%)
2,041 (1.8%)
172 (1.9%)
1,238 (1.1%)
71 (0.8%)
8,670 (2.4%)
846 (2.5%)
11,949 (2.0%)
1,089 (2.1%)
-0.01
Cerebrovascular procedure; n (%)
63 (0.1%)
3 (0.0%)
63 (0.1%)
3 (0.0%)
192 (0.1%)
11 (0.0%)
318 (0.1%)
17 (0.0%)
0.04
Heart failure (CHF); n (%)
13,795 (12.1%)
1,146 (12.9%)
10,022 (8.8%)
822 (9.4%)
54,617 (14.9%)
5,354 (16.0%)
78,434 (13.2%)
7,322 (14.3%)
-0.03
Peripheral Vascular Disease (PVD) or PVD Surgery ; n (%)
10,030 (8.8%)
875 (9.8%)
6,941 (6.1%)
559 (6.4%)
45,805 (12.5%)
4,977 (14.9%)
62,776 (10.6%)
6,411 (12.6%)
-0.06
Atrial fibrillation; n (%)
12,216 (10.7%)
849 (9.5%)
9,816 (8.6%)
734 (8.4%)
55,664 (15.2%)
4,895 (14.7%)
77,696 (13.1%)
6,478 (12.7%)
0.01
Other cardiac dysrhythmia; n (%)
13,746 (12.1%)
1,109 (12.5%)
9,751 (8.6%)
803 (9.2%)
55,599 (15.2%)
5,545 (16.6%)
79,096 (13.3%)
7,457 (14.6%)
-0.04
Cardiac conduction disorders; n (%)
4,173 (3.7%)
329 (3.7%)
2,960 (2.6%)
238 (2.7%)
18,071 (4.9%)
1,582 (4.7%)
25,204 (4.2%)
2,149 (4.2%)
0.00
Other CVD; n (%)
16,453 (14.4%)
1,283 (14.4%)
13,648 (12.0%)
1,135 (13.0%)
65,860 (18.0%)
6,376 (19.1%)
95,961 (16.2%)
8,794 (17.2%)
-0.03
Diabetes-related complications
Diabetic retinopathy; n (%)
6,853 (6.0%)
677 (7.6%)
4,623 (4.1%)
398 (4.6%)
22,873 (6.2%)
2,677 (8.0%)
34,349 (5.8%)
3,752 (7.4%)
-0.06
Diabetes with other ophthalmic manifestations; n (%)
793 (0.7%)
58 (0.7%)
3,389 (3.0%)
255 (2.9%)
8,854 (2.4%)
943 (2.8%)
13,036 (2.2%)
1,256 (2.5%)
-0.02
Retinal detachment, vitreous hemorrhage, vitrectomy; n 
(%)
459 (0.4%)
62 (0.7%)
356 (0.3%)
52 (0.6%)
1,303 (0.4%)
165 (0.5%)
2,118 (0.4%)
279 (0.5%)
-0.01
Retinal laser coagulation therapy; n (%)
578 (0.5%)
70 (0.8%)
602 (0.5%)
67 (0.8%)
1,792 (0.5%)
253 (0.8%)
2,972 (0.5%)
390 (0.8%)
-0.04
Occurrence of Diabetic Neuropathy  ; n (%)
21,622 (19.0%)
1,842 (20.7%)
12,232 (10.7%)
1,115 (12.8%)
65,212 (17.8%)
7,325 (21.9%)
99,066 (16.7%)
10,282 (20.1%)
-0.09
Unmatched
Optum
MarketScan
Medicare
POOLED
Table 1

Occurrence of diabetic nephropathy  with ICD10 ; n (%)
23,814 (20.9%)
2,283 (25.6%)
8,997 (7.9%)
1,121 (12.8%)
40,660 (11.1%)
6,463 (19.3%)
73,471 (12.4%)
9,867 (19.3%)
-0.19
Hypoglycemia ; n (%)
2,895 (2.5%)
227 (2.5%)
3,373 (3.0%)
207 (2.4%)
10,042 (2.7%)
1,090 (3.3%)
16,310 (2.7%)
1,524 (3.0%)
-0.02
Hyperglycemia; n (%)
5,084 (4.5%)
547 (6.1%)
3,784 (3.3%)
344 (3.9%)
17,473 (4.8%)
2,169 (6.5%)
26,341 (4.4%)
3,060 (6.0%)
-0.07
Disorders of fluid electrolyte and acid-base balance; n (%)
10,275 (9.0%)
1,058 (11.9%)
7,196 (6.3%)
620 (7.1%)
38,971 (10.6%)
4,031 (12.1%)
56,442 (9.5%)
5,709 (11.2%)
-0.06
Diabetic ketoacidosis; n (%)
356 (0.3%)
35 (0.4%)
391 (0.3%)
24 (0.3%)
1,273 (0.3%)
126 (0.4%)
2,020 (0.3%)
185 (0.4%)
-0.02
Hyperosmolar hyperglycemic nonketotic syndrome 
(HONK); n (%)
590 (0.5%)
55 (0.6%)
452 (0.4%)
41 (0.5%)
1,806 (0.5%)
217 (0.6%)
2,848 (0.5%)
313 (0.6%)
-0.01
Diabetes with peripheral circulatory disorders with ICD-
10  ; n (%)
9,520 (8.4%)
811 (9.1%)
4,372 (3.8%)
400 (4.6%)
29,150 (8.0%)
3,138 (9.4%)
43,042 (7.2%)
4,349 (8.5%)
-0.05
Diabetic Foot; n (%)
2,764 (2.4%)
269 (3.0%)
2,556 (2.2%)
199 (2.3%)
11,287 (3.1%)
1,082 (3.2%)
16,607 (2.8%)
1,550 (3.0%)
-0.01
Gangrene ; n (%)
361 (0.3%)
31 (0.3%)
272 (0.2%)
16 (0.2%)
1,087 (0.3%)
101 (0.3%)
1,720 (0.3%)
148 (0.3%)
0.00
Lower extremity amputation; n (%)
894 (0.8%)
96 (1.1%)
413 (0.4%)
38 (0.4%)
2,771 (0.8%)
277 (0.8%)
4,078 (0.7%)
411 (0.8%)
-0.01
Osteomyelitis; n (%)
772 (0.7%)
78 (0.9%)
681 (0.6%)
46 (0.5%)
2,477 (0.7%)
211 (0.6%)
3,930 (0.7%)
335 (0.7%)
0.00
Skin infections ; n (%)
6,727 (5.9%)
540 (6.1%)
6,925 (6.1%)
522 (6.0%)
26,721 (7.3%)
2,539 (7.6%)
40,373 (6.8%)
3,601 (7.1%)
-0.01
Erectile dysfunction; n (%)
2,715 (2.4%)
241 (2.7%)
2,209 (1.9%)
216 (2.5%)
6,905 (1.9%)
647 (1.9%)
11,829 (2.0%)
1,104 (2.2%)
-0.01
Diabetes with unspecified complication; n (%)
5,499 (4.8%)
613 (6.9%)
3,886 (3.4%)
389 (4.5%)
16,369 (4.5%)
2,081 (6.2%)
25,754 (4.3%)
3,083 (6.0%)
-0.08
Diabetes mellitus without mention of complications; n 
(%)
98,647 (86.5%)
7,625 (85.6%)
105,362 (92.4%)
7,961 (91.1%)
342,350 (93.5%)
30,829 (92.3%)
546,359 (92.0%)
46,415 (90.9%)
0.04
Hypertension: 1 inpatient or 2 outpatient claims within 
365 days; n (%)
98,566 (86.5%)
7,879 (88.5%)
82,028 (71.9%)
6,834 (78.2%)
336,292 (91.8%)
31,533 (94.4%)
516,886 (87.0%)
46,246 (90.6%)
-0.11
Hyperlipidemia ; n (%)
81,202 (71.2%)
6,711 (75.4%)
64,841 (56.9%)
5,646 (64.6%)
275,172 (75.2%)
26,459 (79.2%)
421,215 (70.9%)
38,816 (76.0%)
-0.12
Edema; n (%)
8,887 (7.8%)
811 (9.1%)
5,991 (5.3%)
557 (6.4%)
39,092 (10.7%)
4,456 (13.3%)
53,970 (9.1%)
5,824 (11.4%)
-0.08
Renal Dysfunction (non-diabetic) ; n (%)
37,562 (33.0%)
3,755 (42.2%)
20,954 (18.4%)
2,525 (28.9%)
104,923 (28.7%)
14,337 (42.9%)
163,439 (27.5%)
20,617 (40.4%)
-0.27
Occurrence of acute renal disease ; n (%)
5,514 (4.8%)
609 (6.8%)
3,904 (3.4%)
423 (4.8%)
18,677 (5.1%)
2,393 (7.2%)
28,095 (4.7%)
3,425 (6.7%)
-0.09
Occurrence of chronic renal insufficiency; n (%)
33,235 (29.2%)
3,393 (38.1%)
16,471 (14.4%)
2,164 (24.8%)
89,032 (24.3%)
12,832 (38.4%)
138,738 (23.4%)
18,389 (36.0%)
-0.28
Chronic kidney disease ; n (%)
32,418 (28.4%)
3,336 (37.5%)
16,038 (14.1%)
2,116 (24.2%)
85,680 (23.4%)
12,415 (37.2%)
134,136 (22.6%)
17,867 (35.0%)
-0.28
CKD Stage 3-4; n (%)
25,804 (22.6%)
2,799 (31.4%)
12,085 (10.6%)
1,713 (19.6%)
64,688 (17.7%)
9,828 (29.4%)
102,577 (17.3%)
14,340 (28.1%)
-0.26
Occurrence of hypertensive nephropathy; n (%)
14,013 (12.3%)
1,488 (16.7%)
6,307 (5.5%)
758 (8.7%)
38,737 (10.6%)
5,386 (16.1%)
59,057 (9.9%)
7,632 (15.0%)
-0.15
Occurrence of miscellaneous renal insufficiency ; n (%)
7,420 (6.5%)
794 (8.9%)
5,159 (4.5%)
589 (6.7%)
29,680 (8.1%)
3,744 (11.2%)
42,259 (7.1%)
5,127 (10.0%)
-0.10
Glaucoma or cataracts ; n (%)
22,333 (19.6%)
1,771 (19.9%)
17,722 (15.5%)
1,514 (17.3%)
91,357 (25.0%)
9,149 (27.4%)
131,412 (22.1%)
12,434 (24.4%)
-0.05
Cellulitis or abscess of toe; n (%)
1,682 (1.5%)
138 (1.5%)
1,126 (1.0%)
101 (1.2%)
5,368 (1.5%)
594 (1.8%)
8,176 (1.4%)
833 (1.6%)
-0.02
Foot ulcer; n (%)
2,718 (2.4%)
257 (2.9%)
2,566 (2.3%)
194 (2.2%)
11,316 (3.1%)
1,073 (3.2%)
16,600 (2.8%)
1,524 (3.0%)
-0.01
Bladder stones; n (%)
159 (0.1%)
16 (0.2%)
126 (0.1%)
17 (0.2%)
657 (0.2%)
66 (0.2%)
942 (0.2%)
99 (0.2%)
0.00
Kidney stones; n (%)
2,539 (2.2%)
272 (3.1%)
2,472 (2.2%)
260 (3.0%)
9,310 (2.5%)
1,017 (3.0%)
14,321 (2.4%)
1,549 (3.0%)
-0.04
Urinary tract infections (UTIs); n (%)
11,118 (9.8%)
1,016 (11.4%)
7,802 (6.8%)
641 (7.3%)
53,506 (14.6%)
6,142 (18.4%)
72,426 (12.2%)
7,799 (15.3%)
-0.09
Dipstick urinalysis; n (%)
39,810 (34.9%)
3,686 (41.4%)
33,397 (29.3%)
3,102 (35.5%)
145,826 (39.8%)
16,212 (48.5%)
219,033 (36.9%)
23,000 (45.1%)
-0.17
Non-dipstick urinalysis; n (%)
44,276 (38.8%)
3,916 (44.0%)
29,777 (26.1%)
2,820 (32.3%)
130,875 (35.7%)
14,659 (43.9%)
204,928 (34.5%)
21,395 (41.9%)
-0.15
Urine function test; n (%)
2,905 (2.5%)
212 (2.4%)
2,885 (2.5%)
281 (3.2%)
12,778 (3.5%)
1,377 (4.1%)
18,568 (3.1%)
1,870 (3.7%)
-0.03
Cytology; n (%)
888 (0.8%)
90 (1.0%)
1,110 (1.0%)
120 (1.4%)
3,902 (1.1%)
439 (1.3%)
5,900 (1.0%)
649 (1.3%)
-0.03
Cystos; n (%)
1,367 (1.2%)
111 (1.2%)
1,490 (1.3%)
151 (1.7%)
5,876 (1.6%)
563 (1.7%)
8,733 (1.5%)
825 (1.6%)
-0.01
Other Covariates
Liver disease; n (%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
#VALUE!
000 (0.0%)
#VALUE!
Osteoarthritis; n (%)
18,149 (15.9%)
1,516 (17.0%)
13,857 (12.2%)
1,082 (12.4%)
85,234 (23.3%)
8,776 (26.3%)
117,240 (19.7%)
11,374 (22.3%)
-0.06
Other arthritis, arthropathies and musculoskeletal pain; n 
(%)
40,678 (35.7%)
3,528 (39.6%)
36,555 (32.1%)
2,991 (34.2%)
165,558 (45.2%)
16,538 (49.5%)
242,791 (40.9%)
23,057 (45.2%)
-0.09
Dorsopathies; n (%)
24,710 (21.7%)
2,038 (22.9%)
21,713 (19.0%)
1,834 (21.0%)
96,989 (26.5%)
9,505 (28.5%)
143,412 (24.1%)
13,377 (26.2%)
-0.05
Fractures; n (%)
3,692 (3.2%)
305 (3.4%)
3,370 (3.0%)
223 (2.6%)
16,248 (4.4%)
1,513 (4.5%)
23,310 (3.9%)
2,041 (4.0%)
-0.01
Falls ; n (%)
4,478 (3.9%)
392 (4.4%)
1,629 (1.4%)
107 (1.2%)
18,341 (5.0%)
1,807 (5.4%)
24,448 (4.1%)
2,306 (4.5%)
-0.02
Osteoporosis; n (%)
5,505 (4.8%)
541 (6.1%)
3,204 (2.8%)
263 (3.0%)
28,297 (7.7%)
3,994 (12.0%)
37,006 (6.2%)
4,798 (9.4%)
-0.12
Hyperthyroidism; n (%)
699 (0.6%)
97 (1.1%)
500 (0.4%)
55 (0.6%)
3,221 (0.9%)
427 (1.3%)
4,420 (0.7%)
579 (1.1%)
-0.04
Hypothyroidism ; n (%)
17,357 (15.2%)
1,673 (18.8%)
11,200 (9.8%)
1,124 (12.9%)
54,516 (14.9%)
5,258 (15.7%)
83,073 (14.0%)
8,055 (15.8%)
-0.05
Other disorders of thyroid gland ; n (%)
3,224 (2.8%)
422 (4.7%)
2,773 (2.4%)
387 (4.4%)
12,515 (3.4%)
1,791 (5.4%)
18,512 (3.1%)
2,600 (5.1%)
-0.10
Depression; n (%)
9,096 (8.0%)
805 (9.0%)
7,304 (6.4%)
557 (6.4%)
38,741 (10.6%)
3,845 (11.5%)
55,141 (9.3%)
5,207 (10.2%)
-0.03
Anxiety; n (%)
7,943 (7.0%)
784 (8.8%)
5,215 (4.6%)
448 (5.1%)
30,541 (8.3%)
3,196 (9.6%)
43,699 (7.4%)
4,428 (8.7%)
-0.05
Sleep_Disorder; n (%)
8,147 (7.1%)
590 (6.6%)
11,134 (9.8%)
870 (10.0%)
29,743 (8.1%)
2,723 (8.2%)
49,024 (8.3%)
4,183 (8.2%)
0.00
Dementia; n (%)
5,612 (4.9%)
540 (6.1%)
3,565 (3.1%)
223 (2.6%)
32,684 (8.9%)
3,540 (10.6%)
41,861 (7.0%)
4,303 (8.4%)
-0.05
Delirium; n (%)
1,424 (1.2%)
149 (1.7%)
1,104 (1.0%)
72 (0.8%)
7,315 (2.0%)
849 (2.5%)
9,843 (1.7%)
1,070 (2.1%)
-0.03
Psychosis; n (%)
1,263 (1.1%)
129 (1.4%)
968 (0.8%)
55 (0.6%)
7,939 (2.2%)
793 (2.4%)
10,170 (1.7%)
977 (1.9%)
-0.02
Obesity; n (%)
16,061 (14.1%)
1,661 (18.7%)
10,204 (8.9%)
989 (11.3%)
37,005 (10.1%)
3,919 (11.7%)
63,270 (10.6%)
6,569 (12.9%)
-0.07
Overweight; n (%)
5,405 (4.7%)
591 (6.6%)
1,779 (1.6%)
164 (1.9%)
11,533 (3.1%)
1,342 (4.0%)
18,717 (3.2%)
2,097 (4.1%)
-0.05
Smoking; n (%)
12,866 (11.3%)
1,123 (12.6%)
6,558 (5.8%)
472 (5.4%)
48,039 (13.1%)
4,237 (12.7%)
67,463 (11.4%)
5,832 (11.4%)
0.00
Alcohol abuse or dependence; n (%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
#VALUE!
00 (0.0%)
#VALUE!
Drug abuse or dependence; n (%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
#VALUE!
00 (0.0%)
#VALUE!
COPD; n (%)
12,993 (11.4%)
882 (9.9%)
9,142 (8.0%)
618 (7.1%)
50,518 (13.8%)
4,685 (14.0%)
72,653 (12.2%)
6,185 (12.1%)
0.00
Table 1

