Diabetes mellitus in patients with idiopathic Parkinson s disease

Transcription

1 Diabetes Care Publish Ahead of Print, published online June 16, 2008 Parkinson and diabetes Diabetes mellitus in patients with idiopathic Parkinson s disease Claudia Becker 1, PhD, Gunnar P. Brobert 2, PhD, Saga Johansson 3,4, MD, PhD, Susan S. Jick 5, DSc, and Christoph R. Meier 1,5, PhD 1 Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Switzerland; 2 AstraZeneca Research & Development, Södertälje, Sweden; 3 AstraZeneca Research & Development, Mölndal, Sweden; 4 Institute of Medicine, Sahlgrenska Academy, Göteborg University, Sweden; 5 Boston Collaborative Drug Surveillance Program, Boston University Medical Center, Lexington, MA, USA Corresponding author: Christoph R. Meier, PhD, MSc Meierch@uhbs.ch Received 7 March 2008 and accepted 9 June This is an uncopyedited electronic version of an article accepted for publication in Diabetes Care. The American Diabetes Association, publisher of Diabetes Care, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes Care in print and online at Copyright American Diabetes Association, Inc., 2008

2 Objective: Previous observational studies reported inconsistent results on the association between diabetes and Parkinson s disease (PD), and data on the risk of developing incident diabetes in relation to PD are scarce. We aimed at comparing the diabetes prevalence between patients with or without PD, and at exploring the risk of developing incident diabetes associated with PD. Research Design and Methods: We used the UK-based General Practice Research Database (GPRD) to a) compare the diabetes prevalence between PD cases and a matched comparison group free of PD between 1994 and 2005, and to b) conduct a follow-up study with a nested case-control analysis to quantify the risk of developing new onset diabetes in association with PD. Results: The diabetes prevalence was similar in PD patients and in PD-free patients (adjusted odds ratio [OR] 0.95, 95% CI ). In the cohort analysis (incidence rate ratio [IRR] 0.55, 95% CI ) and in the nested case-control analysis (adjusted OR 0.53, 95% CI ), the risk of developing diabetes was lower in PD patients than in subjects without PD. The adjusted OR for PD patients who were current levodopa users of 5 prescriptions was 0.22 (95% CI ), and 1.11 (95% CI ) for PD patients not using levodopa. Conclusions: In this observational study the diabetes prevalence was closely similar between PD cases and patients without PD. The risk of developing incident diabetes was lower for PD patients than for patients without PD, a finding which was limited to PD patients using levodopa. 2

3 I diopathic Parkinson s disease (PD) is a common neurodegenerative disease which may be related to mitochondrial dysfunction, oxidative stress, excitotoxicity, apoptosis and inflammation (1, 2). Chronic systemic inflammation as well as impaired mitochondrial metabolism have also been suspected of playing a role in the development of type 2 diabetes mellitus (3,4,5), and the possibility of a shared pathophysiology of PD and type 2 diabetes mellitus has been put forth (6,7). However, observational studies investigating the association of these two disorders are scarce. Two recent case-control studies provided evidence for a possibly reduced risk for PD in diabetic patients (8,9), others reported a higher diabetes prevalence in PD patients (10,11), and recent data from the Nurses Health Study suggest that the risk of developing PD does not differ between patients with or without diabetes mellitus (12). To our knowledge, the risk of developing an incident diagnosis of diabetes mellitus in PD patients has not yet been explored. Studies from the seventies described PD patients with hyperglycemia and hyperinsulinemia and raised the proposition that levodopa may be associated with an increased diabetes risk (13, 14), whereas bromocriptine increased insulin sensitivity in an animal model (15). We conducted a large population-based study in two parts. The aim of the first part was to assess the prevalence of diabetes mellitus in patients with newly diagnosed PD and to compare it to patients without PD. The aim of the second part was to quantify the risk of new onset diabetes mellitus in PD patients and to compare it to patients free of PD, as well as to assess the possible role of antiparkinson medication on the risk of developing an incident diabetes diagnosis. RESEARCH DESIGN AND METHODS Data Source: We used the UK-based General Practice Research Database (GPRD) which contains computerized medical records of over five million people who are registered with selected general practitioners (GPs) (16, 17, 18). In the UK, GPs are responsible for primary healthcare as well as for referrals to specialists and for hospitalizations (except in emergency situations). They record information on patient demographics (age, gender, weight, and height), diagnoses, drug prescriptions, referrals and hospital admissions as well as some lifestyle information (e.g. smoking status). The recorded information on drug exposure and on diagnoses in the GPRD has been validated repeatedly and proven to be of high quality (19,20). The GPRD, one of the world s largest databases of anonymized patient records, is managed by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. The patients enrolled in the GPRD are representative of the UKpopulation with regard to age, gender, geographic distribution and annual turnover rate (16), and GPRD data have been used in previous studies on PD (21,22,23,24,25). The study protocol was reviewed and approved by the Independent Scientific Advisory Committee for MHRA database research (ISAC). The investigators had only access to anonymized information. Study population: The base population consisted of all patients in the GPRD who were 40 years old between January 1, 1994 and December 31, Within this base population we identified all patients with a recorded first-time diagnosis of idiopathic PD and - at random - an equally sized comparison group of subjects without PD. We matched this comparison group to PD patients on age (same year of birth), gender, general practice (i.e. PD patients and the comparison subject 3

