Healthy Subjects (Treated With no Diabetes Therapies), Type 2 Diabetes (Treated With Exenatide or Other Oral Antidiabetic Therapies)
Conditions
Keywords
pancreatitis, exenatide, Byetta, Amylin, Lilly
Brief summary
The purpose of this research was to assess the absolute and relative incidence of acute pancreatitis in persons initiating exenatide compared with persons initiating a different antidiabetic agent, and secondarily, persons without diabetes. This protocol summarizes a retrospective cohort study using eligibility, pharmacy claims, and medical claims data from a large US health plan affiliated with i3 Drug Safety.
Detailed description
Limitations of the study: The results provided below should be interpreted in light of the following limitations: * Misclassification of acute pancreatitis may have distorted our estimates of absolute and relative IRs. In cases where the degree of misclassification is non-differential with respect to the exposure cohort, as is likely the case in administrative data, the RR would be biased toward the null value, although the magnitude of bias will depend on the amount of misclassification. * Lack of information on important potential confounders, like obesity and alcohol use, is another limitation of the present analysis. Although we adjusted for propensity scores of exenatide initiation, which included a large number of factors derived from the claims data, it is likely that the present estimates are somewhat inaccurate due to residual confounding. * Our definition of current use in the time-on-drug analysis, which extended 31 days past the nominal end of the last dispensing of the cohort-defining drug, may be too long in duration and thus misclassify exposure during the relevant etiologic period. * Additionally, these analyses assume that when pharmacies submit a claim for a medication that patients receive and consume the medication. While it is possible that misclassification of exposure by non-adherence to the medications dispensed occurred, prior work showed that pharmacy claims are valid for ascertaining medication exposure.
Interventions
DRUGexenatide
subcutaneous injection, dosing according to normal clinical practice
DRUGOther antidiabetic therapies
Includes metformin, thiazolidinediones, insulins, sulfonylureas, non-sulfonylurea secretagogues, sitagliptin, and alpha-glucosidase inhibitors; In all cases, dosing according to normal clinical practice
OTHERNo diabetes therapy
Subjects not diagnosed with diabetes
Sponsors
AstraZeneca
Eli Lilly and Company
i3 Drug Safety
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Exenatide Initiators: The date of the first dispensing of exenatide under which a potential cohort member might qualify will be 1 June 2005, and the latest date will be 31 December 2007. We will note the first initiation of exenatide, and also note subsequent initiation of other antidiabetic drugs. Eligible exenatide initiators will be included in the exenatide initiator cohort on the first eligible dispensing following at least 9 months of continuous health plan enrollment. * Other Antidiabetic Drug Initiators: The date of the first dispensing of an antidiabetic drug other than exenatide under which a potential cohort member might qualify will be 1 June 2005, and the latest date will be 31 December 2007. We will note the earliest date of other antidiabetic drug dispensings within their cohort membership, and also note subsequent initiation of other antidiabetic drugs. We will choose a subset of this comparator cohort randomly selected to be approximately 9 times larger than the exenatide initiators and will oversample patients receiving certain drugs to the extent necessary to ensure inclusion of at least as many persons initiating these drugs as initiating exenatide. Specifically, oversampling will be performed as needed on initiators of metformin, TZDs, SUs, sitagliptin and insulin glargine to allow for further sub-analysis. * Exenatide and Other Antidiabetic Drug Initiators: For all patients in these two study cohorts, the date of cohort entry (the date ranged between January 1, 2005 and December 31, 2007) marked the beginning of observation for study outcomes (follow-up). The end of observation for a given patient happened on the earliest of occurrence of likely acute pancreatitis, end of the study period (March 31, 2008), or disenrollment from the health plan. * Non-Diabetes Cohort: A third cohort will consist of randomly-selected Ingenix Research Data Mart members who have no claim associated with a diabetes diagnosis or antidiabetic drug dispensing in the baseline continuous enrollment period. This cohort will enter as of the later of 1 June 2005 or completion of 9 months continuous baseline enrollment and will provide follow-up through end of enrollment or 31 March 2008, or the receipt of an antidiabetic drug dispensing or diabetes diagnosis, at which point they may enter one of the other exposure cohorts.