Asthma; n (%)
5,959 (5.2%)
569 (6.4%)
5,213 (4.6%)
426 (4.9%)
22,404 (6.1%)
2,223 (6.7%)
33,576 (5.7%)
3,218 (6.3%)
-0.03
Obstructive sleep apnea; n (%)
9,320 (8.2%)
876 (9.8%)
10,424 (9.1%)
939 (10.7%)
22,520 (6.2%)
2,217 (6.6%)
42,264 (7.1%)
4,032 (7.9%)
-0.03
Pneumonia; n (%)
3,866 (3.4%)
318 (3.6%)
3,558 (3.1%)
241 (2.8%)
16,296 (4.5%)
1,507 (4.5%)
23,720 (4.0%)
2,066 (4.0%)
0.00
Imaging; n (%)
155 (0.1%)
17 (0.2%)
131 (0.1%)
7 (0.1%)
712 (0.2%)
54 (0.2%)
998 (0.2%)
78 (0.2%)
0.00
Diabetes Medications
DM Medications - AGIs; n (%)
359 (0.3%)
32 (0.4%)
308 (0.3%)
32 (0.4%)
1,322 (0.4%)
202 (0.6%)
1,989 (0.3%)
266 (0.5%)
-0.03
DM Medications - Glitazones; n (%)
7,693 (6.7%)
617 (6.9%)
9,595 (8.4%)
839 (9.6%)
22,794 (6.2%)
2,478 (7.4%)
40,082 (6.7%)
3,934 (7.7%)
-0.04
DM Medications - Insulin; n (%)
15,753 (13.8%)
2,424 (27.2%)
15,075 (13.2%)
1,908 (21.8%)
55,854 (15.3%)
9,388 (28.1%)
86,682 (14.6%)
13,720 (26.9%)
-0.31
DM Medications - Meglitinides; n (%)
719 (0.6%)
184 (2.1%)
1,020 (0.9%)
248 (2.8%)
3,957 (1.1%)
1,190 (3.6%)
5,696 (1.0%)
1,622 (3.2%)
-0.15
DM Medications - Metformin; n (%)
67,785 (59.5%)
4,911 (55.2%)
68,989 (60.5%)
4,989 (57.1%)
211,273 (57.7%)
17,663 (52.9%)
348,047 (58.6%)
27,563 (54.0%)
0.09
Concomitant initiation or current use of SGLT2i; n (%)
222 (0.2%)
268 (3.0%)
167 (0.1%)
566 (6.5%)
259 (0.1%)
412 (1.2%)
#VALUE!
1,246 (2.4%)
#VALUE!
Concomitant initiation or current use of AGIs; n (%)
260 (0.2%)
26 (0.3%)
230 (0.2%)
23 (0.3%)
938 (0.3%)
134 (0.4%)
1,428 (0.2%)
183 (0.4%)
-0.04
Concomitant initiation or current use of Glitazones; n (%)
5,876 (5.2%)
424 (4.8%)
7,225 (6.3%)
527 (6.0%)
17,490 (4.8%)
1,741 (5.2%)
30,591 (5.1%)
2,692 (5.3%)
-0.01
Concomitant initiation or current use of Insulin; n (%)
10,884 (9.5%)
1,862 (20.9%)
10,876 (9.5%)
1,443 (16.5%)
39,560 (10.8%)
7,259 (21.7%)
61,320 (10.3%)
10,564 (20.7%)
-0.29
Concomitant initiation or current use of Meglitinides; n 
(%)
453 (0.4%)
134 (1.5%)
655 (0.6%)
195 (2.2%)
2,488 (0.7%)
892 (2.7%)
3,596 (0.6%)
1,221 (2.4%)
-0.15
Concomitant initiation or current use of Metformin; n (%)
56,752 (49.8%)
3,913 (43.9%)
58,199 (51.0%)
3,978 (45.5%)
177,256 (48.4%)
13,934 (41.7%)
292,207 (49.2%)
21,825 (42.8%)
0.13
Past use of SGLT2i; n (%)
1 (0.0%)
0 (0.0%)
19 (0.0%)
1 (0.0%)
4 (0.0%)
0 (0.0%)
#VALUE!
001 (0.0%)
#VALUE!
Past use of AGIs ; n (%)
99 (0.1%)
6 (0.1%)
78 (0.1%)
9 (0.1%)
384 (0.1%)
68 (0.2%)
561 (0.1%)
83 (0.2%)
-0.03
Past use of Glitazones ; n (%)
1,817 (1.6%)
193 (2.2%)
2,371 (2.1%)
312 (3.6%)
5,304 (1.4%)
737 (2.2%)
9,492 (1.6%)
1,242 (2.4%)
-0.06
Past use of Insulin ; n (%)
4,869 (4.3%)
562 (6.3%)
4,199 (3.7%)
465 (5.3%)
16,297 (4.5%)
2,129 (6.4%)
25,365 (4.3%)
3,156 (6.2%)
-0.09
Past use of Meglitinides ; n (%)
266 (0.2%)
50 (0.6%)
365 (0.3%)
53 (0.6%)
1,469 (0.4%)
298 (0.9%)
2,100 (0.4%)
401 (0.8%)
-0.05
Past use of metformin  ; n (%)
11,033 (9.7%)
998 (11.2%)
10,790 (9.5%)
1,011 (11.6%)
34,017 (9.3%)
3,729 (11.2%)
55,840 (9.4%)
5,738 (11.2%)
-0.06
Other Medications
Use of ACE inhibitors; n (%)
52,181 (45.8%)
3,676 (41.3%)
50,776 (44.5%)
3,495 (40.0%)
163,750 (44.7%)
12,790 (38.3%)
266,707 (44.9%)
19,961 (39.1%)
0.12
Use of ARBs; n (%)
28,284 (24.8%)
2,777 (31.2%)
28,769 (25.2%)
2,858 (32.7%)
97,329 (26.6%)
11,969 (35.8%)
154,382 (26.0%)
17,604 (34.5%)
-0.19
Use of Loop Diuretics ; n (%)
20,910 (18.3%)
1,833 (20.6%)
19,444 (17.1%)
1,688 (19.3%)
88,445 (24.2%)
9,010 (27.0%)
128,799 (21.7%)
12,531 (24.6%)
-0.07
Use of other diuretics; n (%)
4,374 (3.8%)
435 (4.9%)
4,519 (4.0%)
441 (5.0%)
16,078 (4.4%)
1,632 (4.9%)
24,971 (4.2%)
2,508 (4.9%)
-0.03
Use of nitrates-United; n (%)
10,414 (9.1%)
772 (8.7%)
11,043 (9.7%)
747 (8.6%)
42,214 (11.5%)
3,874 (11.6%)
63,671 (10.7%)
5,393 (10.6%)
0.00
Use of other hypertension drugs; n (%)
10,825 (9.5%)
920 (10.3%)
9,771 (8.6%)
794 (9.1%)
37,611 (10.3%)
3,867 (11.6%)
58,207 (9.8%)
5,581 (10.9%)
-0.04
Use of digoxin; n (%)
3,374 (3.0%)
219 (2.5%)
3,676 (3.2%)
272 (3.1%)
16,616 (4.5%)
1,350 (4.0%)
23,666 (4.0%)
1,841 (3.6%)
0.02
Use of Anti-arrhythmics; n (%)
2,343 (2.1%)
176 (2.0%)
2,629 (2.3%)
216 (2.5%)
10,532 (2.9%)
1,055 (3.2%)
15,504 (2.6%)
1,447 (2.8%)
-0.01
Use of COPD/asthma meds; n (%)
16,005 (14.0%)
1,608 (18.1%)
16,846 (14.8%)
1,465 (16.8%)
61,145 (16.7%)
7,008 (21.0%)
93,996 (15.8%)
10,081 (19.8%)
-0.10
Use of statins; n (%)
77,398 (67.9%)
6,449 (72.4%)
74,851 (65.6%)
6,099 (69.8%)
249,773 (68.2%)
24,666 (73.8%)
402,022 (67.7%)
37,214 (72.9%)
-0.11
Use of other lipid-lowering drugs; n (%)
12,848 (11.3%)
1,223 (13.7%)
16,602 (14.6%)
1,528 (17.5%)
42,913 (11.7%)
4,879 (14.6%)
72,363 (12.2%)
7,630 (14.9%)
-0.08
Use of antiplatelet agents; n (%)
19,863 (17.4%)
1,752 (19.7%)
23,347 (20.5%)
1,865 (21.3%)
70,313 (19.2%)
7,213 (21.6%)
113,523 (19.1%)
10,830 (21.2%)
-0.05
Use of oral anticoagulants (Dabigatran, Rivaroxaban, 
Apixaban, Warfarin); n (%)
10,082 (8.8%)
749 (8.4%)
9,718 (8.5%)
793 (9.1%)
44,487 (12.2%)
4,020 (12.0%)
64,287 (10.8%)
5,562 (10.9%)
0.00
Use of heparin and other low-molecular weight heparins; 
n (%)
469 (0.4%)
50 (0.6%)
23 (0.0%)
1 (0.0%)
1,950 (0.5%)
157 (0.5%)
2,442 (0.4%)
208 (0.4%)
0.00
Use of NSAIDs; n (%)
15,070 (13.2%)
1,274 (14.3%)
15,571 (13.7%)
1,294 (14.8%)
52,701 (14.4%)
5,618 (16.8%)
83,342 (14.0%)
8,186 (16.0%)
-0.06
Use of oral corticosteroids; n (%)
18,755 (16.5%)
1,600 (18.0%)
18,563 (16.3%)
1,501 (17.2%)
70,096 (19.1%)
6,887 (20.6%)
107,414 (18.1%)
9,988 (19.6%)
-0.04
Use of bisphosphonate (United); n (%)
2,806 (2.5%)
227 (2.5%)
1,930 (1.7%)
137 (1.6%)
11,978 (3.3%)
1,663 (5.0%)
16,714 (2.8%)
2,027 (4.0%)
-0.07
Use of opioids; n (%)
28,735 (25.2%)
2,259 (25.4%)
30,829 (27.0%)
2,294 (26.3%)
100,433 (27.4%)
9,027 (27.0%)
159,997 (26.9%)
13,580 (26.6%)
0.01
Use of antidepressants; n (%)
25,596 (22.5%)
2,240 (25.2%)
25,079 (22.0%)
2,142 (24.5%)
92,511 (25.3%)
9,505 (28.5%)
143,186 (24.1%)
13,887 (27.2%)
-0.07
Use of antipsychotics; n (%)
2,655 (2.3%)
305 (3.4%)
2,436 (2.1%)
213 (2.4%)
12,838 (3.5%)
1,506 (4.5%)
17,929 (3.0%)
2,024 (4.0%)
-0.05
Use of anticonvulsants; n (%)
17,961 (15.8%)
1,682 (18.9%)
14,538 (12.7%)
1,316 (15.1%)
63,740 (17.4%)
7,030 (21.0%)
96,239 (16.2%)
10,028 (19.6%)
-0.09
Use of lithium; n (%)
160 (0.1%)
9 (0.1%)
188 (0.2%)
15 (0.2%)
453 (0.1%)
40 (0.1%)
801 (0.1%)
064 (0.1%)
0.00
Use of Benzos; n (%)
10,450 (9.2%)
1,032 (11.6%)
13,201 (11.6%)
1,036 (11.9%)
38,343 (10.5%)
4,251 (12.7%)
61,994 (10.4%)
6,319 (12.4%)
-0.06
Use of anxiolytics/hypnotics; n (%)
6,200 (5.4%)
596 (6.7%)
7,418 (6.5%)
642 (7.3%)
23,082 (6.3%)
2,419 (7.2%)
36,700 (6.2%)
3,657 (7.2%)
-0.04
Use of dementia meds; n (%)
3,527 (3.1%)
323 (3.6%)
2,889 (2.5%)
206 (2.4%)
21,174 (5.8%)
2,631 (7.9%)
27,590 (4.6%)
3,160 (6.2%)
-0.07
Use of antiparkinsonian meds; n (%)
2,831 (2.5%)
261 (2.9%)
2,799 (2.5%)
207 (2.4%)
13,280 (3.6%)
1,369 (4.1%)
18,910 (3.2%)
1,837 (3.6%)
-0.02
Any use of pramlintide; n (%)
8 (0.0%)
5 (0.1%)
29 (0.0%)
5 (0.1%)
**
**
**
**
#VALUE!
Any use of 1st generation sulfonylureas; n (%)
34 (0.0%)
1 (0.0%)
92 (0.1%)
1 (0.0%)
**
**
**
**
0.00
Entresto (sacubitril/valsartan); n (%)
153 (0.1%)
25 (0.3%)
46 (0.0%)
6 (0.1%)
212 (0.1%)
40 (0.1%)
411 (0.1%)
071 (0.1%)
0.00
Labs
                                       228,016                                           17,640 
Lab values- HbA1c (%) ; n (%)
38,300 (33.6%)
3,628 (40.7%)
7,256 (6.4%)
411 (4.7%)
N/A
N/A
45,556 (20.0%)
4,039 (22.9%)
-0.07
Lab values- HbA1c (%) (within 3 months) ; n (%)
29,271 (25.7%)
2,900 (32.6%)
5,567 (4.9%)
334 (3.8%)
N/A
N/A
34,838 (15.3%)
3,234 (18.3%)
-0.08
Lab values- HbA1c (%) (within 6 months) ; n (%)
38,300 (33.6%)
3,628 (40.7%)
7,256 (6.4%)
411 (4.7%)
N/A
N/A
45,556 (20.0%)
4,039 (22.9%)
-0.07
Lab values- BNP; n (%)
940 (0.8%)
116 (1.3%)
159 (0.1%)
11 (0.1%)
N/A
N/A
1,099 (0.5%)
127 (0.7%)
-0.03
Lab values- BNP (within 3 months); n (%)
586 (0.5%)
66 (0.7%)
96 (0.1%)
8 (0.1%)
N/A
N/A
682 (0.3%)
074 (0.4%)
-0.02
Lab values- BNP (within 6 months); n (%)
940 (0.8%)
116 (1.3%)
159 (0.1%)
11 (0.1%)
N/A
N/A
1,099 (0.5%)
127 (0.7%)
-0.03
Lab values- BUN (mg/dl); n (%)
39,671 (34.8%)
3,848 (43.2%)
5,599 (4.9%)
460 (5.3%)
N/A
N/A
45,270 (19.9%)
4,308 (24.4%)
-0.11
Table 1