4 had to be enrolled with the same GP), date of the first PD diagnosis and years of history in the GPRD prior to this PD diagnosis date. PD cases and patients from the comparison group had to have at least three years of medical history in the computer record prior to the index date. The PD patients and the 1:1 matched sample of PD-free patients (i.e. the comparison group) formed the study population. We only included PD cases with an incident diagnosis of idiopathic PD, which we defined as follows: PD cases must not have had more than one prescription for an antiparkinson medication recorded prior to the index date which was characterized by the first recording of an OXMIS- [Oxford Medical Information System] code 342 [ Paralysis agitans ] or 342 D [ idiopathic parkinsonism ] or READ-codes F [ Parkinson s disease ], F12z.00 [ Parkinson s disease NOS ] or F [ Paralysis agitans ], must not have received any prescription for drugs known to induce parkinsonism ( typical antipsychotic drugs, metoclopramide or cinnarizine) within 180 days prior to the recorded PD diagnosis, and must have received at least two prescriptions for antiparkinson drugs after the index date in order to be eligible to be included in the analysis. Part 1: Assessment of the diabetes prevalence in PD patients and in the comparison group We assessed and compared the prevalence of diabetes mellitus, demographic characteristics and a range of previously recorded diagnoses of chronic diseases such as hyperlipidemia, asthma / COPD, dementia, and various cardiovascular and neurological diseases prior to the PD diagnosis date (and the corresponding date in the comparison group). We expressed relative risk estimates as odds ratios (ORs) with 95% confidence intervals (CI), and we adjusted the crude OR for comorbidities in a multivariate conditional logistic regression analysis. Part 2: Assessment of incident diabetes in PD patients and in the comparison group: Cohort analysis From the study population of PD cases and matched PD-free comparison patients, we excluded those with a history of diabetes prior to the first recorded PD diagnosis (or the corresponding date in the matched comparison group), as well as patients with a history of cancer, HIV, alcoholism or drug abuse. We followed both, the remaining newly diagnosed PD patients and the matched PD-free comparison group, from the start of follow-up date (i.e. the date of the PD diagnosis or the corresponding date in the PD-free comparison group) and identified all patients in the study population who developed new onset diabetes mellitus during follow-up. We accumulated persontime from the start date until a patient developed diabetes, died, the medical record ended or the end of the study was reached (December 31, 2005), whichever came first. The date when a case had the first-time diagnosis of diabetes recorded will be referred to as index date. In order to be included in the analysis as a valid incident diabetes case, a patient had to have a documented code for diabetes mellitus recorded and must have either received treatment with antidiabetic drugs (insulin or oral antidiabetics or both) after the date of the first diabetes diagnosis, or if no antidiabetic drug use was recorded in the medical record notes such as diabetic on diet only had to be recorded by the GP. If no treatment and no diet recommendation were recorded, we excluded the case. If a potential case had antidiabetic treatment recorded shortly prior to the index date, we included the case and corrected the index date. If a case had a long-standing history of antidiabetic drug use prior to the index date, and/or if the index date was not clear for other reasons, we excluded the case. For the purpose of this case validation we manually reviewed computer records of all potential 4