Exclusion criteria
* The 3 cohorts (exenatide initiators, other antidiabetic initiators, and those without diabetes) will be subject to minimal exclusions in order to observe acute pancreatitis across a wide spectrum of patient characteristics. We will apply a baseline enrollment requirement of 9 months prior to cohort entry so that the first day of follow-up (on which acute pancreatitis could occur) will be characterized with the same level of detail (based on 9 months of preceding health insurance claims) as any other day during the study. * Consistent with the principle of minimal exclusions, we will only exclude from the cohorts people who have baseline claims associated with pancreatitis (in the 9-month period preceding cohort entry) as these people either had pre-existing pancreatitis or had a pre-existing suspicion of pancreatitis. We will not exclude persons with a type I diabetes diagnosis as we intend to observe the spectrum of clinical practice with respect to antidiabetic drug initiation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (During Current Use Period) - Time on Drug Analysis | 43 months | Crude time-on-drug incidence rate per 100,000 person-years of likely acute pancreatitis in initiators of exenatide, initiators of other antidiabetic drugs and the non-diabetes cohort. Analysis period is current use period, described as time during current day's supply plus 31 days. |
| Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (Among Recent Use Period) - Time on Drug Analysis | 43 months | Crude time-on-drug incidence rate per 100,000 person-years of likely acute pancreatitis in initiators of exenatide, initiators of other antidiabetic drugs and the non-diabetes cohort. Analysis period is the recent use period, described as time following current use plus an additional 31 days excluding subsequent current use. |
| Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (During Past Use Period) - Time on Drug Analysis | 43 months | Crude time-on-drug incidence rate per 100,000 person-years of likely acute pancreatitis in initiators of exenatide, initiators of other antidiabetic drugs and the non-diabetes cohort. Analysis period is past use period, described as time following recent use excluding subsequent current or recent use. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis Among Initiators of Exenatide, Diabetics Initiating Other Antidiabetic Drugs, and the Non-diabetes Cohort - Intent to Treat Analysis | 43 months | Crude intent-to-treat incidence rate per 100,000 person-years of likely acute pancreatitis in initiators of exenatide, initiators of other antidiabetic drugs and the non-diabetes cohort. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Initiators Exenatide initiators were persons with a pharmacy claim associated with a dispensing of exenatide preceded by 9 months of continuous enrollment in the underlying health insurance plan without an exenatide dispensing. Patients eligible for both the exenatide cohort and the other antidiabetic drug medication cohort were preferentially entered into the former. | 25,719 |
| Other Antidiabetic Drug (OADs) Initiators Initiators of other antidiabetic medications were persons with a pharmacy claim associated with a dispensing of one of the following drugs preceded by 9 months of continuous enrollment in the underlying health insurance program without a dispensing of the same medication: sulfonylureas (e.g. glyburide); metformin; TZDs (e.g. rosiglitazone); insulins (e.g. insulin glargine); sitagliptin; pramlintide; non-sulfonylurea secretagogues (e.g. repaglinide); α-glucosidase inhibitors (e.g. miglitol). | 234,536 |
| Non-Diabetes Cohort The Non-Diabetes Cohort was composed of persons who had 9 months of continuous enrollment in the underlying health insurance program prior to their assigned index dates and no claims associated with a diagnosis of diabetes, no dispensing of a diabetes drug, and no diagnosis of pancreatic disease in the baseline period. | 103,511 |
| Total | 363,766 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | <9 months enroll before drug dispensed | 11,226 | 263,954 | 11,655,523 |
| Overall Study | Baseline diagnosis of pancreatic disease | 152 | 2,080 | 120 |
| Overall Study | Dispensing of drug in baseline period | 0 | 120,229 | 256,446 |
Baseline characteristics
| Characteristic | Exenatide Initiators | Other Antidiabetic Drug (OADs) Initiators | Non-Diabetes Cohort | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 54 Participants | 2982 Participants | 24963 Participants | 27999 Participants |
| Age, Categorical >=65 years | 2169 Participants | 29237 Participants | 4926 Participants | 36332 Participants |
| Age, Categorical Between 18 and 65 years | 23496 Participants | 202317 Participants | 73622 Participants | 299435 Participants |
| Has a History of Congestive Heart Failure | 820 participants | 8227 participants | 315 participants | 9362 participants |
| Has a History of Hyperlipidemia | 19741 participants | 127384 participants | 13178 participants | 160303 participants |
| Has a History of Hypertension | 16336 participants | 114593 participants | 10121 participants | 141050 participants |
| Has a History of Ischemic Heart Disease | 3228 participants | 24900 participants | 1775 participants | 29903 participants |
| Has a History of Myocardial Infarction | 301 participants | 3951 participants | 193 participants | 4445 participants |
| Has a History of Obesity | 4107 participants | 18933 participants | 1230 participants | 24270 participants |
| Has a History of Peripheral Neuropathy | 2456 participants | 9581 participants | 11 participants | 12048 participants |
| Has a History of Renal Impairment/Dialysis | 961 participants | 8257 participants | 312 participants | 9530 participants |
| Has a History of Retinopathy | 1279 participants | 6693 participants | 76 participants | 8048 participants |
| Has a History of Stroke/Transient Ischemic Attack | 423 participants | 5088 participants | 336 participants | 5847 participants |
| Has a History of Type 1 Diabetes | 2794 participants | 19368 participants | 0 participants | 22162 participants |
| Has a History of Type 2 Diabetes | 21709 participants | 138218 participants | 0 participants | 159927 participants |
| Sex: Female, Male Female | 14381 Participants | 114960 Participants | 52444 Participants | 181785 Participants |
| Sex: Female, Male Male | 11338 Participants | 119576 Participants | 51067 Participants | 181981 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (Among Recent Use Period) - Time on Drug Analysis
Crude time-on-drug incidence rate per 100,000 person-years of likely acute pancreatitis in initiators of exenatide, initiators of other antidiabetic drugs and the non-diabetes cohort. Analysis period is the recent use period, described as time following current use plus an additional 31 days excluding subsequent current use.