Lab values- BUN (mg/dl) (within 3 months); n (%)
30,338 (26.6%)
3,054 (34.3%)
4,205 (3.7%)
362 (4.1%)
N/A
N/A
34,543 (15.1%)
3,416 (19.4%)
-0.11
Lab values- BUN (mg/dl) (within 6 months); n (%)
39,671 (34.8%)
3,848 (43.2%)
5,599 (4.9%)
460 (5.3%)
N/A
N/A
45,270 (19.9%)
4,308 (24.4%)
-0.11
Lab values- Creatinine (mg/dl) ; n (%)
40,504 (35.5%)
3,967 (44.6%)
5,824 (5.1%)
501 (5.7%)
N/A
N/A
46,328 (20.3%)
4,468 (25.3%)
-0.12
Lab values- Creatinine (mg/dl) (within 3 months) ; n (%)
30,955 (27.2%)
3,154 (35.4%)
4,374 (3.8%)
392 (4.5%)
N/A
N/A
35,329 (15.5%)
3,546 (20.1%)
-0.12
Lab values- Creatinine (mg/dl) (within 6 months) ; n (%)
40,504 (35.5%)
3,967 (44.6%)
5,824 (5.1%)
501 (5.7%)
N/A
N/A
46,328 (20.3%)
4,468 (25.3%)
-0.12
Lab values- HDL level (mg/dl); n (%)
31,938 (28.0%)
3,092 (34.7%)
6,175 (5.4%)
398 (4.6%)
N/A
N/A
38,113 (16.7%)
3,490 (19.8%)
-0.08
Lab values- HDL level (mg/dl) (within 3 months); n (%)
23,022 (20.2%)
2,313 (26.0%)
4,413 (3.9%)
307 (3.5%)
N/A
N/A
27,435 (12.0%)
2,620 (14.9%)
-0.09
Lab values- HDL level (mg/dl) (within 6 months); n (%)
31,938 (28.0%)
3,092 (34.7%)
6,175 (5.4%)
398 (4.6%)
N/A
N/A
38,113 (16.7%)
3,490 (19.8%)
-0.08
Lab values- LDL level (mg/dl) ; n (%)
32,964 (28.9%)
3,182 (35.7%)
6,625 (5.8%)
403 (4.6%)
N/A
N/A
39,589 (17.4%)
3,585 (20.3%)
-0.07
Lab values- LDL level (mg/dl) (within 3 months) ; n (%)
23,766 (20.8%)
2,384 (26.8%)
4,732 (4.1%)
310 (3.5%)
N/A
N/A
28,498 (12.5%)
2,694 (15.3%)
-0.08
Lab values- LDL level (mg/dl) (within 6 months) ; n (%)
32,964 (28.9%)
3,182 (35.7%)
6,625 (5.8%)
403 (4.6%)
N/A
N/A
39,589 (17.4%)
3,585 (20.3%)
-0.07
Lab values- NT-proBNP; n (%)
131 (0.1%)
12 (0.1%)
12 (0.0%)
2 (0.0%)
N/A
N/A
143 (0.1%)
14 (0.1%)
0.00
Lab values- NT-proBNP (within 3 months); n (%)
84 (0.1%)
6 (0.1%)
6 (0.0%)
1 (0.0%)
N/A
N/A
90 (0.0%)
7 (0.0%)
-
Lab values- NT-proBNP (within 6 months); n (%)
131 (0.1%)
12 (0.1%)
12 (0.0%)
2 (0.0%)
N/A
N/A
143 (0.1%)
14 (0.1%)
-
Lab values- Total cholesterol (mg/dl) ; n (%)
32,336 (28.4%)
3,154 (35.4%)
6,131 (5.4%)
405 (4.6%)
N/A
N/A
38,467 (16.9%)
3,559 (20.2%)
-0.08
Lab values- Total cholesterol (mg/dl) (within 3 months) ; n 
(%)
23,343 (20.5%)
2,357 (26.5%)
4,361 (3.8%)
312 (3.6%)
N/A
N/A
27,704 (12.2%)
2,669 (15.1%)
-0.08
Lab values- Total cholesterol (mg/dl) (within 6 months) ; n 
(%)
32,336 (28.4%)
3,154 (35.4%)
6,131 (5.4%)
405 (4.6%)
N/A
N/A
38,467 (16.9%)
3,559 (20.2%)
-0.08
Lab values- Triglyceride level (mg/dl); n (%)
32,012 (28.1%)
3,140 (35.3%)
6,014 (5.3%)
400 (4.6%)
N/A
N/A
38,026 (16.7%)
3,540 (20.1%)
-0.09
Lab values- Triglyceride level (mg/dl) (within 3 months); n 
(%)
23,144 (20.3%)
2,346 (26.3%)
4,302 (3.8%)
307 (3.5%)
N/A
N/A
27,446 (12.0%)
2,653 (15.0%)
-0.09
Lab values- Triglyceride level (mg/dl) (within 6 months); n 
(%)
32,012 (28.1%)
3,140 (35.3%)
6,014 (5.3%)
400 (4.6%)
N/A
N/A
38,026 (16.7%)
3,540 (20.1%)
-0.09
Lab result number- HbA1c (%) mean (only 2 to 20 
included) 
38,074
                                         
3,615
                                            
5,890
                                            
390
                                                
N/A
N/A                                           43,964                                              4,005 
...mean (sd)
7.99 (1.81)
8.01 (1.81)
8.11 (1.90)
7.88 (1.83)
N/A
N/A
8.01 (1.82)
8.00 (1.81)
0.01
...median [IQR]
7.55 [6.80, 8.73]
7.60 [6.70, 8.80]
7.60 [6.80, 8.95]
7.42 [6.60, 8.60]
N/A
N/A
7.56 (1.82)
7.58 (1.81)
-0.01
...Missing; n (%)
75,917 (66.6%)
5,289 (59.4%)
108,135 (94.8%)
8,346 (95.5%)
N/A
N/A
184,052 (80.7%)
13,635 (77.3%)
0.08
Lab result number- BNP mean 
940
                                                
116
                                                
159
                                                
11
                                                   
N/A
N/A                                              1,099                                                  127 
...mean (sd)
227.35 (358.83)
199.85 (371.31)
2,946.36 (33,054.02)
607.19 (1,393.52)
N/A
N/A
620.73 (12554.50)
235.13 (533.36)
0.04
...median [IQR]
97.30 [38.75, 251.23]
82.60 [32.35, 208.35]
109.00 [40.00, 327.00]
49.00 [15.10, 188.00]
N/A
N/A
#VALUE!
#VALUE!
#VALUE!
...Missing; n (%)
113,051 (99.2%)
8,788 (98.7%)
113,866 (99.9%)
8,725 (99.9%)
N/A
N/A
226,917 (99.5%)
17,513 (99.3%)
0.03
Lab result number- BUN (mg/dl) mean 
                                          39,671                                              3,848                                              5,599                                                  460 
N/A
N/A                                           45,270                                              4,308 
...mean (sd)
20.56 (9.20)
22.06 (10.35)
782.69 (11,615.02)
306.16 (6,060.48)
N/A
N/A
114.82 (4084.57)
52.40 (1978.94)
0.02
...median [IQR]
18.50 [14.50, 24.00]
19.67 [15.00, 27.00]
17.00 [13.50, 22.00]
18.25 [14.00, 25.88]
N/A
N/A
#VALUE!
#VALUE!
#VALUE!
...Missing; n (%)
74,320 (65.2%)
5,056 (56.8%)
108,426 (95.1%)
8,276 (94.7%)
N/A
N/A
182,746 (80.1%)
13,332 (75.6%)
0.11
Lab result number- Creatinine (mg/dl) mean (only 0.1 to 
15 included) 
                                          40,229                                              3,945                                              5,443                                                  469 
N/A
N/A                                           45,672                                              4,414 
...mean (sd)
1.14 (0.45)
1.24 (0.52)
1.09 (0.46)
1.18 (0.61)
N/A
N/A
1.13 (0.45)
1.23 (0.53)
-0.20
...median [IQR]
1.04 [0.85, 1.32]
1.14 [0.88, 1.48]
1.00 [0.82, 1.21]
1.02 [0.84, 1.35]
N/A
N/A
1.04 (0.45)
1.13 (0.53)
-0.18
...Missing; n (%)
73,762 (64.7%)
4,959 (55.7%)
108,582 (95.2%)
8,267 (94.6%)
N/A
N/A
182,344 (80.0%)
13,226 (75.0%)
0.12
Lab result number- HDL level (mg/dl) mean (only =<5000 
included) 
                                          31,938                                              3,092                                              6,157                                                  397 
N/A
N/A                                           38,095                                              3,489 
...mean (sd)
46.04 (13.96)
46.52 (14.16)
43.97 (14.10)
51.75 (174.25)
N/A
N/A
45.71 (13.98)
47.12 (60.22)
-0.03
...median [IQR]
44.00 [37.00, 53.00]
44.50 [37.00, 54.00]
43.00 [36.00, 51.00]
41.00 [34.00, 52.00]
N/A
N/A
43.84 (13.98)
44.10 (60.22)
-0.01
...Missing; n (%)
82,053 (72.0%)
5,812 (65.3%)
107,868 (94.6%)
8,339 (95.5%)
N/A
N/A
189,921 (83.3%)
14,151 (80.2%)
0.08
Lab result number- LDL level (mg/dl) mean (only =<5000 
included) 
                                          32,245                                              3,111                                              5,964                                                  377 
N/A
N/A                                           38,209                                              3,488 
...mean (sd)
85.89 (40.32)
85.56 (40.40)
87.23 (42.41)
85.12 (45.45)
N/A
N/A
86.10 (40.65)
85.51 (40.98)
0.01
...median [IQR]
82.00 [61.00, 108.00]
82.50 [61.00, 109.00]
84.50 [63.00, 111.00]
85.00 [59.00, 111.25]
N/A
N/A
82.39 (40.65)
82.77 (40.98)
-0.01
...Missing; n (%)
81,746 (71.7%)
5,793 (65.1%)
108,061 (94.8%)
8,359 (95.7%)
N/A
N/A
189,807 (83.2%)
14,152 (80.2%)
0.08
Lab result number- Total cholesterol (mg/dl) mean (only 
=<5000 included) 
                                          32,317                                              3,153                                              6,112                                                  403 
N/A
N/A                                           38,429                                              3,556 
...mean (sd)
172.24 (48.74)
173.80 (47.85)
173.02 (52.38)
174.06 (57.08)
N/A
N/A
172.36 (49.34)
173.83 (48.99)
-0.03
...median [IQR]
165.50 [140.00, 197.00]
166.00 [142.00, 197.50]
168.00 [142.00, 200.00]
170.00 [141.00, 205.00]
N/A
N/A
165.90 (49.34)
166.45 (48.99)
-0.01
...Missing; n (%)
81,674 (71.6%)
5,751 (64.6%)
107,913 (94.6%)
8,333 (95.4%)
N/A
N/A
189,587 (83.1%)
14,084 (79.8%)
0.08
Lab result number- Triglyceride level (mg/dl) mean (only 
=<5000 included) 
                                          32,008                                              3,140                                              5,996                                                  398 
N/A
N/A                                           38,004                                              3,538 
...mean (sd)
185.40 (155.50)
189.62 (172.91)
193.09 (188.17)
212.32 (232.65)
N/A
N/A
186.61 (161.10)
192.17 (180.63)
-0.03
...median [IQR]
151.00 [108.00, 217.00]
152.00 [107.00, 222.00]
151.00 [107.00, 221.00]
159.00 [107.25, 235.00]
N/A
N/A
151.00 (161.10)
152.79 (180.63)
-0.01
...Missing; n (%)
81,983 (71.9%)
5,764 (64.7%)
108,029 (94.7%)
8,338 (95.4%)
N/A
N/A
190,012 (83.3%)
14,102 (79.9%)
0.09
Table 1

Lab result number- Hemoglobin mean (only >0 included)
                                          28,631                                              2,909                                              3,766                                                  353 
N/A
N/A                                           32,397                                              3,262 
...mean (sd)
13.29 (1.75)
13.17 (1.73)
6,103.13 (230,642.43)
443.69 (8,089.45)
N/A
N/A
721.21 (78630.20)
59.76 (2658.57)
0.01
...median [IQR]
13.30 [12.10, 14.50]
13.20 [11.95, 14.40]
13.60 [12.30, 14.75]
13.30 [12.00, 14.53]
N/A
N/A
#VALUE!
#VALUE!
#VALUE!
...Missing; n (%)
85,360 (74.9%)
5,995 (67.3%)
110,259 (96.7%)
8,383 (96.0%)
N/A
N/A
195,619 (85.8%)
14,378 (81.5%)
0.12
Lab result number- Serum sodium mean (only > 90 and < 
190 included)
                                          39,251                                              3,841                                              5,097                                                  458 
N/A
N/A                                           44,348                                              4,299 
...mean (sd)
139.42 (2.88)
139.59 (2.83)
138.84 (2.83)
139.10 (2.65)
N/A
N/A
139.35 (2.87)
139.54 (2.81)
-0.07
...median [IQR]
139.75 [138.00, 141.00]
140.00 [138.00, 141.50]
139.00 [137.00, 141.00]
139.37 [137.00, 141.00]
N/A
N/A
139.66 (2.87)
139.93 (2.81)
-0.10
...Missing; n (%)
74,740 (65.6%)
5,063 (56.9%)
108,928 (95.5%)
8,278 (94.8%)
N/A
N/A
183,668 (80.6%)
13,341 (75.6%)
0.12
Lab result number- Albumin mean (only >0 and <=10 
included)
                                          36,154                                              3,614                                              4,374                                                  398 
N/A
N/A                                           40,528                                              4,012 
...mean (sd)
4.21 (0.33)
4.21 (0.36)
4.12 (0.64)
4.09 (0.71)
N/A
N/A
4.20 (0.38)
4.20 (0.41)
0.00
...median [IQR]
4.20 [4.00, 4.40]
4.20 [4.00, 4.45]
4.20 [4.00, 4.40]
4.20 [4.00, 4.40]
N/A
N/A
4.20 (0.38)
4.20 (0.41)
0.00
...Missing; n (%)
77,837 (68.3%)
5,290 (59.4%)
109,651 (96.2%)
8,338 (95.4%)
N/A
N/A
187,488 (82.2%)
13,628 (77.3%)
0.12
Lab result number- Glucose (fasting or random) mean 
(only 10-1000 included)
                                          39,051                                              3,838                                              4,988                                                  457 
N/A
N/A                                           44,039                                              4,295 
...mean (sd)
168.55 (73.40)
164.67 (71.92)
177.16 (79.94)
166.24 (76.35)
N/A
N/A
169.53 (74.17)
164.84 (72.41)
0.06
...median [IQR]
150.00 [121.00, 195.00]
146.00 [118.50, 187.00]
156.00 [124.00, 208.00]
145.00 [120.92, 188.00]
N/A
N/A
150.68 (74.17)
145.89 (72.41)
0.07
...Missing; n (%)
74,940 (65.7%)
5,066 (56.9%)
109,037 (95.6%)
8,279 (94.8%)
N/A
N/A
183,977 (80.7%)
13,345 (75.7%)
0.12
Lab result number- Potassium mean (only 1-7 included)
                                          40,186                                              3,936                                              5,475                                                  450 
N/A
N/A                                           45,661                                              4,386 
...mean (sd)
4.47 (0.45)
4.49 (0.46)
4.35 (0.46)
4.36 (0.50)
N/A
N/A
4.46 (0.45)
4.48 (0.46)
-0.04
...median [IQR]
4.45 [4.20, 4.75]
4.50 [4.20, 4.80]
4.32 [4.00, 4.60]
4.38 [4.07, 4.70]
N/A
N/A
4.43 (0.45)
4.49 (0.46)
-0.13
...Missing; n (%)
73,805 (64.7%)
4,968 (55.8%)
108,550 (95.2%)
8,286 (94.8%)
N/A
N/A
182,355 (80.0%)
13,254 (75.1%)
0.12
Comorbidity Scores
CCI (180 days)- ICD9 and ICD10 
...mean (sd)
2.99 (2.02)
3.36 (2.10)
2.08 (1.78)
2.46 (1.86)
3.19 (2.08)
3.77 (2.11)
2.94 (2.01)
3.47 (2.07)
-0.26
...median [IQR]
3.00 [1.00, 4.00]
3.00 [2.00, 5.00]
2.00 [1.00, 3.00]
2.00 [1.00, 4.00]
3.00 [2.00, 4.00]
4.00 [2.00, 5.00]
2.81 (2.01)
3.48 (2.07)
-0.33
Frailty Score: Qualitative Version 365 days as Categories, 
v1
...0; n (%)
44,743 (39.3%)
4,273 (48.0%)
28,949 (25.4%)
2,610 (29.9%)
87,576 (23.9%)
9,710 (29.1%)
161,268 (27.1%)
16,593 (32.5%)
-0.12
...1 to 2; n (%)
39,522 (34.7%)
2,883 (32.4%)
50,470 (44.3%)
3,722 (42.6%)
119,132 (32.5%)
10,236 (30.6%)
209,124 (35.2%)
16,841 (33.0%)
0.05
...3 or more; n (%)
29,726 (26.1%)
1,748 (19.6%)
34,606 (30.3%)
2,404 (27.5%)
159,428 (43.5%)
13,455 (40.3%)
223,760 (37.7%)
17,607 (34.5%)
0.07
Frailty Score: Empirical Version 365 days as Categories, 
...< 0.12908; n (%)
14,662 (12.9%)
1,228 (13.8%)
16,898 (14.8%)
1,340 (15.3%)
20,704 (5.7%)
1,564 (4.7%)
52,264 (8.8%)
4,132 (8.1%)
0.03
...0.12908 - 0.1631167; n (%)
33,703 (29.6%)
2,522 (28.3%)
33,908 (29.7%)
2,586 (29.6%)
67,558 (18.5%)
5,402 (16.2%)
135,169 (22.7%)
10,510 (20.6%)
0.05
...>= 0.1631167; n (%)
65,626 (57.6%)
5,154 (57.9%)
63,219 (55.4%)
4,810 (55.1%)
277,874 (75.9%)
26,435 (79.1%)
406,719 (68.5%)
36,399 (71.3%)
-0.06
Non-Frailty; n (%)
63,097 (55.4%)
5,173 (58.1%)
55,924 (49.0%)
4,718 (54.0%)
15,747 (4.3%)
1,403 (4.2%)
134,768 (22.7%)
11,294 (22.1%)
0.01
Frailty Score (mean): Qualitative Version 365 days, v1
...mean (sd)
1.68 (2.08)
1.33 (1.90)
1.97 (1.98)
1.79 (1.89)
2.57 (2.41)
2.36 (2.39)
2.28 (2.27)
2.08 (2.23)
0.09
...median [IQR]
1.00 [0.00, 3.00]
1.00 [0.00, 2.00]
2.00 [0.00, 3.00]
1.00 [0.00, 3.00]
2.00 [1.00, 4.00]
2.00 [0.00, 4.00]
1.81 (2.27)
1.65 (2.23)
0.07
Frailty Score (mean): Empirical Version 365 days, 
...mean (sd)
0.18 (0.06)
0.18 (0.06)
0.17 (0.05)
0.17 (0.05)
0.21 (0.07)
0.21 (0.07)
0.20 (0.06)
0.20 (0.07)
0.00
...median [IQR]
0.17 [0.14, 0.21]
0.17 [0.14, 0.21]
0.16 [0.14, 0.20]
0.16 [0.14, 0.19]
0.20 [0.16, 0.24]
0.20 [0.17, 0.25]
0.19 (0.06)
0.19 (0.07)
0.00
Healthcare Utilization
Any hospitalization; n (%)
11,956 (10.5%)
920 (10.3%)
13,485 (11.8%)
899 (10.3%)
50,583 (13.8%)
4,291 (12.8%)
76,024 (12.8%)
6,110 (12.0%)
0.02
Any hospitalization within prior 30 days; n (%)
4,508 (4.0%)
319 (3.6%)
4,953 (4.3%)
263 (3.0%)
18,266 (5.0%)
1,389 (4.2%)
27,727 (4.7%)
1,971 (3.9%)
0.04
Any hospitalization during prior 31-180 days; n (%)
8,158 (7.2%)
653 (7.3%)
9,220 (8.1%)
679 (7.8%)
35,844 (9.8%)
3,185 (9.5%)
53,222 (9.0%)
4,517 (8.8%)
0.01
Endocrinologist Visit; n (%)
6,826 (6.0%)
1,500 (16.8%)
7,000 (6.1%)
1,485 (17.0%)
27,770 (7.6%)
5,512 (16.5%)
41,596 (7.0%)
8,497 (16.6%)
-0.30
Endocrinologist Visit (30 days prior); n (%)
3,954 (3.5%)
1,079 (12.1%)
4,239 (3.7%)
1,088 (12.5%)
15,203 (4.2%)
3,902 (11.7%)
23,396 (3.9%)
6,069 (11.9%)
-0.30
Endocrinologist Visit (31 to 180 days prior); n (%)
4,733 (4.2%)
966 (10.8%)
4,701 (4.1%)
963 (11.0%)
20,849 (5.7%)
3,759 (11.3%)
30,283 (5.1%)
5,688 (11.1%)
-0.22
Internal medicine/family medicine visits; n (%)
98,689 (86.6%)
7,064 (79.3%)
94,269 (82.7%)
7,569 (86.6%)
306,858 (83.8%)
27,861 (83.4%)
499,816 (84.1%)
42,494 (83.3%)
0.02
Internal medicine/family medicine visits (30 days prior) ; 
n (%)
72,530 (63.6%)
5,239 (58.8%)
68,880 (60.4%)
5,670 (64.9%)
214,056 (58.5%)
20,278 (60.7%)
355,466 (59.8%)
31,187 (61.1%)
-0.03
Internal medicine/family medicine visits (31 to 180 days 
prior) ; n (%)
85,493 (75.0%)
6,235 (70.0%)
79,062 (69.3%)
6,601 (75.6%)
268,278 (73.3%)
25,080 (75.1%)
432,833 (72.8%)
37,916 (74.3%)
-0.03
Cardiologist visit; n (%)
40,644 (35.7%)
3,396 (38.1%)
33,564 (29.4%)
2,878 (32.9%)
153,453 (41.9%)
14,288 (42.8%)
227,661 (38.3%)
20,562 (40.3%)
-0.04
Number of Cardiologist visits (30 days prior); n (%)
14,207 (12.5%)
1,245 (14.0%)
11,295 (9.9%)
980 (11.2%)
52,867 (14.4%)
4,868 (14.6%)
78,369 (13.2%)
7,093 (13.9%)
-0.02
Number of Cardiologist visits (31 to 180 days prior); n (%)
34,459 (30.2%)
2,890 (32.5%)
28,626 (25.1%)
2,486 (28.5%)
132,578 (36.2%)
12,584 (37.7%)
195,663 (32.9%)
17,960 (35.2%)
-0.05
Electrocardiogram ; n (%)
39,835 (34.9%)
3,371 (37.9%)
39,798 (34.9%)
3,239 (37.1%)
142,743 (39.0%)
13,763 (41.2%)
222,376 (37.4%)
20,373 (39.9%)
-0.05
Use of glucose test strips; n (%)
3,782 (3.3%)
428 (4.8%)
3,883 (3.4%)
401 (4.6%)
12,324 (3.4%)
1,343 (4.0%)
19,989 (3.4%)
2,172 (4.3%)
-0.05
Dialysis; n (%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
000 (0.0%)
000 (0.0%)
#DIV/0!
Naive new user  ; n (%)
34,575 (30.3%)
2,522 (28.3%)
35,230 (30.9%)
2,410 (27.6%)
97,997 (26.8%)
8,357 (25.0%)
167,802 (28.2%)
13,289 (26.0%)
0.05
Table 1

