The Food and Drug Administration recently updated the safety warning concerning the association between statin therapy and new-onset diabetes mellitus (NODM). For prediabetes, little information is available for statins on cardiovascular outcome reduction and diabetogenic consequences. This study aimed to examine the risk of NODM and the reduction of cardiovascular events and death (MACE) after statin therapy in the prediabetic subjects. The medical and pharmacy claims of the prediabetic beneficiaries were retrieved from Taiwan National Health Insurance research database. The occurrence of NODM, MACE, and morbidity indexed by hospitalizations and emergency visits was ascertained by ambulatory and inpatient database. A propensity score–matched model was constructed for statin users and nonusers. During follow-up (4.1 ± 2.5 years), NODM and MACE occurred in 23.5% and 16.7%, respectively, of nonusers and 28.5% and 12.0%, respectively, of users. Statin therapy was associated with a greater risk of NODM (hazard ratio 1.20, 95% confidence interval 1.08 to 1.32) and less risk of MACE (hazard ratio 0.70, 95% confidence interval 0.61 to 0.80), both in dose-dependent fashions. The earlier and more persistent use correlated with the greater increase in risk of NODM offset by the proportionally larger reduction in MACE. Furthermore, the early persistent users had the lowest rate of hospitalizations and emergency visits. In conclusion, our findings suggested that the relation between NODM and therapeutic advantages of statins was parallel in the prediabetic population. Treatment benefits outweighed diabetic consequences in subjects receiving the earlier and more persistent treatment.
Statins effectively reduce atherosclerotic complications, irrespective of the level of glucose metabolism disturbance. However, statin therapy is associated with an increased risk of new-onset diabetes mellitus (NODM). Previous analyses indicated that the risk of NODM was significantly outweighed by the reduction in vascular events or deaths among subjects with cardiovascular disease (CVD). Post hoc analyses of clinical trials identified that subjects with diabetes mellitus (DM) risk factors were at greater risk of NODM after statin therapy, particularly those who had impaired fasting glucose. Because clinical trials enrolled subjects who can be randomized into therapeutic allocations among prespecified populations, the conducts in trials do not always reflect usual clinical practice. Meanwhile, the population studies demonstrated the ethnic differences in the risk of NODM and in the distributions of metabolic risk factors attributed to CVD. The purpose of this study was to evaluate the disadvantages and advantages of statin therapy with regards to NODM and the reduction of major adverse cardiovascular events (MACEs) in the prediabetic population and to explore whether the earlier and more persistent statin therapy attenuates subsequent adverse outcomes in prediabetic subjects.
Methods
The Taiwan National Health Insurance research database (NHIRD) is the representative healthcare database of the Taiwan population. The longitudinal data from 2001 to 2010 were obtained for this retrospective analysis.
Prediabetic subjects as the presence of International Classification of Diseases, Ninth Revision codes for abnormal glucose in the medical claims, who had not been prescribed antidiabetic medications at the consecutive visits (≥30 days apart), were identified. Among them, subjects aged ≥45 years, who continuously received statins ≥7 days before having a DM diagnosis, or those naive to statins before a DM diagnosis were enrolled. Those who had endocrine disorders, who ever received systemic steroid or hypolipidemic agents other than statins, or who had follow-up <30 days were excluded. Co-morbidities were confirmed by International Classification of Diseases, Ninth Revision codes in the medical claims.
The length of statin exposure was counted cumulatively from the date of prescription. The cumulative dose was calculated and converted to the dose equivalent to the strength of simvastatin 20 mg according to the Food and Drug Administration recommendation ( http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm ). According to the prescription patterns from the pharmacy claims, statin users were further divided into following 3 groups: statin users after prediabetes (the initial statin prescription date on or after the first prediabetes diagnosis date), early nonpersistent users (the initial statin prescription date before the first prediabetes diagnosis date and the adherence <80%), and early persistent users (the initial statin prescription date before the first prediabetes diagnosis date and the adherence ≥80%).
The follow-up started from the date of a confirmed prediabetes diagnosis or the start of the continuous use of statins (for whom received statins after prediabetes). The occurrence of NODM was ascertained by the continuous prescription of antidiabetic medications ≥30 days. MACE was the composite of myocardial infarction, ischemic stroke, coronary revascularization, and death. The morbidity was assessed by overall hospitalizations and emergency visits.
Because the use of statins was not randomly assigned to study subjects, the effect of treatment selection bias and potential confounding in this observational study were mitigated by the propensity score–matching approach. The propensity for statin therapy was determined by using the logistic regression model regardless of outcomes, and a propensity score for the use of statins was calculated for each subject.
Baseline characteristics among groups are expressed as mean ± SDs or counts with percentages, as applicable. Continuous variables were compared by Student t tests or one-way analysis of variance, and categorical variables were compared by chi-square tests. Kaplan-Meier plots were constructed with comparisons between curves by log-rank tests. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI). To assess the impact of different patterns of statin therapy, multivariate Cox models adjusted for baseline characteristics were further applied. The Mantel-Haenszel test evaluated whether the linear relation between statin therapy and the composite of hospitalizations and emergency visits existed.
The data were linked and processed by Microsoft SQL Server 2008, and the statistical analyses were performed with SPSS 16 (SPSS Inc., Chicago, Illinois). A 2-tailed p value <0.05 was considered statistically significant for all analyses.