5 cases, blinded to the subject s exposure status (i.e. PD or non-pd group). We assessed incidence rates (IRs) of firsttime diagnosed diabetes in the PD population and in the PD-free comparison group, and we calculated relative risk estimates with 95% CIs by comparing diabetes incidence rates between PD patients and the comparison group. Nested case-control analysis: In order to identify potential risk factors for diabetes, to adjust the analysis on the association between PD and the risk of developing diabetes for such potential confounders, and to stratify PD patients by antiparkinson medication used, we conducted a nested case-control analysis. We identified at random for each incident diabetes case up to four control patients from the study population who did not develop diabetes, and we matched these controls to cases on age (± 3 years), gender, and calendar time. Controls had to be alive at the index date. We assessed for all diabetes cases and their controls whether they had PD or not, what antiparkinson medication (if any) they were using prior to the index date, how many prescriptions they had and at what point in time the last prescription was recorded prior to the index date. If the last prescription was recorded within 90 days prior to the index date, the patient was a current user, and if this was > 3 months before the index date the patient was a past user. We also assessed smoking status (non, current, ex, unknown), body mass index (BMI) (< 25, , 30+ kg/m 2 or unknown), as well as recorded chronic diseases such as hypertension, hyperlipidemia or ischemic heart disease (IHD). We conducted conditional logistic regression analyses to explore the relative risk of developing a diabetes diagnosis in association with previously recorded PD, expressed as ORs with 95% CI, and adjusted this analysis by the parameters described above. In addition, since beta-blockers, diuretics and systemic steroids are known to be associated with an increased diabetes risk, we also assessed the number and the timing of previous prescriptions for these drugs and compared such drug use prior to the index date between diabetes cases and controls. Furthermore, we stratified the main analysis on the PD-diabetes association by age, sex and antiparkinson medication used. All statistical analyses were performed with SAS software, Version 9.1 (SAS Institute, NC, USA). RESULTS The study population encompassed subjects (3 637 PD cases and matched subjects in the comparison group free of PD), of which 60% were men. Approximately 90% of the PD cases had their first PD diagnosis recorded after the age of 60 years. Part 1: Assessment of the diabetes prevalence in PD patients and in the comparison group--a prevalent diagnosis of diabetes mellitus was recorded in 291 (8%) of PD cases and in 308 (8.5%) of patients free of PD, yielding an OR of 0.95 (95% CI ), adjusted for BMI, smoking, asthma / COPD, dementia, hypertension, IHD, congestive heart failure (CHF), stroke / transient ischemic attack (TIA), arrhythmia, hyperlipidemia, epilepsy, affective disorders, schizophrenia, neurotic and somatoform disorders. Part 2: Assessment of incident diabetes in PD patients and in the comparison group Cohort analysis: During follow-up, we identified 106 patients with an incident diabetes diagnosis who met the inclusion criteria as described above. Based on the specific codes used by the GP and on the treatment pattern, all had type 2 diabetes; of them, 35 (33%) had a prior PD diagnosis, and 71 (67%) had no history of PD, yielding a crude relative risk of 0.55 (95% CI ) for PD patients as compared to patients in the comparison group. The results of the person- 5

