Diabetes Mellitus, Type 2
Conditions
Brief summary
This protocol is for a series of comparative effectiveness and safety analyses within periodically updated cohorts of patients initiating linagliptin, other DPP-4 inhibitors, and other oral hypoglycemic medications, followed longitudinally for the occurrence of a variety of health outcomes. The primary analysis will be conducted among patients without prior within-class medication use.
Interventions
None listed
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A dispensing of an oral hypoglycemic medication * A diagnosis of type 2 diabetes mellitus (T2DM)
Exclusion criteria
* less than 18 years old * missing or ambiguous age or sex information * at least one diagnosis of type 1 diabetes mellitus * less than 6 months enrolment in the database preceding the date of the first dispensing * secondary diabetes * history of cancer * end-stage renal disease (ESRD) * HIV * organ transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Stroke | Up to 5 years and 7 months | Number of participants with ischemic or hemorrhagic stroke. Both types of stroke were included in the definition for stroke, but were not assessed separately |
| Number of Participants With Major Adverse Cardiovascular Event | Up to 5 years and 7 months | Number of participants with major adverse cardiovascular event is presented by the number of patients reported a composite of: * Coronary revascularization (elective and non-elective procedure) * Acute coronary syndrome (ACS), including acute myocardial infarction (MI) * Stroke (Ischemic and hemorrhagic stroke) |
| Number of Participants With Coronary Revascularization | Up to 5 years and 7 month | Number of participants with coronary revascularization (elective and non-elective procedure) |
| Number of Participants With Acute Coronary Syndrome | Up to 5 years and 7 months | Number of participants with acute coronary syndrome (ACS). The definition for ACS included acute myocardial infarction (MI), but acute MI was not assessed separately. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Incident End Stage Renal Disease | Up to 5 years and 7 months | Number of participants with incident end stage renal disease (ESRD) |
| Number of Participants With Heart Failure Hospitalization | Up to 5 years and 7 months | Number of participants with heart failure hospitalization |
| Number of Participants With Acute Renal Failure | Up to 5 years and 7 months | Number of participants with acute renal failure |
| Number of Participants With Acute Renal Failure Requiring Dialysis | Up to 5 years and 7 months | Number of patients with acute renal failure requiring dialysis |
Countries
United States
Participant flow
Recruitment details
From Clinformatics and MarketScan source data, patients with a recorded diagnosis of type 2 diabetes mellitus (T2DM) who initiated linagliptin, sitagliptin, saxagliptin, alogliptin, pioglitazone, or 2nd generation sulfonylureas were identified between May 2011 and December 2016.
Pre-assignment details
Only participants with no use of a medication in the same class or comparator class during the 6 months prior to index date, who were at least 18 years of age and enrolled for a minimum of 6 months in the data source before treatment initiation were included.
Participants by arm
| Arm | Count |
|---|---|
| Other DPP-4I - Clinformatics 1:1 propensity score matched cohort of initiators of other Dipeptidyl peptidase-4 (DPP-4) and initiators of linagliptin, within Clinformatics database | 14,688 |
| Linagliptin 1 - Clinformatics 1:1 propensity score matched cohort of initiators of other Dipeptidyl peptidase-4 (DPP-4) and initiators of linagliptin, within Clinformatics database | 14,688 |
| Pioglitazone - Clinformatics 1:1 propensity score matched cohort of initiators of pioglitazone and initiators of linagliptin, within Clinformatics database | 10,614 |
| Linagliptin 2 - Clinformatics 1:1 propensity score matched cohort of initiators of pioglitazone and initiators of linagliptin, within Clinformatics database | 10,614 |
| 2nd Gen SUs - Clinformatics 1:1 propensity score matched cohort of initiators of second generation sulfonylureas (2nd gen SUs) and initiators of linagliptin, within Clinformatics database | 9,538 |
| Linagliptin 3 - Clinformatics 1:1 propensity score matched cohort of initiators of second generation sulfonylureas (2nd gen SUs) and initiators of linagliptin, within Clinformatics database | 9,538 |