Results
There were 9,055 subjects enrolled in this study. Of them, 3,288 subjects had received statins. Table 1 reports baseline characteristics before and after propensity score matching. The cardiovascular and noncardiovascular background of 3,069 pairs of subjects after matching was similar as opposed to the entire cohort. During the mean follow-up of 4.1 ± 2.5 years, NODM and MACE occurred in 23.5% and 16.7%, respectively, of nonusers and 28.5% and 12.0%, respectively, of users. Statin therapy was associated with the increased occurrence of NODM (HR 1.20, 95% CI 1.08 to 1.32, p <0.001) and the reduction in MACE (HR 0.70, 95% CI 0.61 to 0.80, p <0.001) compared with nonusers ( Figure 1 ).
| Variable | Overall Cohort | Propensity Score–Matched Cohort | ||||
|---|---|---|---|---|---|---|
| Nonuser, n = 5,767 (%) | Statin User, n = 3,288 (%) | p Value | Nonuser, n = 3,069 (%) | Statin User, n = 3,069 (%) | p Value | |
| Age (yrs) | 67 ± 9 | 66 ± 9 | <0.001 | 66 ± 9 | 66 ± 9 | 0.927 |
| Women | 2,910 (51) | 1,793 (55) | <0.001 | 1,689 (55) | 1,692 (55) | 0.939 |
| Hypertension | 4,389 (76) | 2,570 (78) | 0.026 | 2,400 (78) | 2,378 (78) | 0.499 |
| Coronary heart disease | 2,623 (46) | 1,358 (41) | <0.001 | 1,256 (41) | 1,250 (41) | 0.876 |
| Coronary revascularization | 30 (1) | 93 (3) | <0.001 | 6 (<1) | 3 (<1) | 0.317 |
| Myocardial infarction | 83 (1) | 123 (4) | <0.001 | 59 (2) | 56 (2) | 0.778 |
| Ischemic stroke | 271 (5) | 195 (6) | 0.011 | 178 (6) | 165 (5) | 0.470 |
| Heart failure | 546 (10) | 291 (9) | 0.329 | 250 (8) | 257 (8) | 0.746 |
| Peripheral arterial disease | 143 (3) | 88 (3) | 0.568 | 80 (3) | 84 (3) | 0.752 |
| Charlson index | 2 ± 2 | 2 ± 2 | 0.851 | 2 ± 2 | 2 ± 2 | 0.221 |
| Ambulatory care visit, per yr | 14 ± 14 | 18 ± 22 | <0.001 | 16 ± 15 | 16 ± 14 | 0.462 |
| Plasma glucose test, per yr | 1.6 ± 4.9 | 1.9 ± 5.1 | 0.013 | 1.7 ± 5.1 | 1.7 ± 3.8 | 0.834 |
The most commonly prescribed statins were lovastatin, followed by atorvastatin and simvastatin. The average dose was 10 mg/day for atorvastatin, 46 mg/day for fluvastatin, 21 mg/day for lovastatin, 11 mg/day for pravastatin, 17 mg/day for simvastatin, and 8 mg/day for rosuvastatin. Table 2 summaries the relation of the characteristic use of stains with NODM and MACE. The commonly prescribed statins were more pronouncedly associated with NODM development. All statins, except rosuvastatin, were consistently associated with a lower rate of MACE. Statin therapy constantly correlated with the increased occurrence of NODM and the reduction in MACE across dosages and treatment duration. Furthermore, there was a consistent trend of dose-proportional diabetogenic risk of statins (both maximal and mean daily doses and exposure duration).
| NODM | MACE | |||
|---|---|---|---|---|
| HR (95% CI) | p | HR (95% CI) | p | |
| Statin nonuser (n = 3,069) | Reference | Reference | ||
| Atorvastatin (n = 1,136) | 1.28 (1.12–1.47) | <0.001 | 0.78 (0.64–0.95) | 0.012 |
| Fluvastatin (n = 653) | 1.13 (0.96–1.33) | 0.157 | 0.66 (0.52–0.85) | 0.001 |
| Lovastatin (n = 1,352) | 1.14 (1.01–1.30) | 0.035 | 0.63 (0.53–0.76) | <0.001 |
| Pravastatin (n = 662) | 1.15 (0.98–1.35) | 0.085 | 0.70 (0.56–0.88) | 0.002 |
| Rosuvastatin (n = 167) | 1.19 (0.79–1.78) | 0.412 | 0.58 (0.27–1.22) | 0.149 |
| Simvastatin (n = 1,098) | 1.22 (1.07–1.39) | 0.004 | 0.77 (0.64–0.92) | 0.004 |
| Single statin (n = 1,764) | 1.22 (1.09–1.36) | 0.001 | 0.72 (0.62–0.84) | <0.001 |
| Multiple statins (n = 1,305) | 1.17 (1.03–1.33) | 0.019 | 0.67 (0.55–0.80) | <0.001 |
| Maximal daily equivalent dose ∗ | <0.001 † | <0.001 † | ||
| <20 mg (n = 1,569) | 1.17 (1.04–1.31) | 0.009 | 0.69 (0.58–0.81) | <0.001 |
| ≥20 mg (n = 1,500) | 1.23 (1.09–1.39) | 0.001 | 0.71 (0.60–0.85) | <0.001 |
| Mean daily equivalent dose ∗ | <0.001 † | <0.001 † | ||
| <20 mg (n = 2,224) | 1.16 (1.05–1.29) | 0.005 | 0.71 (0.61–0.82) | <0.001 |
| ≥20 mg (n = 845) | 1.30 (1.12–1.51) | 0.001 | 0.66 (0.53–0.84) | 0.001 |
| Persistence | <0.001 † | <0.001 † | ||
| Statin <1 yr (n = 2,101) | 1.12 (1.00–1.25) | 0.048 | 0.71 (0.62–0.83) | <0.001 |
| Statin ≥1 yr (n = 968) | 1.40 (1.22–1.61) | <0.001 | 0.66 (0.53–0.82) | <0.001 |
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