Time frame: 43 months
Population: Time on Drug Analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Initiators | Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (Among Recent Use Period) - Time on Drug Analysis | 321.4 Cases per 100,000 person-years |
| Other Antidiabetic Drug (OADs) Initiators | Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (Among Recent Use Period) - Time on Drug Analysis | 325.5 Cases per 100,000 person-years |
| Non-Diabetes Cohort | Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (Among Recent Use Period) - Time on Drug Analysis | 56.2 Cases per 100,000 person-years |
95% CI: [0.36, 2.09]
Primary
Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (During Current Use Period) - Time on Drug Analysis
Crude time-on-drug incidence rate per 100,000 person-years of likely acute pancreatitis in initiators of exenatide, initiators of other antidiabetic drugs and the non-diabetes cohort. Analysis period is current use period, described as time during current day's supply plus 31 days.
Time frame: 43 months
Population: Time on Drug Analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Initiators | Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (During Current Use Period) - Time on Drug Analysis | 219.7 Cases per 100,000 person-years |
| Other Antidiabetic Drug (OADs) Initiators | Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (During Current Use Period) - Time on Drug Analysis | 226.7 Cases per 100,000 person-years |
| Non-Diabetes Cohort | Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (During Current Use Period) - Time on Drug Analysis | 56.2 Cases per 100,000 person-years |
95% CI: [0.59, 1.28]
Primary
Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (During Past Use Period) - Time on Drug Analysis
Crude time-on-drug incidence rate per 100,000 person-years of likely acute pancreatitis in initiators of exenatide, initiators of other antidiabetic drugs and the non-diabetes cohort. Analysis period is past use period, described as time following recent use excluding subsequent current or recent use.
Time frame: 43 months
Population: Time on Drug Analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Initiators | Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (During Past Use Period) - Time on Drug Analysis | 354.5 Cases per 100,000 person-years |
| Other Antidiabetic Drug (OADs) Initiators | Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (During Past Use Period) - Time on Drug Analysis | 218.1 Cases per 100,000 person-years |
| Non-Diabetes Cohort | Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis (During Past Use Period) - Time on Drug Analysis | 56.2 Cases per 100,000 person-years |
95% CI: [0.86, 2.25]
Secondary
Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis Among Initiators of Exenatide, Diabetics Initiating Other Antidiabetic Drugs, and the Non-diabetes Cohort - Intent to Treat Analysis
Crude intent-to-treat incidence rate per 100,000 person-years of likely acute pancreatitis in initiators of exenatide, initiators of other antidiabetic drugs and the non-diabetes cohort.
Time frame: 43 months
Population: Intent to Treat Analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Initiators | Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis Among Initiators of Exenatide, Diabetics Initiating Other Antidiabetic Drugs, and the Non-diabetes Cohort - Intent to Treat Analysis | 272.7 Cases per 100,000 person-years |
| Other Antidiabetic Drug (OADs) Initiators | Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis Among Initiators of Exenatide, Diabetics Initiating Other Antidiabetic Drugs, and the Non-diabetes Cohort - Intent to Treat Analysis | 227.6 Cases per 100,000 person-years |
| Non-Diabetes Cohort | Incidence Rates Per 100,000 Person-Years of Likely Acute Pancreatitis Among Initiators of Exenatide, Diabetics Initiating Other Antidiabetic Drugs, and the Non-diabetes Cohort - Intent to Treat Analysis | 56.2 Cases per 100,000 person-years |
95% CI: [0.8, 1.5]