Data Analysis for Drug Repurposing for Effective Alzheimer's Medicines (DREAM)- Semaglutide v DPP4 Inhibitors
Conditions: Diabetes
Sponsor: Brigham and Women's Hospital

Data Analysis for Drug Repurposing for Effective 
Alzheimer’s Medicines – Semaglutide vs DPP4 Inhibitors 
 
 
NCT05768945 
 
 
July 7, 2023 
 

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
1 
1. Comparison Details 
 
a. Intended aim(s) 
 
To evaluate the comparative risk of dementia onset between patients treated with Semaglutide v DPP4 inhibitors 
in patients with diabetes 
 
b. Primary endpoint  
Incident dementia (i.e., Alzheimer’s disease, vascular dementia, senile, presenile, or unspecified dementia, or 
dementia in other diseases classified elsewhere). 
 
2. Person responsible for implementation of replication in Aetion 
Mufaddal Mahesri 
 
3. Data Source(s) 
Medicare, 2008-2019 
 
 

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DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
4 
5. Cohort Identification  
 
a. Cohort Summary 
This study will employ a new user, active comparator, observational cohort study design comparing Semaglutide v 
DPP4 inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin). The patients will be required to have continuous 
enrollment during the baseline period of 365 days before initiation of study drugs (index date). Follow-up for the 
outcome (dementia) differs between analyses. Follow-up begins the day after drug initiation (analysis 1, 3, 4); 180 
days after drug initiation (analysis 2). 
 
b. Key details regarding cohort creation 
 
Index date: 
• Day of initiation of new Semaglutide or DPP4 inhibitors 
 
Inclusion criteria for analyses 1, 3, 4: 
• Aged > 65 years on the index date 
• 365 days enrollment in Medicare Parts A, B, and D with no HMO coverage 
• No use of any GLP receptor agonists (semaglutide, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide) 
or DPP4 inhibitors 
• No use of Semaglutide or DPP4 inhibitors concomitantly on index date 
• No diagnosis of dementia any time prior to and including index date 
• Diagnosis code for type 2 diabetes recorded in 365 days prior to index date 
 
Inclusion criteria for analysis 2: 
• Aged > 65 years on the index date 
• 365 days enrollment in Medicare Parts A, B, and D with no HMO coverage 
• No use of any GLP receptor agonists (semaglutide, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide) 
or DPP4 inhibitors 
• No use of Semaglutide or DPP4 inhibitors concomitantly on index date 
• No diagnosis of dementia any time prior to and including index date 
• Diagnosis code for type 2 diabetes recorded in 365 days prior to index date 
• 180-day continuous use of Semaglutide or DPP4 inhibitors starting on the index date 

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
5 
 
Flowchart of the study cohort assembly 
 
 
  
Less Excluded Patients 
Remaining Patients 
All patients 
  
27,099,355 
Did not meet cohort entry criteria 
-24,529,389 
2,569,966 
Excluded due to insufficient enrollment 
-900,367 
1,669,599 
Excluded due to prior use of referent 
-828,655 
840,944 
Excluded due to prior use of exposure 
-20,252 
820,692 
Excluded because patient qualified in >1 exposure 
category 
-7 
820,685 
Excluded based on Dementia Exclusion  
-26,498 
794,187 
Excluded based on Nursing home admission  
-23,376 
770,811 
Excluded based on Semaglutide OR DPP4i  
-15,281 
755,530 
Excluded based on Semaglutide AND DPP4i 
concomitantly on index date  
0 
755,530 
Excluded based on GLP-1 RA (except Semaglutide)  
-8,231 
747,299 
Excluded based on Diabetes  
-3,306 
743,993 
Excluded based on Age <65 
-1,323 
742,670 
Final cohort 
  
742,670 
 
 
 
 

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
6 
6. Variables  
 
a. Exposure-related variables:  
 
Study drug:  
The study exposure of interest is initiation of Semaglutide 
 
Comparator: 
Initiation of DPP4 inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin) 
 
b. Covariates: 
 
Demographics 
Age 
Region 
Gender 
Calendar year of index date 
Race 
Low income subsidy 
 