| Other DPP-4I - MarketScan 1:1 propensity score matched cohort of initiators of other Dipeptidyl peptidase-4 (DPP-4) and initiators of linagliptin, within MarketScan database | 25,135 |
| Linagliptin 1 - MarketScan 1:1 propensity score matched cohort of initiators of other Dipeptidyl peptidase-4 (DPP-4) and initiators of linagliptin, within MarketScan database | 25,135 |
| Pioglitazone - MarketScan 1:1 propensity score matched cohort of initiators of pioglitazone and initiators of linagliptin, within MarketScan database | 18,996 |
| Linagliptin 2 - MarketScan 1:1 propensity score matched cohort of initiators of pioglitazone and initiators of linagliptin, within MarketScan database | 18,996 |
| 2nd Gen SUs - MarketScan 1:1 propensity score matched cohort of initiators of second generation of sulfonylureas (2nd gen SUs) and initiators of linagliptin, within MarketScan database | 15,742 |
| Linagliptin 3 - MarketScan 1:1 propensity score matched cohort of initiators of second generation of sulfonylureas (2nd gen SUs) and initiators of linagliptin, within MarketScan database | 15,742 |
| Total | 189,426 |
Baseline characteristics
| Characteristic | Other DPP-4I - Clinformatics | Linagliptin 1 - Clinformatics | Pioglitazone - Clinformatics | Linagliptin 2 - Clinformatics | 2nd Gen SUs - Clinformatics | Linagliptin 3 - Clinformatics | Other DPP-4I - MarketScan | Linagliptin 1 - MarketScan | Pioglitazone - MarketScan | Linagliptin 2 - MarketScan | 2nd Gen SUs - MarketScan | Linagliptin 3 - MarketScan | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 56.31 Years STANDARD_DEVIATION 12.45 | 56.30 Years STANDARD_DEVIATION 12.35 | 56.53 Years STANDARD_DEVIATION 12.48 | 56.77 Years STANDARD_DEVIATION 12.54 | 55.03 Years STANDARD_DEVIATION 12.18 | 55.00 Years STANDARD_DEVIATION 12.21 | 55.25 Years STANDARD_DEVIATION 11.26 | 55.27 Years STANDARD_DEVIATION 11.36 | 54.71 Years STANDARD_DEVIATION 11.22 | 54.73 Years STANDARD_DEVIATION 11.28 | 54.41 Years STANDARD_DEVIATION 11.28 | 54.40 Years STANDARD_DEVIATION 11.31 | 55.39 Years STANDARD_DEVIATION 11.83 |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | — | — | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 6118 Participants | 6098 Participants | 4266 Participants | 4337 Participants | 3985 Participants | 3968 Participants | 10377 Participants | 10309 Participants | 7805 Participants | 7850 Participants | 6527 Participants | 6582 Participants | 78222 Participants |
| Sex: Female, Male Male | 8570 Participants | 8590 Participants | 6348 Participants | 6277 Participants | 5553 Participants | 5570 Participants | 14758 Participants | 14826 Participants | 11191 Participants | 11146 Participants | 9215 Participants | 9160 Participants | 111204 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Participants With Acute Coronary Syndrome
Number of participants with acute coronary syndrome (ACS). The definition for ACS included acute myocardial infarction (MI), but acute MI was not assessed separately.
Time frame: Up to 5 years and 7 months
Population: 1:1 propensity score matched cohorts of linagliptin initiators and comparator groups initiators, identified from Clinformatics and MarketScan database between May 2011 and December 2016.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Other DPP-4I - Clinformatics | Number of Participants With Acute Coronary Syndrome | 93 Participants |
| Linagliptin 1 - Clinformatics | Number of Participants With Acute Coronary Syndrome | 72 Participants |
| Pioglitazone - Clinformatics | Number of Participants With Acute Coronary Syndrome | 76 Participants |
| Linagliptin 2 - Clinformatics | Number of Participants With Acute Coronary Syndrome | 48 Participants |
| 2nd Gen SUs - Clinformatics | Number of Participants With Acute Coronary Syndrome | 72 Participants |
| Linagliptin 3 - Clinformatics | Number of Participants With Acute Coronary Syndrome | 43 Participants |
| Other DPP-4I - MarketScan | Number of Participants With Acute Coronary Syndrome | 238 Participants |
| Linagliptin 1 - MarketScan | Number of Participants With Acute Coronary Syndrome | 221 Participants |
| Pioglitazone - MarketScan | Number of Participants With Acute Coronary Syndrome | 163 Participants |
| Linagliptin 2 - MarketScan | Number of Participants With Acute Coronary Syndrome | 160 Participants |
| 2nd Gen SUs - MarketScan | Number of Participants With Acute Coronary Syndrome | 161 Participants |
| Linagliptin 3 - MarketScan | Number of Participants With Acute Coronary Syndrome | 115 Participants |