N antidiabetic drugs at index date  
...mean (sd)
1.67 (0.64)
1.75 (0.68)
1.70 (0.65)
1.77 (0.71)
1.66 (0.63)
1.73 (0.67)
1.67 (0.64)
1.74 (0.68)
-0.11
...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 (0.64)
2.00 (0.68)
0.00
number of different/distinct medication prescriptions
...mean (sd)
9.76 (4.67)
11.09 (5.37)
9.57 (4.62)
10.67 (5.07)
10.00 (4.50)
11.47 (5.03)
9.87 (4.56)
11.27 (5.10)
-0.29
...median [IQR]
9.00 [6.00, 12.00]
10.00 [7.00, 14.00]
9.00 [6.00, 12.00]
10.00 [7.00, 14.00]
9.00 [7.00, 12.00]11.00 [8.00, 14.00]
9.00 (4.56)
10.65 (5.10)
-0.34
Number of Hospitalizations
...mean (sd)
0.13 (0.41)
0.13 (0.41)
0.14 (0.41)
0.12 (0.39)
0.18 (0.50)
0.16 (0.48)
0.16 (0.47)
0.15 (0.45)
0.02
...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 (0.47)
0.00 (0.45)
0.00
Number of hospital days
...mean (sd)
0.69 (3.15)
0.67 (2.66)
0.77 (3.34)
0.66 (2.86)
1.09 (4.32)
1.02 (3.97)
0.95 (3.94)
0.90 (3.60)
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 (3.94)
0.00 (3.60)
0.00
Number of Emergency Department (ED) visits 
...mean (sd)
0.47 (1.25)
0.49 (1.40)
0.22 (1.51)
0.19 (1.26)
0.64 (1.48)
0.63 (1.44)
0.53 (1.44)
0.53 (1.40)
0.00
...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 (1.44)
0.00 (1.40)
0.00
Number of Office visits
...mean (sd)
4.81 (3.84)
5.54 (4.37)
4.90 (4.19)
5.87 (4.32)
5.48 (4.37)
6.38 (4.77)
5.24 (4.24)
6.15 (4.63)
-0.20
...median [IQR]
4.00 [2.00, 6.00]
5.00 [3.00, 7.00]
4.00 [2.00, 6.00]
5.00 [3.00, 8.00]
4.00 [2.00, 7.00]
5.00 [3.00, 9.00]
4.00 (4.24)
5.00 (4.63)
-0.23
Number of Endocrinologist visits
...mean (sd)
0.26 (1.68)
0.81 (2.91)
0.26 (1.60)
0.84 (3.11)
0.41 (2.46)
0.95 (3.72)
0.35 (2.18)
0.91 (3.49)
-0.19
...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 (2.18)
0.00 (3.49)
0.00
Number of internal medicine/family medicine visits
...mean (sd)
10.22 (13.48)
9.35 (14.19)
6.96 (10.00)
7.84 (9.99)
8.22 (10.66)
8.99 (11.61)
8.36 (11.14)
8.86 (11.85)
-0.04
...median [IQR]
6.00 [2.00, 13.00]
5.00 [1.00, 12.00]
4.00 [1.00, 9.00]
5.00 [2.00, 10.00]
5.00 [2.00, 11.00] 6.00 [2.00, 12.00]
5.00 (11.14)
5.65 (11.85)
-0.06
Number of Cardiologist visits
...mean (sd)
1.70 (3.99)
1.95 (4.52)
1.27 (3.33)
1.48 (3.46)
2.19 (4.88)
2.34 (5.18)
1.92 (4.46)
2.12 (4.81)
-0.04
...median [IQR]
0.00 [0.00, 2.00]
0.00 [0.00, 2.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 2.00]
0.00 [0.00, 2.00]
0.00 (4.46)
0.00 (4.81)
0.00
Number electrocardiograms received 
...mean (sd)
0.71 (1.48)
0.76 (1.50)
0.66 (1.30)
0.67 (1.23)
0.82 (1.50)
0.86 (1.50)
0.77 (1.46)
0.81 (1.46)
-0.03
...median [IQR]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 (1.46)
0.00 (1.46)
0.00
Number of HbA1c tests ordered
...mean (sd)
1.14 (0.90)
1.30 (0.95)
0.81 (0.87)
0.98 (0.94)
1.26 (0.88)
1.47 (0.91)
1.15 (0.88)
1.36 (0.92)
-0.23
...median [IQR]
1.00 [1.00, 2.00]
1.00 [1.00, 2.00]
1.00 [0.00, 1.00]
1.00 [0.00, 2.00]
1.00 [1.00, 2.00]
1.00 [1.00, 2.00]
1.00 (0.88)
1.00 (0.92)
0.00
Number of glucose tests ordered
...mean (sd)
0.47 (2.91)
1.00 (8.11)
0.38 (1.34)
0.49 (1.26)
0.39 (1.05)
0.58 (1.32)
0.40 (1.63)
0.64 (3.59)
-0.09
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 1.00]
0.00 [0.00, 0.00]
0.00 [0.00, 1.00]
0.00 [0.00, 0.00]
0.00 [0.00, 1.00]
0.00 (1.63)
0.00 (3.59)
0.00
Number of lipid tests ordered
...mean (sd)
0.91 (0.94)
1.03 (1.00)
0.69 (1.15)
0.86 (1.33)
0.92 (0.83)
1.08 (0.90)
0.87 (0.92)
1.03 (1.00)
-0.17
...median [IQR]
1.00 [0.00, 1.00]
1.00 [0.00, 2.00]
0.00 [0.00, 1.00]
1.00 [0.00, 1.00]
1.00 [0.00, 1.00]
1.00 [0.00, 2.00]
0.81 (0.92)
1.00 (1.00)
-0.20
Number of creatinine tests ordered
...mean (sd)
0.06 (0.35)
0.07 (0.47)
0.10 (0.49)
0.07 (0.58)
0.10 (0.43)
0.09 (0.40)
0.09 (0.43)
0.08 (0.45)
0.02
...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 (0.43)
0.00 (0.45)
0.00
Number of BUN tests ordered
...mean (sd)
0.04 (0.29)
0.04 (0.38)
0.06 (0.40)
0.05 (0.58)
0.06 (0.34)
0.06 (0.32)
0.06 (0.34)
0.05 (0.39)
0.03
...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 (0.34)
0.00 (0.39)
0.00
Number of tests for microalbuminuria
...mean (sd)
0.73 (1.16)
0.87 (1.32)
0.44 (0.92)
0.58 (1.05)
0.42 (0.70)
0.57 (0.84)
0.48 (0.85)
0.62 (0.98)
-0.15
...median [IQR]
0.00 [0.00, 2.00]
0.00 [0.00, 2.00]
0.00 [0.00, 0.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 (0.85)
0.00 (0.98)
0.00
Total N distinct ICD9/ICD10 diagnoses at the 3rd digit 
level 
...mean (sd)
5.56 (7.61)
7.38 (8.79)
2.27 (5.00)
2.87 (5.40)
6.02 (8.58)
7.70 (9.44)
5.21 (7.83)
6.82 (8.76)
-0.19
...median [IQR]
3.00 [0.00, 9.00]
5.00 [0.00, 11.00]
0.00 [0.00, 3.00]
0.00 [0.00, 4.00]
3.00 [0.00, 9.00] 5.00 [0.00, 12.00]
2.42 (7.83)
4.14 (8.76)
-0.21
Use of thiazide; n (%)
14,325 (12.6%)
1,077 (12.1%)
13,611 (11.9%)
1,008 (11.5%)
50,169 (13.7%)
4,605 (13.8%)
78,105 (13.1%)
6,690 (13.1%)
0.00
Use of beta blockers; n (%)
57,310 (50.3%)
4,545 (51.0%)
57,096 (50.1%)
4,427 (50.7%)
202,981 (55.4%)
19,093 (57.2%)
317,387 (53.4%)
28,065 (55.0%)
-0.03
Use of calcium channel blockers; n (%)
35,824 (31.4%)
3,051 (34.3%)
33,870 (29.7%)
2,789 (31.9%)
128,069 (35.0%)
13,043 (39.0%)
197,763 (33.3%)
18,883 (37.0%)
-0.08
Table 1