 
Dementia risk factors 
Diabetes 
Anxiety 
Obesity 
Bipolar disorder 
Coronary artery disease 
Schizophrenia 
Depression 
 
 
Markers for healthy behavior, frailty, healthcare use 
Smoking 
Number of hospitalizations  
Mammography 
Number of physician office visits 
Colonoscopy 
Number of serum creatinine tests ordered 
Fecal occult blood test 
Composite frailty score 
Influenza vaccination 
Number of C-reactive protein tests ordered 
Pneumococcal vaccination 
Osteoporosis 
Herpes zoster vaccination 
Fractures 

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
7 
Bone mineral density test 
Falls 
Number of distinct generic agents 
Use of supplemental oxygen 
Number of emergency room visits 
Combined comorbidity score 
Number of outpatient visits 
 
 
Comedication use 
Lithium 
Nitrates 
Anti-epileptic mood stabilizers 
Lipid lowering drugs 
Anti-epileptics (other than mood stabilizers) 
Non-insulin diabetes medications 
Atypical antipsychotics 
Insulin 
Benzodiazepines 
Antidepressants 
Serotonin-norepinephrine reuptake Inhibitors 
Typical antipsychotics 
Selective serotonin reuptake inhibitors 
Anticoagulants 
Tricyclic antidepressants (TCAs) 
Antiplatelet agents 
 
Comorbid conditions 
Atrial fibrillation 
Chronic liver disease 
Coronary artery disease 
Asthma 
Heart failure 
Ischemic heart disease 
Stroke or transient ischemic attack 
Chronic obstructive pulmonary disease 
Peripheral vascular disease 
Malignancy 
Hyperlipidemia 
Drug or alcohol abuse or dependence 
Renal dysfunction 
Venous thromboembolism 
 
Diabetes-related conditions and treatments 
Diabetic nephropathy 
Hyperglycemia 
Diabetes with peripheral circulatory disorders  
Hypoglycemia 
Diabetic foot  
Diabetes with other ophthalmic conditions or 
ophthalmic procedures 
Diabetic neuropathy  
Diabetic retinopathy 
Insulin 
Number of oral hypoglycemic agents 
SGLT2 inhibitors 
Metformin  

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
8 
Sulfonylureas 
 
 
 
ICD-9, ICD-10, HCPCS, and NDC codes used to define the covariates listed above are available in Appendix A. 
 
c. Outcome variables and study follow-up:  
• Primary outcome: incident dementia, i.e., Alzheimer’s disease, vascular dementia, senile, presenile, or 
unspecified dementia, or dementia in other diseases classified elsewhere. Outcome will be defined by 1 inpatient 
claim or 2 outpatient claims in analysis 1, 2, 3. In analysis 4, the outcome will be defined by 1 inpatient or 1 
outpatient claims and 1 prescription claim for a symptomatic treatment [donepezil, galantamine, rivastigmine, and 
memantine] within 6 months of each other with outcome date assigned to second event in the sequence.  
• Secondary outcomes: Individual component: 
Alzheimer’s disease 
 
Condition 
ICD-9 and ICD-10 codes 
Alzheimer’s disease 
331.0*, F00*, G30* 
Vascular dementia 
290.4*, F01* 
Senile, presenile, or unspecified dementia 
290.0*, 290.1*. 290.3*, 797*, F03* 
Dementia in other diseases classified elsewhere 
331.1*, 331.2*, 331.7*, 294.1*, F02* 
 
For analysis 1,3, and 4 the follow-up will start the day after initiation of Propranolol and Carvedilol and Atenolol, 
Bisoprolol, Sotalol and will continue until the earliest date of the following events: 
• The first occurrence of the outcome of interest  
• The date of end of continuous registration in the database, 
• End of the study period, 
• Measured death event occurs, 
• The date of drug discontinuation, defined as the date of the last continuous treatment episode of the index drug 
(Propranolol and Carvedilol  and hydrochlorothiazide) plus a defined grace period (i.e., 90 days after the end of 
the last prescription’s days’ supply in main analyses). 
 
