There are no data on the incidence of new-onset diabetes mellitus (NODM ) in nondiabetic dyslipidaemia patients treated with fibrates. The aim of our study was to clarify these issues, to investigate the relationship between NODM and fibrate and whether the fibrates lead to increased risk for developing NODM. A retrospective cohort study was conducted by analyzing the Longitudinal Health Insurance Database (LHID 2005) of the National Health Insurance Research Database (NHIRD) from 2005 to 2010 to investigate all fibrate prescriptions for patients with dyslipidaemia. We estimated the hazard ratios (HRs) of NODM associated with fibrate use. We identified 145 NODM patients among 3,815 dyslipidaemic patients in the database for the study period. The risk estimates for NODM for users of fenofibrate (HR 1.30; 95% CI 0.82, 2.05) and gemfibrozil (HR 0.771; 95% CI 0.49, 1.22) were not associated with an increased risk of developing NODM (
Many trials demonstrated the effectiveness of fibrates in improving dyslipidemia by lowering elevated plasma triglycerides, which are the most clinically used therapeutics in the treatment of hypertriglyceridemia. Several clinical trials have indicated a benefit of fibrate treatment in cardiovascular risk reduction and improvement of lipid profiles [
Statins are the first-choice agents for reducing LDL-C that significantly reduces cardiovascular events, these benefits apply to people with and without a history of diabetes mellitus (DM) [
Three subtypes of PPAR (peroxisome proliferator-activated receptors) receptors, PPAR
Studies demonstrated that intensive-dose statin therapy was associated with a higher risk for NODM compared with moderate dosing, and the results confirmed a dose-dependent relationship for NODM [
A retrospective cohort study was conducted using the Longitudinal Health Insurance Database (LHID 2005) of the National Health Insurance Research Database (NHIRD) from 2005 to 2010 to investigate the fibrate prescriptions of patients with dyslipidaemia. We used the International Classification of Diseases, Ninth Revision (ICD-9) Clinical Modification code to define dyslipidaemia (ICD-9 codes 272), and diabetes mellitus (ICD-9 code 250).
This study initially included 54,161 patients that had dyslipidaemia without diabetes mellitus at baseline (1 January 2005), excluded 19,209 patients with diabetes mellitus from 2002 to 2004, and excluded another 8,494 patients that had used fibrates from 1 January 2004 to 1 December 2004. We identified subjects who received a diagnosis of NODM during the 5-year study period. Two types of fibrates (fenofibrate and gemfibrozil) were included for analysis. In Taiwan, these two drugs are available only by prescription. Patients who had used only one type of fibrate on a regular basis before the date NODM was diagnosed were categorized according to the fibrate type that they took. Of the remaining patients, 22,643 were excluded based on the use of nonfibrate drugs between 1 January 2005 and 1 December 2010. In January 2005, 3,815 nondiabetic dyslipidaemia outpatients (mean age, 55.59) were enrolled in the study. The primary endpoint of the study was NODM, which was defined as the first time that a diabetes code or prescription for antihyperglycemic drugs appeared in the outpatient claim records (Figure
Flowchart of the selection of patients for inclusion.
Continuous variables are presented as mean ± SD. Differences in continuous variables were analysed using the unpaired Student’s
Of the 3,815 eligible participants, 145 (3.8%) developed NODM. There was no significant difference in age between the NODM and non-NODM patients; the mean ages in the female and male group were 56.10 and 55.57 years. Males comprised more than half (2,385 (62.52%)) of the sample population (Table
Descriptive characteristics of fibrate prescriptions in the population, 2005–2010.