95% CI: [0.51, 0.94]
95% CI: [0.44, 0.9]
95% CI: [0.41, 0.88]
95% CI: [0.81, 1.17]
95% CI: [0.77, 1.19]
95% CI: [0.6, 0.97]
Primary
Number of Participants With Coronary Revascularization
Number of participants with coronary revascularization (elective and non-elective procedure)
Time frame: Up to 5 years and 7 month
Population: 1:1 propensity score matched cohorts of linagliptin initiators and comparator groups initiators, identified from Clinformatics and MarketScan database between May 2011 and December 2016.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Other DPP-4I - Clinformatics | Number of Participants With Coronary Revascularization | 82 Participants |
| Linagliptin 1 - Clinformatics | Number of Participants With Coronary Revascularization | 81 Participants |
| Pioglitazone - Clinformatics | Number of Participants With Coronary Revascularization | 67 Participants |
| Linagliptin 2 - Clinformatics | Number of Participants With Coronary Revascularization | 54 Participants |
| 2nd Gen SUs - Clinformatics | Number of Participants With Coronary Revascularization | 67 Participants |
| Linagliptin 3 - Clinformatics | Number of Participants With Coronary Revascularization | 46 Participants |
| Other DPP-4I - MarketScan | Number of Participants With Coronary Revascularization | 181 Participants |
| Linagliptin 1 - MarketScan | Number of Participants With Coronary Revascularization | 181 Participants |
| Pioglitazone - MarketScan | Number of Participants With Coronary Revascularization | 129 Participants |
| Linagliptin 2 - MarketScan | Number of Participants With Coronary Revascularization | 133 Participants |
| 2nd Gen SUs - MarketScan | Number of Participants With Coronary Revascularization | 125 Participants |
| Linagliptin 3 - MarketScan | Number of Participants With Coronary Revascularization | 94 Participants |
95% CI: [0.66, 1.23]
95% CI: [0.57, 1.16]
95% CI: [0.48, 1.01]
95% CI: [0.85, 1.28]
95% CI: [0.79, 1.28]
95% CI: [0.62, 1.06]
Primary
Number of Participants With Major Adverse Cardiovascular Event
Number of participants with major adverse cardiovascular event is presented by the number of patients reported a composite of: * Coronary revascularization (elective and non-elective procedure) * Acute coronary syndrome (ACS), including acute myocardial infarction (MI) * Stroke (Ischemic and hemorrhagic stroke)
Time frame: Up to 5 years and 7 months
Population: 1:1 propensity score matched cohorts of linagliptin initiators and comparator groups initiators, identified from Clinformatics and MarketScan database between May 2011 and December 2016
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Other DPP-4I - Clinformatics | Number of Participants With Major Adverse Cardiovascular Event | 165 Participants |
| Linagliptin 1 - Clinformatics | Number of Participants With Major Adverse Cardiovascular Event | 151 Participants |
| Pioglitazone - Clinformatics | Number of Participants With Major Adverse Cardiovascular Event | 120 Participants |
| Linagliptin 2 - Clinformatics | Number of Participants With Major Adverse Cardiovascular Event | 102 Participants |
| 2nd Gen SUs - Clinformatics | Number of Participants With Major Adverse Cardiovascular Event | 127 Participants |
| Linagliptin 3 - Clinformatics | Number of Participants With Major Adverse Cardiovascular Event | 82 Participants |
| Other DPP-4I - MarketScan | Number of Participants With Major Adverse Cardiovascular Event | 403 Participants |
| Linagliptin 1 - MarketScan | Number of Participants With Major Adverse Cardiovascular Event | 369 Participants |
| Pioglitazone - MarketScan | Number of Participants With Major Adverse Cardiovascular Event | 262 Participants |
| Linagliptin 2 - MarketScan | Number of Participants With Major Adverse Cardiovascular Event | 270 Participants |
| 2nd Gen SUs - MarketScan | Number of Participants With Major Adverse Cardiovascular Event | 259 Participants |
| Linagliptin 3 - MarketScan | Number of Participants With Major Adverse Cardiovascular Event | 194 Participants |
95% CI: [0.66, 1.03]
95% CI: [0.65, 1.1]
95% CI: [0.49, 0.86]
95% CI: [0.83, 1.1]
95% CI: [0.85, 1.19]
95% CI: [0.66, 0.96]
Primary
Number of Participants With Stroke
Number of participants with ischemic or hemorrhagic stroke. Both types of stroke were included in the definition for stroke, but were not assessed separately
Time frame: Up to 5 years and 7 months