For analysis 2, the follow-up will start 180 days after initiation of Propranolol and Carvedilol  and Atenolol, Bisoprolol, 
Sotalol 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,  

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
9 
• The date of end of continuous registration in the database, 
• End of the study period, 
• Measured death event occurs, 
• 
Maximum allowed follow-up time (1095 days) reached 
 
 
 

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
10 
7. Propensity score analysis  
We will use a propensity-score (PS)1-based approach to account for measured confounding in this study. The PS 
will be calculated as the predicted probability of initiating the exposure of interest (i.e., the repurposing candidate) 
versus the reference drug conditional on baseline covariates using multivariable logistic regression constructed 
separately in each data source. On average, patients with similar PSs have similar distribution of potential 
confounders used to estimate the PS. Therefore, analyses conditioned on the PS provide effect estimates that are 
free from measured confounding. For all our analyses, initiators of each exposure of interest will be matched with 
initiators of the reference exposure based on their PS within each data source.2 Pair matching will be conducted 
using a nearest-neighbor algorithm, which seeks to minimize the distance between propensity scores in each pair 
of treated and reference patients,3 and a caliper of 0.025 on the natural scale of the PS will be used to ensure 
similarity between the matched patients.4  
 
We report multiple diagnostics for PS analysis in this protocol. First, the PS distributional overlap is provided 
between two groups before and after matching to ensure comparability of these groups.5 Next, balance in each 
individual covariate between two treatment groups is reported using standardized differences.6  
 
 
 
 
 
 
 
 
 
 

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
11 
8. Table for covariate balance 
  
Crude 
  
PS-Matched 
Variable 
DPP4 inhibitors 
Semaglutide 
St. Diff 
DPP4 inhibitors 
Semaglutide 
St. Diff 
(N = 733,597) 
(N = 9,073) 
(N = 7,129) 
(N = 7,129) 
Demographics 
  
  
  
  
  
  
 Age, mean (SD)  
73.86 (6.38) 
70.64 (4.50) 
0.58 
70.70 (4.65) 
70.71 (4.52) 
0.00 
 Gender, n (%)  
  
  
  
  
  
  
 Male  
332,762 (45.4%) 
4,626 (51.0%) 
-0.11 
3,787 (53.1%) 
3,723 (52.2%) 
0.02 
 Female  
400,835 (54.6%) 
4,447 (49.0%) 
0.11 
3,342 (46.9%) 
3,406 (47.8%) 
-0.02 
 Race, n (%)  
  
  
  
  
  
  
 White  
549,974 (75.0%) 
7,530 (83.0%) 
-0.20 
5,968 (83.7%) 
5,943 (83.4%) 
0.01 
 Black  
79,047 (10.8%) 
754 (8.3%) 
0.09 
531 (7.4%) 
547 (7.7%) 
-0.01 
 Hispanic  
34,368 (4.7%) 
152 (1.7%) 
0.17 
116 (1.6%) 
130 (1.8%) 
-0.02 
Asian 
39,243 (5.3%) 
166 (1.8%) 
0.19 
141 (2.0%) 
131 (1.8%) 
0.01 
North American Native 
4,451 (0.6%) 
58 (0.6%) 
0.00 
44 (0.6%) 
44 (0.6%) 
0.00 
Other 
3,170 (42.4%) 
8,009 (38.2%) 
0.09 
132 (1.9%) 
139 (1.9%) 
0.00 
Unknown 
6,409 (0.9%) 
244 (2.7%) 
-0.14 
197 (2.8%) 
195 (2.7%) 
0.01 
 Region, n (%)  
  
  
  
  
  
  
 Northeast; n (%)  
145,176 (19.8%) 
1,522 (16.8%) 
0.08 
1,166 (16.4%) 
1,199 (16.8%) 
-0.01 
 South; n (%)  
304,574 (41.5%) 
4,189 (46.2%) 
-0.09 
3,324 (46.6%) 
3,276 (46.0%) 
0.01 
 Midwest; n (%)  
147,562 (20.1%) 
2,017 (22.2%) 
-0.05 
1,579 (22.1%) 
1,576 (22.1%) 
0.00 
 West; n (%)  
133,760 (18.2%) 
1,338 (14.7%) 
0.09 
1,060 (14.9%) 
1,078 (15.1%) 
-0.01 
Other; n (%) 
2,525 (0.3%) 
7 (0.1%) 
0.04 
  