6 time analyses are displayed in detail in Table 1. Nested case-control analysis: Patient characteristics of the 106 diabetes cases and their 424 matched controls in the nested casecontrol analyses are displayed in Table 2. A previous history of PD was associated with a decreased risk of developing an incident diabetes diagnosis (OR 0.53, 95% CI ), adjusted for age, gender, and calendar time (by matching) and for BMI, smoking status, hypertension, IHD, hyperlipidemia, exposure to systemic steroids, beta-blockers, or diuretics in the multivariate model. The diabetes risk for patients with PD tended to be slightly higher in men than in women, and stratification by age resulted in a reduced risk for patients < 75 years of age (Table 3). Both p-values for effect modification were > We further stratified PD patients by use of antiparkinson medication prior to the diabetes diagnosis. The adjusted OR for developing diabetes for PD patients with current levodopa exposure of more than five prescriptions prior to the diabetes diagnosis was 0.22 (95% CI ), compared to patients without PD (and therefore no levodopa use). The adjusted OR for PD patients not receiving levodopa prior to the diabetes diagnosis was 1.11 (95% CI ), as compared to patients without PD (Table 3). A direct comparison between PD patients with current levodopa use with the reference group of PD patients without levodopa use yielded an OR of 0.30 (95% CI ). There were too few prescriptions for other antiparkinson drugs to conduct further analyses on their effects. CONCLUSIONS In the first part of this large primary-care based observational study, the prevalence of diabetes at the date of the first-time PD diagnosis was closely similar to a randomly selected, matched comparison group of patients without diagnosed PD (OR 0.95, 95% CI ). Two recent case-control studies also explored the association between diabetes and PD (8,9). In one study, encompassing 352 PD cases and 484 controls, the risk for PD was significantly reduced in men with a previous diabetes diagnosis (OR 0.52, 95% CI ), but not in women (OR 0.80, 95% CI ) (8). The authors of the second study, a hospital-based case-control analysis including 178 PD cases and 533 controls, reported a substantially lower diabetes prevalence in PD cases (3.4%) than in controls (10.9%), yielding a crude OR of 0.30 (95% CI ) (9). The authors stated, however, that the OR was no longer statically significantly reduced when they applied a multivariate analysis, but they did not provide more details (9). In contrast, a prospective follow-up study in Finland identified 633 incident PD cases and found an increased risk of developing PD in diabetics as compared to patients without diabetes (Hazard ratio 1.85, 95% CI ) (11). A higher prevalence of diabetes has also been reported in PD patients in a cross-sectional survey (10). Finally, a recent prospective analysis of data from the Nurses Health Study and the Health Professionals Follow-up Study encompassing 530 incident PD cases found no evidence for a difference in the risk of developing PD between patients diabetics and patients without diabetes (Relative risk 1.04, 95% CI ) (12), a finding which is consistent with our observation. Thus, previous studies exploring the association between diabetes and PD risk produced inconsistent results, whereby the methodology of these studies differed substantially: Furthermore, most of these studies were rather small in size with case groups around 200 to 500 patients, while our study encompassed a much larger PD population. A potential confounder of the association between diabetes and PD risk may be obesity. 6

7 While obesity is a well-known risk factor for type 2 diabetes (26), results from observational studies on the association between obesity and PD are ambiguous. Authors of a large US-based observational study concluded that their findings did not support a role of obesity in the PD pathogenesis (27), but others reported an association between obesity and an increased PD risk in observational studies (28,29). In our analysis, the BMIs of PD patients and PDfree controls did not differ substantially at the date of the first PD diagnosis or the corresponding date in the PD-free comparison group; as compared to the reference group of subjects with a BMI < 25 kg/m 2, the relative risk estimates of developing PD for subjects with a BMI of kg/m 2 (OR 1.00, 95% CI ) or of 30 kg/m 2 (OR 0.88, 95% CI ) were close to 1.0. We not only assessed the association between diabetes and the risk of developing PD (part 1), but also of developing new onset diabetes associated with a previous PD diagnosis (part 2). To our knowledge the association between PD and the risk of developing a subsequent incident diabetes diagnosis has not been studied before. The findings of the present analysis suggest that incident diabetes occurs less frequently in patients with PD as compared to those without PD (OR 0.53, 95% CI ). The substantial diabetes risk reduction seen in association with PD was driven by levodopa users, while the risk for developing diabetes was not altered for PD patients not using levodopa. We cannot tell whether this finding points to a causal association, whether it is the result of some bias, or whether it is chance finding. It is in some contrast to a report from the seventies in which levodopa was orally administered for one year to 23 patients and caused substantially impaired glucose tolerance in the majority of these patients (14). The authors explained their findings by a possibly increased glycogenolysis and inhibition of peripheral glucose utilization caused by levodopa. This result was not confirmed by other authors who exposed patients with levodopa for at least three months (13), which lead to a slight improvement of the fasting serum glucose and insulin sensitivity. However, the study was small and the observed effect did not reach statistical significance (13). Our study has several limitations: Both PD and diabetes are diseases of slow onset, and therefore the onset of disease precedes the actual diagnosis date recorded in the database (which we used as the index date). For this reason we only included PD patients who did not have antiparkinson medication prior to the first diagnosis date to reduce the likelihood of including prevalent cases with a longer-term history of PD symptoms. In addition, we only included diabetes cases in the follow-up portion of the study whose medical records provided evidence that the diagnosis was incident, i.e. followed by a newly introduced antidiabetic treatment. It is further possible that we did not capture all diabetes cases during follow-up since diabetes may go undetected due to the lack of specific clinical symptoms. Ideally, this may have occurred at random, i.e. regardless of a previous PD diagnosis, leading to a risk reduction towards to null. However, it is also possible that the likelihood of detecting diabetes did not occur at random, but dependent on disease status and therefore to some degree on medical attention. In this latter case, however, one might rather expect higher medical awareness in PD cases than in the comparison group of patients free of PD, which would have biased towards an increased diabetes risk. We adjusted the nested case-control analysis for a variety of BMI, various chronic diseases and various drugs which reflect overall morbidity and which are known risk factors for diabetes. These adjustments did not materially change the association between 7