Variable
Reference- 2nd 
Generation SUs
Exposure- Linagliptin
Reference- 2nd 
Generation SUs
Exposure- Linagliptin
Reference- 2nd 
Generation SUs
Exposure- Linagliptin
Reference- 2nd 
Generation SUs
Exposure- Linagliptin
St. Diff.
Number of patients
8880
8880
8716
8716
33319
33319                                           50,915                                           50,915 
Age
...mean (sd)
66.96 (10.94)
66.96 (11.63)
63.85 (11.51)
63.76 (11.53)
75.92 (7.38)
75.97 (7.44)
72.29 (8.90)
72.31 (9.09)
0.00
...median [IQR]
68.00 [60.00, 75.00]
67.00 [59.00, 76.00]
63.00 [56.00, 72.00]
62.00 [56.00, 71.00]
75.00 [70.00, 81.00]
75.00 [70.00, 81.00]
71.72 (8.90)
71.38 (9.09)
0.04
Age categories 
...18 - 54; n (%)
1,227 (13.8%)
1,313 (14.8%)
1,726 (19.8%)
1,715 (19.7%)
0 (0.0%)
0 (0.0%)
2,953 (5.8%)
3,028 (5.9%)
0.00
...55 - 64; n (%)
1,986 (22.4%)
2,434 (27.4%)
3,404 (39.1%)
3,524 (40.4%)
307 (0.9%)
339 (1.0%)
5,697 (11.2%)
6,297 (12.4%)
-0.04
...65 - 74; n (%)
3,436 (38.7%)
2,634 (29.7%)
1,870 (21.5%)
1,781 (20.4%)
15,789 (47.4%)
15,632 (46.9%)
21,095 (41.4%)
20,047 (39.4%)
0.04
...>= 75; n (%)
2,231 (25.1%)
2,499 (28.1%)
1,716 (19.7%)
1,696 (19.5%)
17,223 (51.7%)
17,348 (52.1%)
21,170 (41.6%)
21,543 (42.3%)
-0.01
Gender 
...Males; n (%)
4,699 (52.9%)
4,669 (52.6%)
4,973 (57.1%)
5,039 (57.8%)
14,083 (42.3%)
14,131 (42.4%)
23,755 (46.7%)
23,839 (46.8%)
0.00
...Females; n (%)
4,181 (47.1%)
4,211 (47.4%)
3,743 (42.9%)
3,677 (42.2%)
19,236 (57.7%)
19,188 (57.6%)
27,160 (53.3%)
27,076 (53.2%)
0.00
Race 
...White; n (%)
N/A
N/A
N/A
N/A
23,508 (70.6%)
23,421 (70.3%)
23,508 (70.6%)
23,421 (70.3%)
0.01
...Black; n (%)
N/A
N/A
N/A
N/A
4,254 (12.8%)
4,256 (12.8%)
4,254 (12.8%)
4,256 (12.8%)
0.00
...Asian; n (%)
N/A
N/A
N/A
N/A
2,120 (6.4%)
2,151 (6.5%)
2,120 (6.4%)
2,151 (6.5%)
0.00
...Hispanic; n (%)
N/A
N/A
N/A
N/A
1,819 (5.5%)
1,861 (5.6%)
1,819 (5.5%)
1,861 (5.6%)
0.00
...North American Native; n (%)
N/A
N/A
N/A
N/A
273 (0.8%)
270 (0.8%)
273 (0.8%)
270 (0.8%)
0.00
...Other/Unknown; n (%)
N/A
N/A
N/A
N/A
1,345 (4.0%)
1,360 (4.1%)
1,345 (4.0%)
1,360 (4.1%)
-0.01
Region   (lumping missing&other category with 
West)
...Northeast; n (%)
1,134 (12.8%)
1,141 (12.8%)
1,872 (21.5%)
1,936 (22.2%)
6,759 (20.3%)
6,789 (20.4%)
9,765 (19.2%)
9,866 (19.4%)
-0.01
...South; n (%)
4,622 (52.0%)
4,611 (51.9%)
1,654 (19.0%)
1,644 (18.9%)
14,504 (43.5%)
14,319 (43.0%)
20,780 (40.8%)
20,574 (40.4%)
0.01
...Midwest; n (%)
1,575 (17.7%)
1,590 (17.9%)
4,154 (47.7%)
4,147 (47.6%)
5,737 (17.2%)
5,801 (17.4%)
11,466 (22.5%)
11,538 (22.7%)
0.00
...West; n (%)
1,549 (17.4%)
1,538 (17.3%)
934 (10.7%)
895 (10.3%)
6,319 (19.0%)
6,410 (19.2%)
8,802 (17.3%)
8,843 (17.4%)
0.00
...Unknown+missing; n (%)
N/A
N/A
102 (1.2%)
94 (1.1%)
N/A
N/A
102 (1.2%)
94 (1.1%)
0.01
CV Covariates
Ischemic heart disease; n (%)
3,488 (39.3%)
3,469 (39.1%)
3,098 (35.5%)
3,028 (34.7%)
13,743 (41.2%)
13,751 (41.3%)
20,329 (39.9%)
20,248 (39.8%)
0.00
Acute MI; n (%)
203 (2.3%)
211 (2.4%)
156 (1.8%)
164 (1.9%)
583 (1.7%)
570 (1.7%)
942 (1.9%)
945 (1.9%)
0.00
ACS/unstable angina; n (%)
133 (1.5%)
117 (1.3%)
120 (1.4%)
125 (1.4%)
459 (1.4%)
440 (1.3%)
712 (1.4%)
682 (1.3%)
0.01
Old MI; n (%)
416 (4.7%)
428 (4.8%)
242 (2.8%)
241 (2.8%)
1,583 (4.8%)
1,570 (4.7%)
2,241 (4.4%)
2,239 (4.4%)
0.00
Stable angina; n (%)
547 (6.2%)
539 (6.1%)
387 (4.4%)
381 (4.4%)
1,727 (5.2%)
1,702 (5.1%)
2,661 (5.2%)
2,622 (5.1%)
0.00
Coronary atherosclerosis and other forms of chronic 
ischemic heart disease; n (%)
3,205 (36.1%)
3,212 (36.2%)
2,873 (33.0%)
2,834 (32.5%)
13,040 (39.1%)
13,022 (39.1%)
19,118 (37.5%)
19,068 (37.5%)
0.00
Other atherosclerosis with ICD10  ; n (%)
94 (1.1%)
114 (1.3%)
92 (1.1%)
107 (1.2%)
657 (2.0%)
680 (2.0%)
843 (1.7%)
901 (1.8%)
-0.01
Previous cardiac procedure (CABG or PTCA or Stent) ; 
n (%)
55 (0.6%)
56 (0.6%)
66 (0.8%)
80 (0.9%)
168 (0.5%)
170 (0.5%)
289 (0.6%)
306 (0.6%)
0.00
History of CABG or PTCA; n (%)
755 (8.5%)
776 (8.7%)
363 (4.2%)
380 (4.4%)
3,490 (10.5%)
3,405 (10.2%)
4,608 (9.1%)
4,561 (9.0%)
0.00
Any stroke; n (%)
337 (3.8%)
343 (3.9%)
345 (4.0%)
353 (4.1%)
1,782 (5.3%)
1,830 (5.5%)
2,464 (4.8%)
2,526 (5.0%)
-0.01
Ischemic stroke (w and w/o mention of cerebral 
infarction); n (%)
333 (3.8%)
335 (3.8%)
341 (3.9%)
347 (4.0%)
1,754 (5.3%)
1,810 (5.4%)
2,428 (4.8%)
2,492 (4.9%)
0.00
Hemorrhagic stroke; n (%)
6 (0.1%)
13 (0.1%)
7 (0.1%)
10 (0.1%)
33 (0.1%)
32 (0.1%)
046 (0.1%)
055 (0.1%)
0.00
TIA; n (%)
57 (0.6%)
56 (0.6%)
52 (0.6%)
62 (0.7%)
329 (1.0%)
336 (1.0%)
438 (0.9%)
454 (0.9%)
0.00
Other cerebrovascular disease; n (%)
198 (2.2%)
177 (2.0%)
98 (1.1%)
111 (1.3%)
957 (2.9%)
948 (2.8%)
1,253 (2.5%)
1,236 (2.4%)
0.01
Late effects of cerebrovascular disease; n (%)
172 (1.9%)
170 (1.9%)
73 (0.8%)
70 (0.8%)
822 (2.5%)
842 (2.5%)
1,067 (2.1%)
1,082 (2.1%)
0.00
Cerebrovascular procedure; n (%)
4 (0.0%)
3 (0.0%)
4 (0.0%)
3 (0.0%)
13 (0.0%)
11 (0.0%)
021 (0.0%)
017 (0.0%)
#DIV/0!
Heart failure (CHF); n (%)
1,118 (12.6%)
1,140 (12.8%)
839 (9.6%)
820 (9.4%)
5,351 (16.1%)
5,337 (16.0%)
7,308 (14.4%)
7,297 (14.3%)
0.00
Peripheral Vascular Disease (PVD) or PVD Surgery ; n 
(%)
878 (9.9%)
872 (9.8%)
593 (6.8%)
558 (6.4%)
4,957 (14.9%)
4,955 (14.9%)
6,428 (12.6%)
6,385 (12.5%)
0.00
Atrial fibrillation; n (%)
835 (9.4%)
845 (9.5%)
738 (8.5%)
733 (8.4%)
4,861 (14.6%)
4,884 (14.7%)
6,434 (12.6%)
6,462 (12.7%)
0.00
Other cardiac dysrhythmia; n (%)
1,125 (12.7%)
1,103 (12.4%)
799 (9.2%)
800 (9.2%)
5,521 (16.6%)
5,531 (16.6%)
7,445 (14.6%)
7,434 (14.6%)
0.00
Cardiac conduction disorders; n (%)
336 (3.8%)
329 (3.7%)
248 (2.8%)
238 (2.7%)
1,680 (5.0%)
1,576 (4.7%)
2,264 (4.4%)
2,143 (4.2%)
0.01
Other CVD; n (%)
1,272 (14.3%)
1,278 (14.4%)
1,147 (13.2%)
1,134 (13.0%)
6,324 (19.0%)
6,350 (19.1%)
8,743 (17.2%)
8,762 (17.2%)
0.00
Diabetes-related complications
Diabetic retinopathy; n (%)
630 (7.1%)
670 (7.5%)
375 (4.3%)
397 (4.6%)
2,635 (7.9%)
2,651 (8.0%)
3,640 (7.1%)
3,718 (7.3%)
-0.01
Diabetes with other ophthalmic manifestations; n 
(%)
74 (0.8%)
58 (0.7%)
258 (3.0%)
254 (2.9%)
953 (2.9%)
937 (2.8%)
1,285 (2.5%)
1,249 (2.5%)
0.00
Retinal detachment, vitreous hemorrhage, 
vitrectomy; n (%)
44 (0.5%)
61 (0.7%)
36 (0.4%)
52 (0.6%)
137 (0.4%)
163 (0.5%)
217 (0.4%)
276 (0.5%)
-0.01
Retinal laser coagulation therapy; n (%)
41 (0.5%)
70 (0.8%)
51 (0.6%)
67 (0.8%)
205 (0.6%)
253 (0.8%)
297 (0.6%)
390 (0.8%)
-0.02
Occurrence of Diabetic Neuropathy  ; n (%)
1,816 (20.5%)
1,833 (20.6%)
1,090 (12.5%)
1,109 (12.7%)
7,317 (22.0%)
7,280 (21.8%)
10,223 (20.1%)
10,222 (20.1%)
0.00
 PS-matched
MarketScan
Medicare
POOLED
Optum
Table 1

Occurrence of diabetic nephropathy  with ICD10 ; n 
(%)
2,215 (24.9%)
2,268 (25.5%)
1,124 (12.9%)
1,114 (12.8%)
6,355 (19.1%)
6,416 (19.3%)
9,694 (19.0%)
9,798 (19.2%)
-0.01
Hypoglycemia ; n (%)
216 (2.4%)
226 (2.5%)
195 (2.2%)
207 (2.4%)
1,053 (3.2%)
1,079 (3.2%)
1,464 (2.9%)
1,512 (3.0%)
-0.01
Hyperglycemia; n (%)
568 (6.4%)
544 (6.1%)
348 (4.0%)
342 (3.9%)
2,120 (6.4%)
2,159 (6.5%)
3,036 (6.0%)
3,045 (6.0%)
0.00
Disorders of fluid electrolyte and acid-base balance; n 
(%)
1,091 (12.3%)
1,051 (11.8%)
568 (6.5%)
617 (7.1%)
4,041 (12.1%)
4,017 (12.1%)
5,700 (11.2%)
5,685 (11.2%)
0.00
Diabetic ketoacidosis; n (%)
37 (0.4%)
35 (0.4%)
41 (0.5%)
24 (0.3%)
171 (0.5%)
126 (0.4%)
249 (0.5%)
185 (0.4%)
0.01
Hyperosmolar hyperglycemic nonketotic syndrome 
(HONK); n (%)
49 (0.6%)
55 (0.6%)
37 (0.4%)
41 (0.5%)
205 (0.6%)
216 (0.6%)
291 (0.6%)
312 (0.6%)
0.00
Diabetes with peripheral circulatory disorders with 
ICD-10  ; n (%)
808 (9.1%)
808 (9.1%)
373 (4.3%)
400 (4.6%)
3,068 (9.2%)
3,123 (9.4%)
4,249 (8.3%)
4,331 (8.5%)
-0.01
Diabetic Foot; n (%)
268 (3.0%)
269 (3.0%)
184 (2.1%)
199 (2.3%)
1,098 (3.3%)
1,078 (3.2%)
1,550 (3.0%)
1,546 (3.0%)
0.00
Gangrene ; n (%)
31 (0.3%)
31 (0.3%)
14 (0.2%)
16 (0.2%)
107 (0.3%)
101 (0.3%)
152 (0.3%)
148 (0.3%)
0.00
Lower extremity amputation; n (%)
80 (0.9%)
96 (1.1%)
31 (0.4%)
38 (0.4%)
277 (0.8%)
276 (0.8%)
388 (0.8%)
410 (0.8%)
0.00
Osteomyelitis; n (%)
66 (0.7%)
78 (0.9%)
54 (0.6%)
46 (0.5%)
240 (0.7%)
210 (0.6%)
360 (0.7%)
334 (0.7%)
0.00
Skin infections ; n (%)
569 (6.4%)
539 (6.1%)
501 (5.7%)
522 (6.0%)
2,480 (7.4%)
2,528 (7.6%)
3,550 (7.0%)
3,589 (7.0%)
0.00
Erectile dysfunction; n (%)
246 (2.8%)
241 (2.7%)
220 (2.5%)
216 (2.5%)
644 (1.9%)
644 (1.9%)
1,110 (2.2%)
1,101 (2.2%)
0.00
Diabetes with unspecified complication; n (%)
627 (7.1%)
606 (6.8%)
370 (4.2%)
388 (4.5%)
2,097 (6.3%)
2,070 (6.2%)
3,094 (6.1%)
3,064 (6.0%)
0.00
Diabetes mellitus without mention of complications; 
n (%)
7,608 (85.7%)
7,607 (85.7%)
7,937 (91.1%)
7,943 (91.1%)
30,740 (92.3%)
30,751 (92.3%)
46,285 (90.9%)
46,301 (90.9%)
0.00
Hypertension: 1 inpatient or 2 outpatient claims 
within 365 days; n (%)
7,873 (88.7%)
7,855 (88.5%)
6,785 (77.8%)
6,815 (78.2%)
31,536 (94.6%)
31,451 (94.4%)
46,194 (90.7%)
46,121 (90.6%)
0.00
Hyperlipidemia ; n (%)
6,695 (75.4%)
6,689 (75.3%)
5,614 (64.4%)
5,628 (64.6%)
26,315 (79.0%)
26,388 (79.2%)
38,624 (75.9%)
38,705 (76.0%)
0.00
Edema; n (%)
818 (9.2%)
809 (9.1%)
556 (6.4%)
553 (6.3%)
4,504 (13.5%)
4,434 (13.3%)
5,878 (11.5%)
5,796 (11.4%)
0.00
Renal Dysfunction (non-diabetic) ; n (%)
3,697 (41.6%)
3,732 (42.0%)
2,456 (28.2%)
2,511 (28.8%)
13,956 (41.9%)
14,275 (42.8%)
20,109 (39.5%)
20,518 (40.3%)
-0.02
Occurrence of acute renal disease ; n (%)
643 (7.2%)
603 (6.8%)
422 (4.8%)
419 (4.8%)
2,452 (7.4%)
2,378 (7.1%)
3,517 (6.9%)
3,400 (6.7%)
0.01
Occurrence of chronic renal insufficiency; n (%)
3,381 (38.1%)
3,371 (38.0%)
2,101 (24.1%)
2,150 (24.7%)
12,524 (37.6%)
12,774 (38.3%)
18,006 (35.4%)
18,295 (35.9%)
-0.01
Chronic kidney disease ; n (%)
3,319 (37.4%)
3,314 (37.3%)
2,065 (23.7%)
2,102 (24.1%)
12,176 (36.5%)
12,358 (37.1%)
17,560 (34.5%)
17,774 (34.9%)
-0.01
CKD Stage 3-4; n (%)
2,764 (31.1%)
2,781 (31.3%)
1,669 (19.1%)
1,702 (19.5%)
9,803 (29.4%)
9,776 (29.3%)
14,236 (28.0%)
14,259 (28.0%)
0.00
Occurrence of hypertensive nephropathy; n (%)
1,472 (16.6%)
1,471 (16.6%)
723 (8.3%)
751 (8.6%)
5,364 (16.1%)
5,361 (16.1%)
7,559 (14.8%)
7,583 (14.9%)
0.00
Occurrence of miscellaneous renal insufficiency ; n 
(%)
800 (9.0%)
790 (8.9%)
601 (6.9%)
586 (6.7%)
3,837 (11.5%)
3,718 (11.2%)
5,238 (10.3%)
5,094 (10.0%)
0.01
Glaucoma or cataracts ; n (%)
1,689 (19.0%)
1,764 (19.9%)
1,481 (17.0%)
1,507 (17.3%)
9,097 (27.3%)
9,110 (27.3%)
12,267 (24.1%)
12,381 (24.3%)
0.00
Cellulitis or abscess of toe; n (%)
166 (1.9%)
138 (1.6%)
82 (0.9%)
101 (1.2%)
570 (1.7%)
591 (1.8%)
818 (1.6%)
830 (1.6%)
0.00
Foot ulcer; n (%)
250 (2.8%)
257 (2.9%)
185 (2.1%)
194 (2.2%)
1,091 (3.3%)
1,069 (3.2%)
1,526 (3.0%)
1,520 (3.0%)
0.00
Bladder stones; n (%)
17 (0.2%)
16 (0.2%)
17 (0.2%)
17 (0.2%)
70 (0.2%)
66 (0.2%)
104 (0.2%)
099 (0.2%)
0.00
Kidney stones; n (%)
290 (3.3%)
272 (3.1%)
270 (3.1%)
260 (3.0%)
1,031 (3.1%)
1,010 (3.0%)
1,591 (3.1%)
1,542 (3.0%)
0.01
Urinary tract infections (UTIs); n (%)
1,036 (11.7%)
1,013 (11.4%)
622 (7.1%)
641 (7.4%)
6,198 (18.6%)
6,107 (18.3%)
7,856 (15.4%)
7,761 (15.2%)
0.01
Dipstick urinalysis; n (%)
3,574 (40.2%)
3,671 (41.3%)
2,997 (34.4%)
3,094 (35.5%)
15,526 (46.6%)
16,153 (48.5%)
22,097 (43.4%)
22,918 (45.0%)
-0.03
Non-dipstick urinalysis; n (%)
4,002 (45.1%)
3,900 (43.9%)
2,841 (32.6%)
2,809 (32.2%)
14,418 (43.3%)
14,601 (43.8%)
21,261 (41.8%)
21,310 (41.9%)
0.00
Urine function test; n (%)
264 (3.0%)
209 (2.4%)
267 (3.1%)
280 (3.2%)
1,361 (4.1%)
1,370 (4.1%)
1,892 (3.7%)
1,859 (3.7%)
0.00
Cytology; n (%)
81 (0.9%)
88 (1.0%)
105 (1.2%)
120 (1.4%)
438 (1.3%)
437 (1.3%)
624 (1.2%)
645 (1.3%)
-0.01
Cystos; n (%)
114 (1.3%)
111 (1.2%)
154 (1.8%)
150 (1.7%)
666 (2.0%)
561 (1.7%)
934 (1.8%)
822 (1.6%)
0.02
Other Covariates
Liver disease; n (%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
000 (0.0%)
000 (0.0%)
#DIV/0!
Osteoarthritis; n (%)
1,546 (17.4%)
1,513 (17.0%)
1,091 (12.5%)
1,080 (12.4%)
8,803 (26.4%)
8,745 (26.2%)
11,440 (22.5%)
11,338 (22.3%)
0.00
Other arthritis, arthropathies and musculoskeletal 
pain; n (%)
3,601 (40.6%)
3,513 (39.6%)
2,985 (34.2%)
2,986 (34.3%)
16,525 (49.6%)
16,480 (49.5%)
23,111 (45.4%)
22,979 (45.1%)
0.01
Dorsopathies; n (%)
2,069 (23.3%)
2,033 (22.9%)
1,824 (20.9%)
1,828 (21.0%)
9,548 (28.7%)
9,466 (28.4%)
13,441 (26.4%)
13,327 (26.2%)
0.00
Fractures; n (%)
297 (3.3%)
304 (3.4%)
232 (2.7%)
222 (2.5%)
1,576 (4.7%)
1,511 (4.5%)
2,105 (4.1%)
2,037 (4.0%)
0.01
Falls ; n (%)
385 (4.3%)
392 (4.4%)
97 (1.1%)
107 (1.2%)
1,769 (5.3%)
1,804 (5.4%)
2,251 (4.4%)
2,303 (4.5%)
0.00
Osteoporosis; n (%)
547 (6.2%)
538 (6.1%)
266 (3.1%)
262 (3.0%)
3,873 (11.6%)
3,962 (11.9%)
4,686 (9.2%)
4,762 (9.4%)
-0.01
Hyperthyroidism; n (%)
76 (0.9%)
97 (1.1%)
52 (0.6%)
55 (0.6%)
415 (1.2%)
425 (1.3%)
543 (1.1%)
577 (1.1%)
0.00
Hypothyroidism ; n (%)
1,610 (18.1%)
1,667 (18.8%)
1,178 (13.5%)
1,119 (12.8%)
5,372 (16.1%)
5,234 (15.7%)
8,160 (16.0%)
8,020 (15.8%)
0.01
Other disorders of thyroid gland ; n (%)
377 (4.2%)
415 (4.7%)
349 (4.0%)
382 (4.4%)
1,687 (5.1%)
1,772 (5.3%)
2,413 (4.7%)
2,569 (5.0%)
-0.01
Depression; n (%)
817 (9.2%)
801 (9.0%)
567 (6.5%)
557 (6.4%)
3,892 (11.7%)
3,839 (11.5%)
5,276 (10.4%)
5,197 (10.2%)
0.01
Anxiety; n (%)
788 (8.9%)
781 (8.8%)
438 (5.0%)
448 (5.1%)
3,208 (9.6%)
3,189 (9.6%)
4,434 (8.7%)
4,418 (8.7%)
0.00
Sleep_Disorder; n (%)
602 (6.8%)
590 (6.6%)
882 (10.1%)
870 (10.0%)
2,750 (8.3%)
2,717 (8.2%)
4,234 (8.3%)
4,177 (8.2%)
0.00
Dementia; n (%)
534 (6.0%)
533 (6.0%)
247 (2.8%)
223 (2.6%)
3,583 (10.8%)
3,529 (10.6%)
4,364 (8.6%)
4,285 (8.4%)
0.01
Delirium; n (%)
143 (1.6%)
147 (1.7%)
72 (0.8%)
72 (0.8%)
837 (2.5%)
848 (2.5%)
1,052 (2.1%)
1,067 (2.1%)
0.00
Psychosis; n (%)
112 (1.3%)
129 (1.5%)
57 (0.7%)
55 (0.6%)
795 (2.4%)
792 (2.4%)
964 (1.9%)
976 (1.9%)
0.00
Obesity; n (%)
1,752 (19.7%)
1,655 (18.6%)
1,002 (11.5%)
983 (11.3%)
3,985 (12.0%)
3,909 (11.7%)
6,739 (13.2%)
6,547 (12.9%)
0.01
Overweight; n (%)
576 (6.5%)
587 (6.6%)
146 (1.7%)
164 (1.9%)
1,351 (4.1%)
1,340 (4.0%)
2,073 (4.1%)
2,091 (4.1%)
0.00
Smoking; n (%)
1,147 (12.9%)
1,120 (12.6%)
445 (5.1%)
472 (5.4%)
4,307 (12.9%)
4,230 (12.7%)
5,899 (11.6%)
5,822 (11.4%)
0.01
Alcohol abuse or dependence; n (%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
000 (0.0%)
000 (0.0%)
#DIV/0!
Drug abuse or dependence; n (%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
000 (0.0%)
000 (0.0%)
#DIV/0!
COPD; n (%)
947 (10.7%)
878 (9.9%)
636 (7.3%)
617 (7.1%)
4,686 (14.1%)
4,669 (14.0%)
6,269 (12.3%)
6,164 (12.1%)
0.01
Table 1