  
  
Calendar year of index date, n (%) 
  
  
  
  
  
  
2008 
60,272 (8.2%) 
0 (0.0%) 
0.42 
  
  
  

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
12 
2009 
50,311 (6.9%) 
0 (0.0%) 
0.39 
  
  
  
2010 
57,738 (7.9%) 
0 (0.0%) 
0.41 
  
  
  
2011 
79,980 (10.9%) 
0 (0.0%) 
0.49 
  
  
  
2012 
70,365 (9.6%) 
0 (0.0%) 
0.46 
  
  
  
2013 
67,605 (9.2%) 
0 (0.0%) 
0.45 
  
  
  
2014 
70,773 (9.6%) 
0 (0.0%) 
0.46 
  
  
  
2015 
69,656 (9.5%) 
0 (0.0%) 
0.46 
  
  
  
2016 
61,194 (8.3%) 
0 (0.0%) 
0.43 
  
  
  
2017 
54,490 (7.4%) 
0 (0.0%) 
0.40 
  
  
  
2018 
48,195 (6.6%) 
1,425 (15.7%) 
-0.29 
1,138 (16.0%) 
1,174 (16.5%) 
-0.01 
2019 
43,018 (5.9%) 
7,648 (84.3%) 
-2.56 
5,991 (84.0%) 
5,955 (83.5%) 
0.01 
Low income subsidy, n (%) 
242,009 (33.0%) 
1,453 (16.0%) 
0.40 
1,091 (15.3%) 
1,096 (15.4%) 
0.00 
Dementia risk factors, n (%) 
  
  
  
  
  
  
Anxiety 
73,447 (10.0%) 
1,442 (15.9%) 
-0.18 
1,073 (15.1%) 
1,094 (15.3%) 
-0.01 
Bipolar disorder 
7,036 (1.0%) 
171 (1.9%) 
-0.08 
145 (2.0%) 
131 (1.8%) 
0.01 
Coronary artery disease 
247,844 (33.8%) 
3,362 (37.1%) 
-0.07 
2,578 (36.2%) 
2,527 (35.4%) 
0.02 
Depression 
89,683 (12.2%) 
1,708 (18.8%) 
-0.18 
1,362 (19.1%) 
1,335 (18.7%) 
0.01 
Hypertension 
685,085 (93.4%) 
8,478 (93.4%) 
0.00 
6,618 (92.8%) 
6,650 (93.3%) 
-0.02 
Obesity 
151,074 (20.6%) 
5,280 (58.2%) 
-0.83 
4,030 (56.5%) 
4,005 (56.2%) 
0.01 
Schizophrenia 
3,974 (0.5%) 
22 (0.2%) 
0.05 
20 (0.3%) 
15 (0.2%) 
0.02 
Markers for healthy behavior, 
frailty, healthcare use 
  
  
  
  
  
  
Bone mineral density test, n (%) 
500 (0.1%) 
3 (0.0%) 
0.04 
  
  
  
Colonoscopy, n (%) 
78,537 (10.7%) 
1,150 (12.7%) 
-0.06 
918 (12.9%) 
932 (13.1%) 
-0.01 
Fecal occult blood test, n (%) 
61,356 (8.4%) 
624 (6.9%) 
0.06 
504 (7.1%) 
505 (7.1%) 
0.00 
Influenza vaccination, n (%) 
451,885 (61.6%) 
6,603 (72.8%) 
-0.24 
5,224 (73.3%) 
5,207 (73.0%) 
0.01 