8 PD and the risk of developing new onset diabetes. In summary, the findings of the first part of this observational study suggest that the prevalence of diabetes does not substantially differ between patients with newly diagnosed PD and subjects without PD. The results of the second part suggest that the risk of developing an incident diabetes diagnosis tends to be lower in PD patients than in subjects without PD. This effect was limited to PD patients who used levodopa. ACKNOWLEDGEMENT The study was supported by an unconditional grant by AstraZeneca, Sweden. 8

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11 TABLE 1: Number of diabetes cases and incidence rates (IR) per person years, stratified by age and sex Patients with PD diagnosis Non-PD patients N p-years IR (95 % CI) N p-years IR (95 % CI) IRR (95 % CI) All ( ) ( ) 0.55 ( )* Men ( ) ( ) 0.61 ( ) Women ( ) ( ) 0.47 ( ) ys ys ( ) ( ) 0.22 ( ) ys ( ) ( ) 0.73 ( ) ys ( ) ( ) 0.55 ( ) 80 ys ( ) ( ) 0.57 ( ) * as compared to all non-pd patients as compared to male non-pd patients as compared to female non-pd patients as compared to controls of the same age group 11

12 TABLE 2: Distribution of characteristics and comorbidities in cases and controls in the nested case-control analysis Characteristics Diabetic cases (n=106) Controls (n=424) Adjusted OR* (95% CI) No. (%) No. (%) Age, years (10.4) 39 (9.2) (62.3) 266 (62.7) (27.3) 119 (28.1) -- Sex Male 65 (61.3) 260 (61.3) -- Female 41 (38.7) 164 (38.7) -- Smoking status Non 56 (52.8) 243 (57.3) 1.00 (referent) Current 9 (8.5) 47 (11.1) 0.94 ( ) BMI (kg/m²) < (15.1) 141 (33.3) 1.00 (referent) (39.6) 135 (31.8) 2.52 ( ) (26.4) 46 (10.9) 3.80 ( ) Comorbidities IHD 50 (27.2) 163 (22.2) 1.30 ( ) Hypertension 58 (54.7) 144 (34.0) 1.49 ( ) Dyslipidemia 18 (17.0) 43 (10.1) 1.40 ( ) Prior drug use Beta-blockers 26 (24.5) 55 (13.0) 1.44 ( ) Diuretics 47 (44.3) 88 (20.8) 2.79 ( ) Systemic steroids 8 (7.6) 12 (2.8) 6.66 ( ) * adjusted for covariates in this Table most recent drug prescription within 3 months before the index date and 5 prescriptions in total 12

13 TABLE 3: Risk of diabetes in the nested case-control analysis Parameter Cases (%) (n=106) Controls (%) (n=424) Adjusted OR* (95% CI) No PD 71 (67.0) 209 (49.3) 1.00 (ref.) PD 35 (33.0) 215 (50.7) 0.53 ( ) Men 23 (65.7) 136 (63.3) 0.57 ( ) Women 12 (34.3) 79 (36.7) 0.34 ( ) ys 18 (51.4) 121 (56.3) 0.44 ( ) 75 ys 17 (48.6) 94 (43.7) 0.71 ( ) No use of L-Dopa 13 (37.1) 47 (21.9) 1.11 ( ) Current use of L-Dopa 11 (31.4) 131 (60.9) 0.22 ( ) Any other use of L-Dopa 11 (31.4) 37 (17.2) 0.88 ( ) * adjusted for covariates from Table 2 of 5 prescriptions before the diabetes diagnosis current use of < 5 prescriptions or past use 13