Asthma; n (%)
572 (6.4%)
566 (6.4%)
453 (5.2%)
423 (4.9%)
2,227 (6.7%)
2,213 (6.6%)
3,252 (6.4%)
3,202 (6.3%)
0.00
Obstructive sleep apnea; n (%)
916 (10.3%)
873 (9.8%)
947 (10.9%)
934 (10.7%)
2,238 (6.7%)
2,212 (6.6%)
4,101 (8.1%)
4,019 (7.9%)
0.01
Pneumonia; n (%)
325 (3.7%)
313 (3.5%)
229 (2.6%)
240 (2.8%)
1,503 (4.5%)
1,501 (4.5%)
2,057 (4.0%)
2,054 (4.0%)
0.00
Imaging; n (%)
9 (0.1%)
17 (0.2%)
11 (0.1%)
7 (0.1%)
74 (0.2%)
54 (0.2%)
94 (0.2%)
78 (0.2%)
0.00
Diabetes Medications
DM Medications - AGIs; n (%)
40 (0.5%)
32 (0.4%)
33 (0.4%)
32 (0.4%)
210 (0.6%)
194 (0.6%)
283 (0.6%)
258 (0.5%)
0.01
DM Medications - Glitazones; n (%)
625 (7.0%)
616 (6.9%)
856 (9.8%)
836 (9.6%)
2,492 (7.5%)
2,468 (7.4%)
3,973 (7.8%)
3,920 (7.7%)
0.00
DM Medications - Insulin; n (%)
2,377 (26.8%)
2,402 (27.0%)
1,870 (21.5%)
1,896 (21.8%)
9,270 (27.8%)
9,320 (28.0%)
13,517 (26.5%)
13,618 (26.7%)
0.00
DM Medications - Meglitinides; n (%)
171 (1.9%)
179 (2.0%)
249 (2.9%)
240 (2.8%)
1,105 (3.3%)
1,154 (3.5%)
1,525 (3.0%)
1,573 (3.1%)
-0.01
DM Medications - Metformin; n (%)
5,016 (56.5%)
4,907 (55.3%)
5,021 (57.6%)
4,978 (57.1%)
17,725 (53.2%)
17,642 (52.9%)
27,762 (54.5%)
27,527 (54.1%)
0.01
Concomitant initiation or current use of SGLT2i; n 
(%)
51 (0.6%)
267 (3.0%)
62 (0.7%)
559 (6.4%)
22 (0.1%)
412 (1.2%)
#VALUE!
1,238 (2.4%)
#VALUE!
Concomitant initiation or current use of AGIs; n (%)
31 (0.3%)
26 (0.3%)
26 (0.3%)
23 (0.3%)
138 (0.4%)
128 (0.4%)
195 (0.4%)
177 (0.3%)
0.02
Concomitant initiation or current use of Glitazones; 
n (%)
427 (4.8%)
423 (4.8%)
539 (6.2%)
525 (6.0%)
1,750 (5.3%)
1,734 (5.2%)
2,716 (5.3%)
2,682 (5.3%)
0.00
Concomitant initiation or current use of Insulin; n 
(%)
1,806 (20.3%)
1,841 (20.7%)
1,393 (16.0%)
1,435 (16.5%)
7,081 (21.3%)
7,195 (21.6%)
10,280 (20.2%)
10,471 (20.6%)
-0.01
Concomitant initiation or current use of 
Meglitinides; n (%)
118 (1.3%)
129 (1.5%)
191 (2.2%)
187 (2.1%)
821 (2.5%)
860 (2.6%)
1,130 (2.2%)
1,176 (2.3%)
-0.01
Concomitant initiation or current use of Metformin; 
n (%)
4,016 (45.2%)
3,909 (44.0%)
4,013 (46.0%)
3,970 (45.5%)
13,978 (42.0%)
13,920 (41.8%)
22,007 (43.2%)
21,799 (42.8%)
0.01
Past use of SGLT2i; n (%)
0 (0.0%)
0 (0.0%)
1 (0.0%)
1 (0.0%)
0 (0.0%)
0 (0.0%)
001 (0.0%)
001 (0.0%)
#DIV/0!
Past use of AGIs ; n (%)
9 (0.1%)
6 (0.1%)
7 (0.1%)
9 (0.1%)
72 (0.2%)
66 (0.2%)
088 (0.2%)
081 (0.2%)
0.00
Past use of Glitazones ; n (%)
198 (2.2%)
193 (2.2%)
317 (3.6%)
311 (3.6%)
742 (2.2%)
734 (2.2%)
1,257 (2.5%)
1,238 (2.4%)
0.01
Past use of Insulin ; n (%)
571 (6.4%)
561 (6.3%)
477 (5.5%)
461 (5.3%)
2,189 (6.6%)
2,125 (6.4%)
3,237 (6.4%)
3,147 (6.2%)
0.01
Past use of Meglitinides ; n (%)
53 (0.6%)
50 (0.6%)
58 (0.7%)
53 (0.6%)
284 (0.9%)
294 (0.9%)
395 (0.8%)
397 (0.8%)
0.00
Past use of metformin  ; n (%)
1,000 (11.3%)
998 (11.2%)
1,008 (11.6%)
1,008 (11.6%)
3,747 (11.2%)
3,722 (11.2%)
5,755 (11.3%)
5,728 (11.3%)
0.00
Other Medications
Use of ACE inhibitors; n (%)
3,677 (41.4%)
3,668 (41.3%)
3,499 (40.1%)
3,486 (40.0%)
12,931 (38.8%)
12,775 (38.3%)
20,107 (39.5%)
19,929 (39.1%)
0.01
Use of ARBs; n (%)
2,818 (31.7%)
2,768 (31.2%)
2,906 (33.3%)
2,848 (32.7%)
11,910 (35.7%)
11,911 (35.7%)
17,634 (34.6%)
17,527 (34.4%)
0.00
Use of Loop Diuretics ; n (%)
1,851 (20.8%)
1,824 (20.5%)
1,700 (19.5%)
1,683 (19.3%)
8,927 (26.8%)
8,978 (26.9%)
12,478 (24.5%)
12,485 (24.5%)
0.00
Use of other diuretics; n (%)
441 (5.0%)
433 (4.9%)
413 (4.7%)
439 (5.0%)
1,637 (4.9%)
1,626 (4.9%)
2,491 (4.9%)
2,498 (4.9%)
0.00
Use of nitrates-United; n (%)
753 (8.5%)
769 (8.7%)
730 (8.4%)
744 (8.5%)
3,871 (11.6%)
3,853 (11.6%)
5,354 (10.5%)
5,366 (10.5%)
0.00
Use of other hypertension drugs; n (%)
886 (10.0%)
915 (10.3%)
768 (8.8%)
793 (9.1%)
3,857 (11.6%)
3,850 (11.6%)
5,511 (10.8%)
5,558 (10.9%)
0.00
Use of digoxin; n (%)
202 (2.3%)
219 (2.5%)
280 (3.2%)
272 (3.1%)
1,335 (4.0%)
1,344 (4.0%)
1,817 (3.6%)
1,835 (3.6%)
0.00
Use of Anti-arrhythmics; n (%)
160 (1.8%)
176 (2.0%)
211 (2.4%)
216 (2.5%)
1,078 (3.2%)
1,054 (3.2%)
1,449 (2.8%)
1,446 (2.8%)
0.00
Use of COPD/asthma meds; n (%)
1,624 (18.3%)
1,602 (18.0%)
1,488 (17.1%)
1,459 (16.7%)
6,907 (20.7%)
6,986 (21.0%)
10,019 (19.7%)
10,047 (19.7%)
0.00
Use of statins; n (%)
6,456 (72.7%)
6,428 (72.4%)
6,090 (69.9%)
6,081 (69.8%)
24,525 (73.6%)
24,594 (73.8%)
37,071 (72.8%)
37,103 (72.9%)
0.00
Use of other lipid-lowering drugs; n (%)
1,261 (14.2%)
1,221 (13.8%)
1,542 (17.7%)
1,522 (17.5%)
4,758 (14.3%)
4,860 (14.6%)
7,561 (14.9%)
7,603 (14.9%)
0.00
Use of antiplatelet agents; n (%)
1,797 (20.2%)
1,745 (19.7%)
1,849 (21.2%)
1,859 (21.3%)
7,227 (21.7%)
7,176 (21.5%)
10,873 (21.4%)
10,780 (21.2%)
0.00
Use of oral anticoagulants (Dabigatran, Rivaroxaban, 
Apixaban, Warfarin); n (%)
738 (8.3%)
745 (8.4%)
777 (8.9%)
791 (9.1%)
3,971 (11.9%)
4,016 (12.1%)
5,486 (10.8%)
5,552 (10.9%)
0.00
Use of heparin and other low-molecular weight 
heparins; n (%)
48 (0.5%)
50 (0.6%)
0 (0.0%)
1 (0.0%)
153 (0.5%)
157 (0.5%)
201 (0.4%)
208 (0.4%)
0.00
Use of NSAIDs; n (%)
1,244 (14.0%)
1,269 (14.3%)
1,257 (14.4%)
1,290 (14.8%)
5,605 (16.8%)
5,590 (16.8%)
8,106 (15.9%)
8,149 (16.0%)
0.00
Use of oral corticosteroids; n (%)
1,594 (18.0%)
1,591 (17.9%)
1,506 (17.3%)
1,498 (17.2%)
6,811 (20.4%)
6,858 (20.6%)
9,911 (19.5%)
9,947 (19.5%)
0.00
Use of bisphosphonate (United); n (%)
251 (2.8%)
227 (2.6%)
145 (1.7%)
137 (1.6%)
1,662 (5.0%)
1,654 (5.0%)
2,058 (4.0%)
2,018 (4.0%)
0.00
Use of opioids; n (%)
2,261 (25.5%)
2,252 (25.4%)
2,322 (26.6%)
2,292 (26.3%)
9,179 (27.5%)
9,004 (27.0%)
13,762 (27.0%)
13,548 (26.6%)
0.01
Use of antidepressants; n (%)
2,221 (25.0%)
2,233 (25.1%)
2,105 (24.2%)
2,136 (24.5%)
9,564 (28.7%)
9,481 (28.5%)
13,890 (27.3%)
13,850 (27.2%)
0.00
Use of antipsychotics; n (%)
299 (3.4%)
303 (3.4%)
225 (2.6%)
213 (2.4%)
1,538 (4.6%)
1,500 (4.5%)
2,062 (4.0%)
2,016 (4.0%)
0.00
Use of anticonvulsants; n (%)
1,634 (18.4%)
1,672 (18.8%)
1,336 (15.3%)
1,314 (15.1%)
6,898 (20.7%)
7,000 (21.0%)
9,868 (19.4%)
9,986 (19.6%)
-0.01
Use of lithium; n (%)
16 (0.2%)
9 (0.1%)
20 (0.2%)
15 (0.2%)
55 (0.2%)
40 (0.1%)
091 (0.2%)
064 (0.1%)
0.03
Use of Benzos; n (%)
1,041 (11.7%)
1,028 (11.6%)
1,030 (11.8%)
1,033 (11.9%)
4,194 (12.6%)
4,237 (12.7%)
6,265 (12.3%)
6,298 (12.4%)
0.00
Use of anxiolytics/hypnotics; n (%)
592 (6.7%)
594 (6.7%)
633 (7.3%)
641 (7.4%)
2,449 (7.4%)
2,406 (7.2%)
3,674 (7.2%)
3,641 (7.2%)
0.00
Use of dementia meds; n (%)
333 (3.8%)
319 (3.6%)
234 (2.7%)
206 (2.4%)
2,601 (7.8%)
2,618 (7.9%)
3,168 (6.2%)
3,143 (6.2%)
0.00
Use of antiparkinsonian meds; n (%)
283 (3.2%)
259 (2.9%)
222 (2.5%)
207 (2.4%)
1,350 (4.1%)
1,365 (4.1%)
1,855 (3.6%)
1,831 (3.6%)
0.00
Any use of pramlintide; n (%)
0 (0.0%)
5 (0.1%)
10 (0.1%)
5 (0.1%)
**
**
**
**
**
Any use of 1st generation sulfonylureas; n (%)
4 (0.0%)
1 (0.0%)
2 (0.0%)
1 (0.0%)
**
**
**
**
**
Entresto (sacubitril/valsartan); n (%)
12 (0.1%)
25 (0.3%)
8 (0.1%)
6 (0.1%)
29 (0.1%)
40 (0.1%)
049 (0.1%)
071 (0.1%)
0.00
Labs
                                          17,596                                           17,596 
Lab values- HbA1c (%) ; n (%)
3,567 (40.2%)
3,619 (40.8%)
591 (6.8%)
410 (4.7%)
N/A
N/A
4,158 (23.6%)
4,029 (22.9%)
0.02
Lab values- HbA1c (%) (within 3 months) ; n (%)
2,757 (31.0%)
2,895 (32.6%)
460 (5.3%)
333 (3.8%)
N/A
N/A
3,217 (18.3%)
3,228 (18.3%)
0.00
Lab values- HbA1c (%) (within 6 months) ; n (%)
3,567 (40.2%)
3,619 (40.8%)
591 (6.8%)
410 (4.7%)
N/A
N/A
4,158 (23.6%)
4,029 (22.9%)
0.02
Lab values- BNP; n (%)
75 (0.8%)
116 (1.3%)
9 (0.1%)
11 (0.1%)
N/A
N/A
084 (0.5%)
127 (0.7%)
-0.03
Lab values- BNP (within 3 months); n (%)
54 (0.6%)
66 (0.7%)
5 (0.1%)
8 (0.1%)
N/A
N/A
059 (0.3%)
074 (0.4%)
-0.02
Lab values- BNP (within 6 months); n (%)
75 (0.8%)
116 (1.3%)
9 (0.1%)
11 (0.1%)
N/A
N/A
084 (0.5%)
127 (0.7%)
-0.03
Lab values- BUN (mg/dl); n (%)
3,723 (41.9%)
3,839 (43.2%)
534 (6.1%)
459 (5.3%)
N/A
N/A
4,257 (24.2%)
4,298 (24.4%)
0.00
Table 1