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
13 
Mammography, n (%) 
132,978 (18.1%) 
2,410 (26.6%) 
-0.21 
1,843 (25.9%) 
1,886 (26.5%) 
-0.01 
Pneumococcal vaccination, n (%) 
195,654 (26.7%) 
6,598 (72.7%) 
-1.04 
5,223 (73.3%) 
5,204 (73.0%) 
0.01 
Smoking, n (%) 
119,053 (16.2%) 
2,419 (26.7%) 
-0.26 
1,979 (27.8%) 
1,870 (26.2%) 
0.04 
Number of C-reactive protein tests 
ordered, mean (SD) 
0.18 (0.72) 
0.22 (0.77) 
-0.05 
0.23 (0.84) 
0.21 (0.77) 
0.02 
Number of emergency room visits, 
mean (SD) 
1.03 (2.27) 
0.90 (1.92) 
0.06 
0.90 (1.83) 
0.86 (1.87) 
0.02 
Number of distinct prescriptions, 
mean (SD) 
13.30 (6.08) 
14.31 (5.94) 
-0.17 
14.23 (6.01) 
14.12 (5.78) 
0.02 
Number of hospitalizations, mean 
(SD) 
0.33 (0.81) 
0.22 (0.60) 
0.15 
0.21 (0.58) 
0.20 (0.58) 
0.02 
Number of outpatient visits, mean 
(SD) 
13.79 (18.06) 
13.28 (12.00) 
0.03 
12.63 (10.86) 
12.89 (11.82) 
-0.02 
Number of physician office visits, 
mean (SD) 
5.71 (11.87) 
4.19 (6.75) 
0.16 
4.02 (5.15) 
4.16 (6.51) 
-0.02 
Number of serum creatinine tests 
ordered, mean (SD) 
3.83 (3.16) 
3.86 (3.10) 
-0.01 
3.76 (2.83) 
3.73 (2.90) 
0.01 
Composite frailty score, mean (SD) 
0.19 (0.06) 
0.18 (0.05) 
0.18 
0.18 (0.05) 
0.18 (0.05) 
0.00 
Falls, n (%) 
27,171 (3.7%) 
342 (3.8%) 
-0.01 
255 (3.6%) 
255 (3.6%) 
0.00 
Fractures, n (%) 
39,262 (5.4%) 
425 (4.7%) 
0.03 
358 (5.0%) 
330 (4.6%) 
0.02 
Osteoporosis, n (%) 
79,507 (10.8%) 
663 (7.3%) 
0.12 
490 (6.9%) 
504 (7.1%) 
-0.01 
Use of supplemental oxygen, n (%) 
9,663 (1.3%) 
152 (1.7%) 
-0.03 
119 (1.7%) 
106 (1.5%) 
0.02 
Combined comorbidity score, 
mean (SD) 
3.84 (2.69) 
3.94 (2.39) 
-0.04 
3.85 (2.42) 
3.79 (2.32) 
0.03 
Comedication use, n (%) 
  
  
  
  
  
  
Antidepressants 
176,510 (24.1%) 
3,019 (33.3%) 
-0.20 
2,333 (32.7%) 
2,327 (32.6%) 
0.00 