Population: 1:1 propensity score matched cohorts of linagliptin initiators and comparator groups initiators, identified from Clinformatics and MarketScan database between May 2011 and December 2016.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Other DPP-4I - Clinformatics | Number of Participants With Stroke | 42 Participants |
| Linagliptin 1 - Clinformatics | Number of Participants With Stroke | 42 Participants |
| Pioglitazone - Clinformatics | Number of Participants With Stroke | 30 Participants |
| Linagliptin 2 - Clinformatics | Number of Participants With Stroke | 30 Participants |
| 2nd Gen SUs - Clinformatics | Number of Participants With Stroke | 37 Participants |
| Linagliptin 3 - Clinformatics | Number of Participants With Stroke | 16 Participants |
| Other DPP-4I - MarketScan | Number of Participants With Stroke | 113 Participants |
| Linagliptin 1 - MarketScan | Number of Participants With Stroke | 104 Participants |
| Pioglitazone - MarketScan | Number of Participants With Stroke | 66 Participants |
| Linagliptin 2 - MarketScan | Number of Participants With Stroke | 74 Participants |
| 2nd Gen SUs - MarketScan | Number of Participants With Stroke | 76 Participants |
| Linagliptin 3 - MarketScan | Number of Participants With Stroke | 53 Participants |
95% CI: [0.58, 1.38]
95% CI: [0.6, 1.64]
95% CI: [0.24, 0.78]
95% CI: [0.73, 1.25]
95% CI: [0.78, 1.52]
95% CI: [0.52, 1.05]
Secondary
Number of Participants With Acute Renal Failure
Number of participants with acute renal failure
Time frame: Up to 5 years and 7 months
Population: 1:1 propensity score matched cohorts of linagliptin initiators and comparator groups initiators, identified from Clinformatics and MarketScan database between May 2011 and December 2016.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Other DPP-4I - Clinformatics | Number of Participants With Acute Renal Failure | 222 Participants |
| Linagliptin 1 - Clinformatics | Number of Participants With Acute Renal Failure | 300 Participants |
| Pioglitazone - Clinformatics | Number of Participants With Acute Renal Failure | 152 Participants |
| Linagliptin 2 - Clinformatics | Number of Participants With Acute Renal Failure | 198 Participants |
| 2nd Gen SUs - Clinformatics | Number of Participants With Acute Renal Failure | 163 Participants |
| Linagliptin 3 - Clinformatics | Number of Participants With Acute Renal Failure | 167 Participants |
| Other DPP-4I - MarketScan | Number of Participants With Acute Renal Failure | 433 Participants |
| Linagliptin 1 - MarketScan | Number of Participants With Acute Renal Failure | 430 Participants |
| Pioglitazone - MarketScan | Number of Participants With Acute Renal Failure | 240 Participants |
| Linagliptin 2 - MarketScan | Number of Participants With Acute Renal Failure | 263 Participants |
| 2nd Gen SUs - MarketScan | Number of Participants With Acute Renal Failure | 238 Participants |
| Linagliptin 3 - MarketScan | Number of Participants With Acute Renal Failure | 200 Participants |
95% CI: [1.04, 1.47]
95% CI: [1.06, 1.61]
95% CI: [0.84, 1.29]
95% CI: [0.91, 1.19]
95% CI: [0.9, 1.27]
95% CI: [0.75, 1.09]
Secondary
Number of Participants With Acute Renal Failure Requiring Dialysis
Number of patients with acute renal failure requiring dialysis
Time frame: Up to 5 years and 7 months
Population: 1:1 propensity score matched cohorts of linagliptin initiators and comparator groups initiators, identified from Clinformatics and MarketScan database between May 2011 and December 2016.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Other DPP-4I - Clinformatics | Number of Participants With Acute Renal Failure Requiring Dialysis | 7 Participants |
| Linagliptin 1 - Clinformatics | Number of Participants With Acute Renal Failure Requiring Dialysis | 13 Participants |
| Pioglitazone - Clinformatics | Number of Participants With Acute Renal Failure Requiring Dialysis | 6 Participants |
| Linagliptin 2 - Clinformatics | Number of Participants With Acute Renal Failure Requiring Dialysis | 10 Participants |
| 2nd Gen SUs - Clinformatics | Number of Participants With Acute Renal Failure Requiring Dialysis | 5 Participants |
| Linagliptin 3 - Clinformatics | Number of Participants With Acute Renal Failure Requiring Dialysis | 9 Participants |
| Other DPP-4I - MarketScan | Number of Participants With Acute Renal Failure Requiring Dialysis | 14 Participants |
| Linagliptin 1 - MarketScan | Number of Participants With Acute Renal Failure Requiring Dialysis | 16 Participants |