Lab values- BUN (mg/dl) (within 3 months); n (%)
2,904 (32.7%)
3,046 (34.3%)
411 (4.7%)
361 (4.1%)
N/A
N/A
3,315 (18.8%)
3,407 (19.4%)
-0.02
Lab values- BUN (mg/dl) (within 6 months); n (%)
3,723 (41.9%)
3,839 (43.2%)
534 (6.1%)
459 (5.3%)
N/A
N/A
4,257 (24.2%)
4,298 (24.4%)
0.00
Lab values- Creatinine (mg/dl) ; n (%)
3,814 (43.0%)
3,958 (44.6%)
567 (6.5%)
500 (5.7%)
N/A
N/A
4,381 (24.9%)
4,458 (25.3%)
-0.01
Lab values- Creatinine (mg/dl) (within 3 months) ; n 
(%)
2,972 (33.5%)
3,146 (35.4%)
436 (5.0%)
391 (4.5%)
N/A
N/A
3,408 (19.4%)
3,537 (20.1%)
-0.02
Lab values- Creatinine (mg/dl) (within 6 months) ; n 
(%)
3,814 (43.0%)
3,958 (44.6%)
567 (6.5%)
500 (5.7%)
N/A
N/A
4,381 (24.9%)
4,458 (25.3%)
-0.01
Lab values- HDL level (mg/dl); n (%)
2,999 (33.8%)
3,087 (34.8%)
502 (5.8%)
397 (4.6%)
N/A
N/A
3,501 (19.9%)
3,484 (19.8%)
0.00
Lab values- HDL level (mg/dl) (within 3 months); n (%)
2,179 (24.5%)
2,308 (26.0%)
362 (4.2%)
306 (3.5%)
N/A
N/A
2,541 (14.4%)
2,614 (14.9%)
-0.01
Lab values- HDL level (mg/dl) (within 6 months); n (%)
2,999 (33.8%)
3,087 (34.8%)
502 (5.8%)
397 (4.6%)
N/A
N/A
3,501 (19.9%)
3,484 (19.8%)
0.00
Lab values- LDL level (mg/dl) ; n (%)
3,088 (34.8%)
3,177 (35.8%)
528 (6.1%)
402 (4.6%)
N/A
N/A
3,616 (20.6%)
3,579 (20.3%)
0.01
Lab values- LDL level (mg/dl) (within 3 months) ; n (%)
2,230 (25.1%)
2,379 (26.8%)
374 (4.3%)
309 (3.5%)
N/A
N/A
2,604 (14.8%)
2,688 (15.3%)
-0.01
Lab values- LDL level (mg/dl) (within 6 months) ; n (%)
3,088 (34.8%)
3,177 (35.8%)
528 (6.1%)
402 (4.6%)
N/A
N/A
3,616 (20.6%)
3,579 (20.3%)
0.01
Lab values- NT-proBNP; n (%)
15 (0.2%)
12 (0.1%)
0 (0.0%)
2 (0.0%)
N/A
N/A
15 (0.1%)
0 (0.1%)
-
Lab values- NT-proBNP (within 3 months); n (%)
10 (0.1%)
6 (0.1%)
0 (0.0%)
1 (0.0%)
N/A
N/A
10 (0.1%)
0 (0.0%)
-
Lab values- NT-proBNP (within 6 months); n (%)
15 (0.2%)
12 (0.1%)
0 (0.0%)
2 (0.0%)
N/A
N/A
15 (0.1%)
14 (0.1%)
-
Lab values- Total cholesterol (mg/dl) ; n (%)
3,051 (34.4%)
3,149 (35.5%)
505 (5.8%)
404 (4.6%)
N/A
N/A
3,556 (20.2%)
3,553 (20.2%)
0.00
Lab values- Total cholesterol (mg/dl) (within 3 
months) ; n (%)
2,212 (24.9%)
2,352 (26.5%)
361 (4.1%)
311 (3.6%)
N/A
N/A
2,573 (14.6%)
2,663 (15.1%)
-0.01
Lab values- Total cholesterol (mg/dl) (within 6 
months) ; n (%)
3,051 (34.4%)
3,149 (35.5%)
505 (5.8%)
404 (4.6%)
N/A
N/A
3,556 (20.2%)
3,553 (20.2%)
0.00
Lab values- Triglyceride level (mg/dl); n (%)
3,015 (34.0%)
3,135 (35.3%)
500 (5.7%)
399 (4.6%)
N/A
N/A
3,515 (20.0%)
3,534 (20.1%)
0.00
Lab values- Triglyceride level (mg/dl) (within 3 
months); n (%)
2,190 (24.7%)
2,341 (26.4%)
355 (4.1%)
306 (3.5%)
N/A
N/A
2,545 (14.5%)
2,647 (15.0%)
-0.01
Lab values- Triglyceride level (mg/dl) (within 6 
months); n (%)
3,015 (34.0%)
3,135 (35.3%)
500 (5.7%)
399 (4.6%)
N/A
N/A
3,515 (20.0%)
3,534 (20.1%)
0.00
Lab result number- HbA1c (%) mean (only 2 to 20 
included) 
3,541
                                            
3,606
                                            
529
                                                
389
                                                
N/A
N/A                                              4,070                                              3,995 
...mean (sd)
8.14 (1.86)
8.00 (1.81)
8.11 (1.85)
7.88 (1.83)
N/A
N/A
8.14 (1.86)
7.99 (1.81)
0.08
...median [IQR]
7.70 [6.85, 9.04]
7.60 [6.70, 8.80]
7.60 [6.80, 9.00]
7.45 [6.60, 8.60]
N/A
N/A
7.69 (1.86)
7.59 (1.81)
0.05
...Missing; n (%)
5,339 (60.1%)
5,274 (59.4%)
8,187 (93.9%)
8,327 (95.5%)
N/A
N/A
13,526 (76.9%)
13,601 (77.3%)
-0.01
Lab result number- BNP mean 
75
                                                   
116
                                                
9
                                                      
11
                                                   
N/A
N/A                                                     84                                                  127 
...mean (sd)
182.81 (288.14)
199.85 (371.31)
209.22 (333.71)
607.19 (1,393.52)
N/A
N/A
185.64 (294.70)
235.13 (533.36)
-0.11
...median [IQR]
65.50 [32.60, 167.50]
82.60 [32.35, 208.35]
80.00 [47.00, 204.50]
49.00 [15.10, 188.00]
N/A
N/A
#VALUE!
#VALUE!
#VALUE!
...Missing; n (%)
8,805 (99.2%)
8,764 (98.7%)
8,707 (99.9%)
8,705 (99.9%)
N/A
N/A
17,512 (99.5%)
17,469 (99.3%)
0.03
Lab result number- BUN (mg/dl) mean 
                                             3,723                                              3,839                                                  534                                                  459 
N/A
N/A                                              4,257                                              4,298 
...mean (sd)
21.39 (9.92)
22.02 (10.30)
550.42 (9,028.78)
306.80 (6,067.08)
N/A
N/A
87.75 (3195.92)
52.43 (1981.24)
0.01
...median [IQR]
19.00 [15.00, 25.50]
19.50 [15.00, 27.00]
18.00 [13.50, 24.00]
18.50 [14.00, 26.00]
N/A
N/A
#VALUE!
#VALUE!
#VALUE!
...Missing; n (%)
5,157 (58.1%)
5,041 (56.8%)
8,182 (93.9%)
8,257 (94.7%)
N/A
N/A
13,339 (75.8%)
13,298 (75.6%)
0.00
Lab result number- Creatinine (mg/dl) mean (only 0.1 
to 15 included) 
                                             3,791                                              3,936                                                  520                                                  468 
N/A
N/A                                              4,311                                              4,404 
...mean (sd)
1.20 (0.50)
1.24 (0.51)
1.15 (0.52)
1.18 (0.61)
N/A
N/A
1.19 (0.50)
1.23 (0.52)
-0.08
...median [IQR]
1.08 [0.87, 1.41]
1.14 [0.88, 1.48]
1.00 [0.84, 1.36]
1.01 [0.84, 1.35]
N/A
N/A
1.07 (0.50)
1.13 (0.52)
-0.12
...Missing; n (%)
5,089 (57.3%)
4,944 (55.7%)
8,196 (94.0%)
8,248 (94.6%)
N/A
N/A
13,285 (75.5%)
13,192 (75.0%)
0.01
Lab result number- HDL level (mg/dl) mean (only 
=<5000 included) 
                                             2,999                                              3,087                                                  501                                                  396 
N/A
N/A                                              3,500                                              3,483 
...mean (sd)
45.64 (13.89)
46.51 (14.12)
43.93 (15.31)
51.64 (174.45)
N/A
N/A
45.40 (14.10)
47.09 (60.26)
-0.04
...median [IQR]
44.00 [36.00, 53.00]
44.50 [37.00, 54.00]
42.50 [35.00, 52.00]
41.00 [34.00, 52.00]
N/A
N/A
43.79 (14.10)
44.10 (60.26)
-0.01
...Missing; n (%)
5,881 (66.2%)
5,793 (65.2%)
8,215 (94.3%)
8,320 (95.5%)
N/A
N/A
14,096 (80.1%)
14,113 (80.2%)
0.00
Lab result number- LDL level (mg/dl) mean (only 
=<5000 included) 
                                             3,014                                              3,106                                                  481                                                  376 
N/A
N/A                                              3,495                                              3,482 
...mean (sd)
85.21 (41.48)
85.59 (40.41)
86.93 (43.78)
85.05 (45.50)
N/A
N/A
85.45 (41.81)
85.53 (40.99)
0.00
...median [IQR]
81.75 [60.00, 108.00]
82.75 [61.00, 109.00]
85.00 [62.00, 109.58]
84.50 [59.00, 111.38]
N/A
N/A
82.20 (41.81)
82.94 (40.99)
-0.02
...Missing; n (%)
5,866 (66.1%)
5,774 (65.0%)
8,235 (94.5%)
8,340 (95.7%)
N/A
N/A
14,101 (80.1%)
14,114 (80.2%)
0.00
Lab result number- Total cholesterol (mg/dl) mean 
(only =<5000 included) 
                                             3,048                                              3,148                                                  504                                                  402 
N/A
N/A                                              3,552                                              3,550 
...mean (sd)
172.69 (47.81)
173.80 (47.86)
173.39 (53.59)
173.95 (57.11)
N/A
N/A
172.79 (48.68)
173.82 (49.00)
-0.02
...median [IQR]
166.00 [141.00, 199.00]
166.00 [142.00, 197.50]
168.00 [143.00, 202.88]
170.00 [141.00, 205.00]
N/A
N/A
166.28 (48.68)
166.45 (49.00)
0.00
...Missing; n (%)
5,832 (65.7%)
5,732 (64.5%)
8,212 (94.2%)
8,314 (95.4%)
N/A
N/A
14,044 (79.8%)
14,046 (79.8%)
0.00
Lab result number- Triglyceride level (mg/dl) mean 
(only =<5000 included) 
                                             3,015                                              3,135                                                  499                                                  397 
N/A
N/A                                              3,514                                              3,532 
...mean (sd)
193.31 (156.70)
189.61 (172.97)
195.78 (174.50)
212.71 (232.81)
N/A
N/A
193.66 (159.37)
192.21 (180.70)
0.01
...median [IQR]
156.00 [112.00, 225.00]
152.00 [107.00, 222.00]
151.00 [105.00, 224.00]
159.00 [107.67, 235.00]
N/A
N/A
155.29 (159.37)
152.79 (180.70)
0.01
...Missing; n (%)
5,865 (66.0%)
5,745 (64.7%)
8,217 (94.3%)
8,319 (95.4%)
N/A
N/A
14,082 (80.0%)
14,064 (79.9%)
0.00
Table 1