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
14 
Insulin 
115,136 (15.7%) 
3,377 (37.2%) 
-0.50 
2,149 (30.1%) 
2,150 (30.2%) 
0.00 
Lipid lowering drugs 
588,438 (80.2%) 
7,697 (84.8%) 
-0.12 
6,125 (85.9%) 
6,125 (85.9%) 
0.00 
Nitrates 
84,367 (11.5%) 
903 (10.0%) 
0.05 
639 (9.0%) 
639 (9.0%) 
0.00 
Non-insulin diabetes medications 
733,349 (100.0%) 
7,192 (79.3%) 
0.72 
7,008 (98.3%) 
6,982 (97.9%) 
0.03 
Anticoagulants 
81,608 (11.1%) 
1,131 (12.5%) 
-0.04 
914 (12.8%) 
850 (11.9%) 
0.03 
Anti-epileptic mood stabilizers 
7,321 (1.0%) 
109 (1.2%) 
-0.02 
98 (1.4%) 
81 (1.1%) 
0.03 
Antiplatelet agents 
113,790 (15.5%) 
1,195 (13.2%) 
0.07 
888 (12.5%) 
878 (12.3%) 
0.01 
Atypical antipsychotics 
13,218 (1.8%) 
162 (1.8%) 
0.00 
130 (1.8%) 
126 (1.8%) 
0.00 
Benzodiazepines 
60,389 (8.2%) 
1,198 (13.2%) 
-0.16 
880 (12.3%) 
898 (12.6%) 
-0.01 
Lithium 
797 (0.1%) 
11 (0.1%) 
0.00 
12 (0.2%) 
7 (0.1%) 
0.03 
Anti-epileptics (other than mood 
stabilizers) 
122,311 (16.7%) 
2,188 (24.1%) 
-0.18 
1,629 (22.9%) 
1,619 (22.7%) 
0.00 
Serotonin-norepinephrine 
reuptake inhibitors 
34,437 (4.7%) 
854 (9.4%) 
-0.18 
659 (9.2%) 
640 (9.0%) 
0.01 
Selective serotonin reuptake 
inhibitors 
106,415 (14.5%) 
1,658 (18.3%) 
-0.10 
1,269 (17.8%) 
1,291 (18.1%) 
-0.01 
Tricyclic antidepressants (TCAs) 
30,159 (4.1%) 
338 (3.7%) 
0.02 
262 (3.7%) 
261 (3.7%) 
0.00 
Typical antipsychotics 
3,027 (0.4%) 
9 (0.1%) 
0.06 
8 (0.1%) 
8 (0.1%) 
0.00 
Diabetes-related conditions and 
treatments 
  
  
  
  
  
  
Diabetic nephropathy, n(%) 
100,928 (13.8%) 
2,315 (25.5%) 
-0.30 
1,694 (23.8%) 
1,631 (22.9%) 
0.02 
Diabetic foot, n (%) 
27,182 (3.7%) 
446 (4.9%) 
-0.06 
329 (4.6%) 
324 (4.5%) 
0.00 
Diabetes with peripheral 
circulatory disorders, n (%) 
72,825 (9.9%) 
1,214 (13.4%) 
-0.11 
915 (12.8%) 
894 (12.5%) 
0.01 
Diabetic neuropathy, n (%) 
164,659 (22.4%) 
3,201 (35.3%) 
-0.29 
2,318 (32.5%) 
2,348 (32.9%) 
-0.01 

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
15 
Diabetes with other ophthalmic 
manifestations, n(%) 
41,657 (5.7%) 
302 (3.3%) 
0.12 
225 (3.2%) 
218 (3.1%) 
0.01 
Diabetic retinopathy, n (%) 
88,446 (12.1%) 
1,506 (16.6%) 
-0.13 
996 (14.0%) 
1,040 (14.6%) 
-0.02 
Hypoglycemia, n(%) 
38,577 (5.3%) 
1,373 (15.1%) 
-0.33 
1,029 (14.4%) 
1,031 (14.5%) 
0.00 
Hyperglycemia, n(%) 
50,598 (6.9%) 
785 (8.7%) 
-0.07 
575 (8.1%) 
596 (8.4%) 
-0.01 
SGLT-2, n (%) 
16,992 (2.3%) 
1,721 (19.0%) 
-0.56 
1,386 (19.4%) 
1,368 (19.2%) 
0.01 
Number of antidiabetic drugs, 
mean (SD) 
2.68 (0.87) 
2.77 (0.94) 
-0.10 
2.97 (0.91) 
2.95 (0.84) 
0.02 
Number of Endocrinologist visits, 
mean (SD) 
0.42 (1.34) 
0.85 (1.81) 
-0.27 
0.72 (1.97) 
0.73 (1.60) 
-0.01 
Comorbid conditions, n (%) 
  
  
  
  
  