Characteristics | NODM | No-NODM | Total |
|
|||
---|---|---|---|---|---|---|---|
|
% |
|
% |
|
% | ||
Total | 145 | 3.8 | 3,670 | 96.2 | 3,815 | 100 | |
Age (year, mean ± SD) |
|
|
|
0.616 | |||
Gender | |||||||
Female | 58 | 40.00 | 1,372 | 37.38 | 1,430 | 37.48 | 0.523 |
Male | 87 | 60.00 | 2,298 | 62.62 | 2,385 | 62.52 | |
Drug group | |||||||
Fenofibrate | 104 | 71.72 | 2,702 | 73.62 | 2,806 | 73.55 | 0.611 |
Gemfibrozil | 41 | 28.28 | 968 | 26.38 | 1,009 | 26.45 | |
Mean dose | |||||||
Fenofibrate |
|
|
|
0.048 | |||
Gemfibrozil |
|
|
|
0.198 |
Differences in continuous variables were analysed using the unpaired student’s
Categorical variables were analysed using by either Fisher’s exact test or the chi-squared test.
Approximately 73.55% (2,806) of the patients took fenofibrate, and 26.45% (1,009) took gemfibrozil. No significant differences were observed in the mean doses of gemfibrozil prescribed between the groups; however, there was a significant difference in the mean doses of fenofibrate between the NODM and non-NODM patient groups (
Use of fenofibrate (HR 1.30; 95% CI 0.82, 2.05) and gemfibrozil (HR 0.771; 95% CI 0.49, 1.22) was not associated with an increased risk of developing NODM (
Cox analysis of fibrate prescriptions in the population, 2005–2010.
Variables | Unadjusted | Adjusteda | ||||
---|---|---|---|---|---|---|
HR | 95% C.I. |
|
HR | 95% C.I. |
|
|
Fenofibrate | 0.91 | 0.64–1.31 | 0.614 | 1.30 | 0.82–2.05 | 0.263 |
Gemfibrozil | 1.10 | 0.76–1.58 | 0.614 | 0.771 | 0.49–1.22 | 0.263 |
Multiple Cox regression models were used to estimate the relationship between sex, age, medication, and mean dose of fibrates and development of NODM.
In this retrospective longitudinal cohort study, we found that patients with dyslipidaemia who took fenofibrate and gemfibrozil were not associated with an increased risk of developing NODM and had a neutral risk of NODM. The possible reasons may be as follows. The PPAR nuclear receptor subfamily regulates a number of metabolic processes, including fatty acid
There was a significant difference in the mean doses of fenofibrate. We could find that the HR of fenofibrate was 1.30 (95% CI 0.82, 2.05), which tends to increase the risk of developing NODM, and
While FAs are essential biological components, elevated concentrations of circulating FAs are linked to a variety of disease states including obesity, atherosclerosis, and non-insulin-dependent diabetes mellitus (NIDDM). Thus, physiologic levels of FAs levels must be maintained within narrow limits [
Some limitations of this study need to be emphasized. This was a descriptive, retrospective study conducted in Taiwan over a period of 5 years. Establishing cause and effect for each of the fibrates was not possible in this study. All cases in this study were collected from claim datasets of primary care clinics. Diagnoses (diagnostic codes: dyslipidaemia) were based on physician reporting only in Taiwan, and the risk factors for diabetes mellitus, such as obesity, family history, treatment adherence and diet, were not available in these secondary data. However, in the population-based data used here, we assumed that there were no differences among the two fibrate groups; therefore, it is not clear how our findings can be generalized to patients in different areas. Some of the apparent differences between the fibrates might potentially be explained by differences in total exposure to the different fibrates. Our data were taken from claim forms provided to the central regional branch of the BNHI in Taiwan from January 2002 to December 2010. Some of the apparent differences between the fibrates might potentially be explained by differences in total exposure to the different fibrates. Our data were taken from claim forms of the Bureau of National Health Insurance (BNHI) as a surrogate for drug exposure; the actual cholesterol levels that were achieved in the studied population were not known. However, physicians prescribed fibrates according to the BNHI guidelines in Taiwan.
Our results revealed that patients with dyslipidaemia who took fenofibrate and gemfibrozil were not associated with an increased risk of developing NODM and had a neutral risk of NODM. The reasons may be associated with the fact that fibrates have the properties that activate PPAR
All authors have declared no conflict of interests and do not have a direct financial relation with the commercial identity mentioned in this paper.