Lab result number- Hemoglobin mean (only >0 
included)
                                             2,720                                              2,902                                                  370                                                  352 
N/A
N/A                                              3,090                                              3,254 
...mean (sd)
13.16 (1.75)
13.17 (1.73)
377.00 (7,000.31)
444.91 (8,100.93)
N/A
N/A
56.73 (2420.26)
59.87 (2661.83)
0.00
...median [IQR]
13.20 [11.90, 14.40]
13.20 [11.95, 14.40]
13.30 [12.00, 14.70]
13.30 [12.00, 14.54]
N/A
N/A
#VALUE!
#VALUE!
#VALUE!
...Missing; n (%)
6,160 (69.4%)
5,978 (67.3%)
8,346 (95.8%)
8,364 (96.0%)
N/A
N/A
14,506 (82.4%)
14,342 (81.5%)
0.02
Lab result number- Serum sodium mean (only > 90 
and < 190 included)
                                             3,702                                              3,832                                                  514                                                  457 
N/A
N/A                                              4,216                                              4,289 
...mean (sd)
139.51 (2.85)
139.59 (2.84)
139.02 (3.31)
139.09 (2.65)
N/A
N/A
139.45 (2.91)
139.54 (2.82)
-0.03
...median [IQR]
140.00 [138.00, 141.33]
140.00 [138.00, 141.50]
139.00 [137.50, 141.00]
139.33 [137.00, 141.00]
N/A
N/A
139.88 (2.91)
139.93 (2.82)
-0.02
...Missing; n (%)
5,178 (58.3%)
5,048 (56.8%)
8,202 (94.1%)
8,259 (94.8%)
N/A
N/A
13,380 (76.0%)
13,307 (75.6%)
0.01
Lab result number- Albumin mean (only >0 and <=10 
included)
                                             3,422                                              3,605                                                  447                                                  397 
N/A
N/A                                              3,869                                              4,002 
...mean (sd)
4.20 (0.35)
4.21 (0.36)
4.04 (0.76)
4.09 (0.71)
N/A
N/A
4.18 (0.42)
4.20 (0.41)
-0.05
...median [IQR]
4.20 [4.00, 4.40]
4.20 [4.00, 4.45]
4.15 [4.00, 4.40]
4.20 [4.00, 4.40]
N/A
N/A
4.19 (0.42)
4.20 (0.41)
-0.02
...Missing; n (%)
5,458 (61.5%)
5,275 (59.4%)
8,269 (94.9%)
8,319 (95.4%)
N/A
N/A
13,727 (78.0%)
13,594 (77.3%)
0.02
Lab result number- Glucose (fasting or random) mean 
(only 10-1000 included)
                                             3,684                                              3,829                                                  509                                                  456 
N/A
N/A                                              4,193                                              4,285 
...mean (sd)
171.75 (75.07)
164.58 (71.69)
171.74 (71.84)
166.42 (76.33)
N/A
N/A
171.75 (74.69)
164.78 (72.21)
0.09
...median [IQR]
153.00 [122.28, 201.33]
146.00 [118.50, 187.00]
152.50 [124.25, 198.50]
145.00 [121.12, 188.00]
N/A
N/A
152.94 (74.69)
145.89 (72.21)
0.10
...Missing; n (%)
5,196 (58.5%)
5,051 (56.9%)
8,207 (94.2%)
8,260 (94.8%)
N/A
N/A
13,403 (76.2%)
13,311 (75.6%)
0.01
Lab result number- Potassium mean (only 1-7 
included)
                                             3,791                                              3,927                                                  523                                                  449 
N/A
N/A                                              4,314                                              4,376 
...mean (sd)
4.49 (0.46)
4.49 (0.46)
4.34 (0.47)
4.37 (0.50)
N/A
N/A
4.47 (0.46)
4.48 (0.46)
-0.02
...median [IQR]
4.50 [4.20, 4.80]
4.50 [4.20, 4.80]
4.30 [4.00, 4.70]
4.40 [4.07, 4.70]
N/A
N/A
4.48 (0.46)
4.49 (0.46)
-0.02
...Missing; n (%)
5,089 (57.3%)
4,953 (55.8%)
8,193 (94.0%)
8,267 (94.8%)
N/A
N/A
13,282 (75.5%)
13,220 (75.1%)
0.01
Comorbidity Scores
CCI (180 days)- ICD9 and ICD10 
...mean (sd)
3.36 (2.08)
3.35 (2.10)
2.46 (1.88)
2.45 (1.86)
3.77 (2.14)
3.77 (2.11)
3.47 (2.09)
3.47 (2.07)
0.00
...median [IQR]
3.00 [2.00, 5.00]
3.00 [2.00, 5.00]
2.00 [1.00, 4.00]
2.00 [1.00, 4.00]
4.00 [2.00, 5.00]
4.00 [2.00, 5.00]
3.48 (2.09)
3.48 (2.07)
0.00
Frailty Score: Qualitative Version 365 days as 
Categories, v1
...0; n (%)
4,324 (48.7%)
4,263 (48.0%)
2,619 (30.0%)
2,596 (29.8%)
9,977 (29.9%)
9,686 (29.1%)
16,920 (33.2%)
16,545 (32.5%)
0.01
...1 to 2; n (%)
2,752 (31.0%)
2,873 (32.4%)
3,661 (42.0%)
3,717 (42.6%)
10,036 (30.1%)
10,218 (30.7%)
16,449 (32.3%)
16,808 (33.0%)
-0.01
...3 or more; n (%)
1,804 (20.3%)
1,744 (19.6%)
2,436 (27.9%)
2,403 (27.6%)
13,306 (39.9%)
13,415 (40.3%)
17,546 (34.5%)
17,562 (34.5%)
0.00
Frailty Score: Empirical Version 365 days as 
Categories, 
...< 0.12908; n (%)
1,119 (12.6%)
1,228 (13.8%)
1,240 (14.2%)
1,338 (15.4%)
1,500 (4.5%)
1,563 (4.7%)
3,859 (7.6%)
4,129 (8.1%)
-0.02
...0.12908 - 0.1631167; n (%)
2,577 (29.0%)
2,521 (28.4%)
2,640 (30.3%)
2,578 (29.6%)
5,589 (16.8%)
5,398 (16.2%)
10,806 (21.2%)
10,497 (20.6%)
0.01
...>= 0.1631167; n (%)
5,184 (58.4%)
5,131 (57.8%)
4,836 (55.5%)
4,800 (55.1%)
26,230 (78.7%)
26,358 (79.1%)
36,250 (71.2%)
36,289 (71.3%)
0.00
Non-Frailty; n (%)
4,985 (56.1%)
5,157 (58.1%)
4,680 (53.7%)
4,703 (54.0%)
1,469 (4.4%)
1,398 (4.2%)
11,134 (21.9%)
11,258 (22.1%)
0.00
Frailty Score (mean): Qualitative Version 365 days, v1
...mean (sd)
1.34 (1.92)
1.33 (1.90)
1.80 (1.89)
1.79 (1.89)
2.36 (2.43)
2.36 (2.39)
2.09 (2.26)
2.08 (2.23)
0.00
...median [IQR]
1.00 [0.00, 2.00]
1.00 [0.00, 2.00]
1.00 [0.00, 3.00]
1.00 [0.00, 3.00]
2.00 [0.00, 4.00]
2.00 [0.00, 4.00]
1.65 (2.26)
1.65 (2.23)
0.00
Frailty Score (mean): Empirical Version 365 days, 
...mean (sd)
0.19 (0.06)
0.18 (0.06)
0.17 (0.05)
0.17 (0.05)
0.21 (0.07)
0.21 (0.07)
0.20 (0.07)
0.20 (0.07)
0.00
...median [IQR]
0.17 [0.14, 0.21]
0.17 [0.14, 0.21]
0.16 [0.14, 0.20]
0.16 [0.14, 0.19]
0.20 [0.17, 0.25]
0.20 [0.17, 0.25]
0.19 (0.07)
0.19 (0.07)
0.00
Healthcare Utilization
Any hospitalization; n (%)
951 (10.7%)
916 (10.3%)
906 (10.4%)
897 (10.3%)
4,351 (13.1%)
4,278 (12.8%)
6,208 (12.2%)
6,091 (12.0%)
0.01
Any hospitalization within prior 30 days; n (%)
309 (3.5%)
317 (3.6%)
272 (3.1%)
263 (3.0%)
1,445 (4.3%)
1,387 (4.2%)
2,026 (4.0%)
1,967 (3.9%)
0.01
Any hospitalization during prior 31-180 days; n (%)
693 (7.8%)
651 (7.3%)
677 (7.8%)
677 (7.8%)
3,166 (9.5%)
3,174 (9.5%)
4,536 (8.9%)
4,502 (8.8%)
0.00
Endocrinologist Visit; n (%)
1,343 (15.1%)
1,478 (16.6%)
1,393 (16.0%)
1,466 (16.8%)
5,278 (15.8%)
5,440 (16.3%)
8,014 (15.7%)
8,384 (16.5%)
-0.02
Endocrinologist Visit (30 days prior); n (%)
991 (11.2%)
1,058 (11.9%)
1,024 (11.7%)
1,071 (12.3%)
3,820 (11.5%)
3,835 (11.5%)
5,835 (11.5%)
5,964 (11.7%)
-0.01
Endocrinologist Visit (31 to 180 days prior); n (%)
887 (10.0%)
950 (10.7%)
917 (10.5%)
947 (10.9%)
3,673 (11.0%)
3,706 (11.1%)
5,477 (10.8%)
5,603 (11.0%)
-0.01
Internal medicine/family medicine visits; n (%)
7,278 (82.0%)
7,050 (79.4%)
7,636 (87.6%)
7,551 (86.6%)
28,049 (84.2%)
27,792 (83.4%)
42,963 (84.4%)
42,393 (83.3%)
0.03
Internal medicine/family medicine visits (30 days 
prior) ; n (%)
5,304 (59.7%)
5,228 (58.9%)
5,717 (65.6%)
5,661 (64.9%)
20,249 (60.8%)
20,237 (60.7%)
31,270 (61.4%)
31,126 (61.1%)
0.01
Internal medicine/family medicine visits (31 to 180 
days prior) ; n (%)
6,220 (70.0%)
6,222 (70.1%)
6,651 (76.3%)
6,585 (75.6%)
24,952 (74.9%)
25,013 (75.1%)
37,823 (74.3%)
37,820 (74.3%)
0.00
Cardiologist visit; n (%)
3,365 (37.9%)
3,383 (38.1%)
2,819 (32.3%)
2,869 (32.9%)
14,336 (43.0%)
14,230 (42.7%)
20,520 (40.3%)
20,482 (40.2%)
0.00
Number of Cardiologist visits (30 days prior); n (%)
1,244 (14.0%)
1,238 (13.9%)
963 (11.0%)
974 (11.2%)
4,841 (14.5%)
4,850 (14.6%)
7,048 (13.8%)
7,062 (13.9%)
0.00
Number of Cardiologist visits (31 to 180 days prior); 
n (%)
2,851 (32.1%)
2,880 (32.4%)
2,408 (27.6%)
2,477 (28.4%)
12,553 (37.7%)
12,531 (37.6%)
17,812 (35.0%)
17,888 (35.1%)
0.00
Electrocardiogram ; n (%)
3,280 (36.9%)
3,359 (37.8%)
3,176 (36.4%)
3,230 (37.1%)
13,574 (40.7%)
13,706 (41.1%)
20,030 (39.3%)
20,295 (39.9%)
-0.01
Use of glucose test strips; n (%)
423 (4.8%)
427 (4.8%)
410 (4.7%)
399 (4.6%)
1,375 (4.1%)
1,338 (4.0%)
2,208 (4.3%)
2,164 (4.3%)
0.00
Dialysis; n (%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
000 (0.0%)
000 (0.0%)
#DIV/0!
Naive new user  ; n (%)
2,349 (26.5%)
2,521 (28.4%)
2,348 (26.9%)
2,409 (27.6%)
7,673 (23.0%)
8,355 (25.1%)
12,370 (24.3%)
13,285 (26.1%)
-0.04
Table 1

N antidiabetic drugs at index date  
...mean (sd)
1.76 (0.70)
1.75 (0.68)
1.77 (0.72)
1.77 (0.70)
1.73 (0.70)
1.73 (0.67)
1.74 (0.70)
1.74 (0.68)
0.00
...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 (0.70)
2.00 (0.68)
0.00
number of different/distinct medication 
prescriptions
...mean (sd)
11.06 (5.30)
11.07 (5.36)
10.74 (5.13)
10.66 (5.07)
11.45 (5.09)
11.45 (5.01)
11.26 (5.13)
11.25 (5.08)
0.00
...median [IQR]
10.00 [7.00, 14.00]
10.00 [7.00, 14.00]
10.00 [7.00, 13.00]
10.00 [7.00, 14.00]
11.00 [8.00, 14.00]
11.00 [8.00, 14.00]
10.65 (5.13)
10.65 (5.08)
0.00
Number of Hospitalizations
...mean (sd)
0.13 (0.41)
0.13 (0.41)
0.12 (0.38)
0.12 (0.39)
0.17 (0.48)
0.16 (0.48)
0.15 (0.45)
0.15 (0.45)
0.00
...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 (0.45)
0.00 (0.45)
0.00
Number of hospital days
...mean (sd)
0.65 (2.51)
0.67 (2.66)
0.63 (2.74)
0.66 (2.86)
1.03 (3.87)
1.02 (3.97)
0.90 (3.49)
0.90 (3.60)
0.00
...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 (3.49)
0.00 (3.60)
0.00
Number of Emergency Department (ED) visits 
...mean (sd)
0.50 (1.18)
0.49 (1.40)
0.19 (1.07)
0.19 (1.26)
0.63 (1.43)
0.63 (1.44)
0.53 (1.33)
0.53 (1.40)
0.00
...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 (1.33)
0.00 (1.40)
0.00
Number of Office visits
...mean (sd)
5.54 (4.50)
5.53 (4.36)
5.93 (5.53)
5.86 (4.31)
6.33 (4.88)
6.36 (4.75)
6.12 (4.93)
6.13 (4.61)
0.00
...median [IQR]
4.00 [2.00, 7.00]
5.00 [3.00, 7.00]
5.00 [3.00, 8.00]
5.00 [3.00, 8.00]
5.00 [3.00, 9.00]
5.00 [3.00, 9.00]
4.83 (4.93)
5.00 (4.61)
-0.04
Number of Endocrinologist visits
...mean (sd)
0.69 (2.65)
0.80 (2.89)
0.72 (2.77)
0.83 (3.11)
0.94 (3.83)
0.94 (3.69)
0.86 (3.48)
0.90 (3.47)
-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 (3.48)
0.00 (3.47)
0.00
Number of internal medicine/family medicine visits
...mean (sd)
10.20 (14.44)
9.35 (14.18)
7.99 (10.52)
7.84 (10.00)
8.97 (12.50)
8.98 (11.60)
9.02 (12.55)
8.85 (11.84)
0.01
...median [IQR]
6.00 [2.00, 13.00]
5.00 [1.00, 12.00]
5.00 [2.00, 10.00]
5.00 [2.00, 10.00]
5.00 [2.00, 12.00]
6.00 [2.00, 12.00]
5.17 (12.55)
5.65 (11.84)
-0.04
Number of Cardiologist visits
...mean (sd)
1.85 (4.06)
1.95 (4.53)
1.46 (3.59)
1.47 (3.43)
2.25 (5.02)
2.33 (5.16)
2.04 (4.64)
2.12 (4.80)
-0.02
...median [IQR]
0.00 [0.00, 2.00]
0.00 [0.00, 2.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 2.00]
0.00 [0.00, 2.00]
0.00 (4.64)
0.00 (4.80)
0.00
Number electrocardiograms received 
...mean (sd)
0.76 (1.49)
0.76 (1.50)
0.68 (1.29)
0.67 (1.22)
0.86 (1.52)
0.86 (1.50)
0.81 (1.48)
0.81 (1.46)
0.00
...median [IQR]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 (1.48)
0.00 (1.46)
0.00
Number of HbA1c tests ordered
...mean (sd)
1.31 (0.95)
1.30 (0.94)
0.99 (0.95)
0.98 (0.93)
1.47 (1.03)
1.47 (0.91)
1.36 (1.00)
1.36 (0.92)
0.00
...median [IQR]
1.00 [1.00, 2.00]
1.00 [1.00, 2.00]
1.00 [0.00, 2.00]
1.00 [0.00, 2.00]
1.00 [1.00, 2.00]
1.00 [1.00, 2.00]
1.00 (1.00)
1.00 (0.92)
0.00
Number of glucose tests ordered
...mean (sd)
0.80 (6.63)
0.93 (7.31)
0.49 (2.13)
0.49 (1.26)
0.55 (1.52)
0.57 (1.31)
0.58 (3.16)
0.62 (3.27)
-0.01
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 1.00]
0.00 [0.00, 0.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 (3.16)
0.00 (3.27)
0.00
Number of lipid tests ordered
...mean (sd)
1.04 (1.03)
1.03 (1.00)
0.85 (1.36)
0.86 (1.33)
1.08 (0.95)
1.08 (0.89)
1.03 (1.05)
1.03 (1.00)
0.00
...median [IQR]
1.00 [0.00, 2.00]
1.00 [0.00, 2.00]
1.00 [0.00, 1.00]
1.00 [0.00, 1.00]
1.00 [0.00, 2.00]
1.00 [0.00, 2.00]
1.00 (1.05)
1.00 (1.00)
0.00
Number of creatinine tests ordered
...mean (sd)
0.06 (0.33)
0.07 (0.47)
0.07 (0.44)
0.07 (0.58)
0.10 (0.47)
0.09 (0.40)
0.09 (0.44)
0.08 (0.45)
0.02
...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 (0.44)
0.00 (0.45)
0.00
Number of BUN tests ordered
...mean (sd)
0.04 (0.27)
0.04 (0.38)
0.04 (0.38)
0.05 (0.58)
0.06 (0.39)
0.06 (0.32)
0.05 (0.37)
0.05 (0.39)
0.00
...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 (0.37)
0.00 (0.39)
0.00
Number of tests for microalbuminuria
...mean (sd)
0.89 (1.29)
0.87 (1.32)
0.58 (1.12)
0.57 (1.04)
0.56 (0.85)
0.56 (0.84)
0.62 (0.99)
0.62 (0.98)
0.00
...median [IQR]
0.00 [0.00, 2.00]
0.00 [0.00, 2.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.00 (0.99)
0.00 (0.98)
0.00
Total N distinct ICD9/ICD10 diagnoses at the 3rd 
digit level 
...mean (sd)
7.43 (8.69)
7.35 (8.77)
2.83 (5.33)
2.85 (5.39)
7.78 (9.41)
7.69 (9.43)
6.87 (8.72)
6.80 (8.75)
0.01
...median [IQR]
5.00 [0.00, 11.00]
5.00 [0.00, 11.00]
0.00 [0.00, 4.00]
0.00 [0.00, 4.00]
5.00 [0.00, 12.00]
5.00 [0.00, 12.00]
4.14 (8.72)
4.14 (8.75)
0.00
Use of thiazide; n (%)
1,042 (11.7%)
1,075 (12.1%)
1,002 (11.5%)
1,005 (11.5%)
4,626 (13.9%)
4,591 (13.8%)
6,670 (13.1%)
6,671 (13.1%)
0.00
Use of beta blockers; n (%)
4,537 (51.1%)
4,527 (51.0%)
4,436 (50.9%)
4,413 (50.6%)
19,108 (57.3%)
19,031 (57.1%)
28,081 (55.2%)
27,971 (54.9%)
0.01
Use of calcium channel blockers; n (%)
2,943 (33.1%)
3,037 (34.2%)
2,769 (31.8%)
2,780 (31.9%)
13,117 (39.4%)
12,995 (39.0%)
18,829 (37.0%)
18,812 (36.9%)
0.00
Table 1