  
Atrial fibrillation 
99,884 (13.6%) 
1,156 (12.7%) 
0.03 
929 (13.0%) 
877 (12.3%) 
0.02 
Asthma 
90,872 (12.4%) 
1,936 (21.3%) 
-0.24 
1,467 (20.6%) 
1,452 (20.4%) 
0.00 
Chronic obstructive pulmonary 
disease 
140,603 (19.2%) 
1,619 (17.8%) 
0.04 
1,242 (17.4%) 
1,232 (17.3%) 
0.00 
Chronic liver disease 
53,335 (7.3%) 
1,035 (11.4%) 
-0.14 
829 (11.6%) 
800 (11.2%) 
0.01 
Drug or alcohol abuse or 
dependence 
52,626 (7.2%) 
862 (9.5%) 
-0.08 
757 (10.6%) 
664 (9.3%) 
0.04 
Heart failure 
128,305 (17.5%) 
1,364 (15.0%) 
0.07 
1,047 (14.7%) 
952 (13.4%) 
0.04 
Hyperlipidemia 
651,070 (88.8%) 
8,284 (91.3%) 
-0.08 
6,475 (90.8%) 
6,499 (91.2%) 
-0.01 
Ischemic heart disease 
272,351 (37.1%) 
3,292 (36.3%) 
0.02 
2,523 (35.4%) 
2,475 (34.7%) 
0.01 
Malignancy 
171,748 (23.4%) 
2,269 (25.0%) 
-0.04 
1,797 (25.2%) 
1,781 (25.0%) 
0.00 
Peripheral vascular disease 
118,434 (16.1%) 
1,212 (13.4%) 
0.08 
881 (12.4%) 
877 (12.3%) 
0.00 
Renal dysfunction 
201,317 (27.4%) 
2,586 (28.5%) 
-0.02 
1,859 (26.1%) 
1,816 (25.5%) 
0.01 
Stroke or transient ischemic attack 
51,898 (7.1%) 
452 (5.0%) 
0.09 
358 (5.0%) 
337 (4.7%) 
0.01 
Venous thromboembolism 
26,903 (3.7%) 
304 (3.4%) 
0.02 
249 (3.5%) 
229 (3.2%) 
0.02 

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
16 
9. Statistical analysis plans 
Incidence rates for the outcome will be estimated for the treatment and reference groups before and after PS matching. 
The competing risk of death could be of concern for the current set of analyses if mortality is frequent among patients 
included in the cohort and if differences in the risk of mortality between treatment and reference groups are substantial. In 
the PS-matched sample, we will use cause-specific hazard models7 to provide hazard ratios averaged over the entire 
follow-up period as well as interval specific hazard ratios (1, 2, and 3 years) for the association between the treatment of 
interest and risk of ADRD after considering all-cause mortality as a competing event. Pre-specified subgroup analyses will 
be conducted based on age, sex, and baseline cardiovascular disease.  
 
 
 
 

DREAM study protocol - Comparison 14 Semaglutide v DPP4 inhibitors 
 
 
17 
10. References 
 
1. 
Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. 
Biometrika. 1983;70(1):41-55. 
2. 
Rassen JA, Avorn J, Schneeweiss S. Multivariate-adjusted pharmacoepidemiologic analyses of confidential 
information pooled from multiple health care utilization databases. Pharmacoepidemiology and drug safety. 
2010;19(8):848-857. 
3. 
Rassen JA, Shelat AA, Myers J, Glynn RJ, Rothman KJ, Schneeweiss S. One-to-many propensity score matching 
in cohort studies. Pharmacoepidemiol Drug Saf. May 2012;21 Suppl 2:69-80. 
4. 
Austin PC. Some Methods of Propensity-Score Matching had Superior Performance to Others: Results of an 
Empirical Investigation and Monte Carlo simulations. Biometrical Journal. 2009;51(1):171-184. 
5. 
AM Walker AM, Patrick A, Lauer M, et al. Tool for Assessing the Feasibility of Comparative Effectiveness 
Research. Comp Effect Res 2013;3:11-20. 
6. 
Franklin JM, Rassen JA, Ackermann D, Bartels DB, Schneeweiss S. Metrics for covariate balance in cohort studies 
of causal effects. Statistics in medicine. May 10 2014;33(10):1685-1699. 
7. 
Austin PC, Lee DS, Fine JP. Introduction to the analysis of survival data in the presence of competing risks. 
Circulation. 2016;133(6):601-609.