| Pioglitazone - MarketScan | Number of Participants With Acute Renal Failure Requiring Dialysis | 9 Participants |
| Linagliptin 2 - MarketScan | Number of Participants With Acute Renal Failure Requiring Dialysis | 9 Participants |
| 2nd Gen SUs - MarketScan | Number of Participants With Acute Renal Failure Requiring Dialysis | 7 Participants |
| Linagliptin 3 - MarketScan | Number of Participants With Acute Renal Failure Requiring Dialysis | 11 Participants |
95% CI: [0.64, 4.06]
95% CI: [0.61, 4.58]
95% CI: [0.62, 5.48]
95% CI: [0.57, 2.4]
95% CI: [0.38, 2.43]
95% CI: [0.64, 4.27]
Secondary
Number of Participants With Heart Failure Hospitalization
Number of participants with heart failure hospitalization
Time frame: Up to 5 years and 7 months
Population: 1:1 propensity score matched cohorts of linagliptin initiators and comparator groups initiators, identified from Clinformatics and MarketScan database between May 2011 and December 2016.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Other DPP-4I - Clinformatics | Number of Participants With Heart Failure Hospitalization | 53 Participants |
| Linagliptin 1 - Clinformatics | Number of Participants With Heart Failure Hospitalization | 90 Participants |
| Pioglitazone - Clinformatics | Number of Participants With Heart Failure Hospitalization | 27 Participants |
| Linagliptin 2 - Clinformatics | Number of Participants With Heart Failure Hospitalization | 51 Participants |
| 2nd Gen SUs - Clinformatics | Number of Participants With Heart Failure Hospitalization | 43 Participants |
| Linagliptin 3 - Clinformatics | Number of Participants With Heart Failure Hospitalization | 47 Participants |
| Other DPP-4I - MarketScan | Number of Participants With Heart Failure Hospitalization | 117 Participants |
| Linagliptin 1 - MarketScan | Number of Participants With Heart Failure Hospitalization | 111 Participants |
| Pioglitazone - MarketScan | Number of Participants With Heart Failure Hospitalization | 58 Participants |
| Linagliptin 2 - MarketScan | Number of Participants With Heart Failure Hospitalization | 65 Participants |
| 2nd Gen SUs - MarketScan | Number of Participants With Heart Failure Hospitalization | 66 Participants |
| Linagliptin 3 - MarketScan | Number of Participants With Heart Failure Hospitalization | 49 Participants |
95% CI: [1.1, 2.18]
95% CI: [1.19, 3.03]
95% CI: [0.73, 1.68]
95% CI: [0.76, 1.29]
95% CI: [0.77, 1.56]
95% CI: [0.54, 1.14]
Secondary
Number of Participants With Incident End Stage Renal Disease
Number of participants with incident end stage renal disease (ESRD)
Time frame: Up to 5 years and 7 months
Population: 1:1 propensity score matched cohorts of linagliptin initiators and comparator groups initiators, identified from Clinformatics and MarketScan database between May 2011 and December 2016. For this outcome only, patients with ESRD at any time prior to and including the day of treatment initiation were excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Other DPP-4I - Clinformatics | Number of Participants With Incident End Stage Renal Disease | 49 Participants |
| Linagliptin 1 - Clinformatics | Number of Participants With Incident End Stage Renal Disease | 75 Participants |
| Pioglitazone - Clinformatics | Number of Participants With Incident End Stage Renal Disease | 28 Participants |
| Linagliptin 2 - Clinformatics | Number of Participants With Incident End Stage Renal Disease | 48 Participants |
| 2nd Gen SUs - Clinformatics | Number of Participants With Incident End Stage Renal Disease | 38 Participants |
| Linagliptin 3 - Clinformatics | Number of Participants With Incident End Stage Renal Disease | 43 Participants |
| Other DPP-4I - MarketScan | Number of Participants With Incident End Stage Renal Disease | 90 Participants |
| Linagliptin 1 - MarketScan | Number of Participants With Incident End Stage Renal Disease | 116 Participants |
| Pioglitazone - MarketScan | Number of Participants With Incident End Stage Renal Disease | 39 Participants |
| Linagliptin 2 - MarketScan | Number of Participants With Incident End Stage Renal Disease | 61 Participants |
| 2nd Gen SUs - MarketScan | Number of Participants With Incident End Stage Renal Disease | 53 Participants |
| Linagliptin 3 - MarketScan | Number of Participants With Incident End Stage Renal Disease | 57 Participants |
95% CI: [0.97, 2]
95% CI: [1.07, 2.72]
95% CI: [0.75, 1.79]
95% CI: [1.01, 1.76]
95% CI: [1.02, 2.27]
95% CI: [0.81, 1.71]