There have been several reports showing that the statin use is associated with new-onset diabetes mellitus (DM). The aim of the present study was to evaluate the impact of chronic statin use on development of new-onset DM in a series of Asian population. The patients were retrospectively enrolled using the electronic database of Korea University Guro Hospital from January 2004 to February 2010. A total of 10,994 patients without a history of diabetes were analyzed. Baseline lipid profiles, fasting glucose, Hemoglobin (Hb) A1c, and glucose tolerance tests were measured in all patients before statin treatment. Included patients had HbA1c ≤5.7% and fasting glucose level ≤100 (mg/dl). The patients were divided into 2 groups according to the use of statins (the statin group, n = 2,324 patients and the nonstatin group, n = 8,670 patients). To adjust baseline potential confounders, a propensity score–matched analysis was performed using logistic regression model. After propensity score matching, 2 propensity-matched groups (1,699 pairs, n = 3,398, C statistic = 0.859) were generated and analyzed. After propensity score matching, baseline characteristics of both groups were balanced except that the statin group was older and had higher rate of coronary artery disease compared with the nonstatin group. During a 3-year follow-up, the statin group had higher incidence of new-onset DM compared with the nonstatin group (hazard ratio 1.99, 95% CI 1.36 to 2.92, p <0.001), but the statin group showed lower incidence of major adverse cerebral-cardiovascular events compared with the nonstatin group (hazard ratio 0.40, 95% CI 0.19 to 0.85, p <0.001). In the present study, although the use of statins was associated with higher rate of new-onset DM, it markedly improved 3-year cardiovascular outcomes in Asian population.
The statins are widely used for cardiovascular disease prevention and which are clearly supported by clinical evidence. However, there have been several debates, and there have been several reports showing that the statin use is associated with a slightly higher incidence of new-onset diabetes mellitus (DM). However, there are limited data regarding the impact of chronic statin use on the development of new-onset DM in Asian population, especially in patients without DM. Therefore, the aim of the present study was to evaluate the impact of chronic statin use on the development of new-onset DM in patients without DM and impaired glucose tolerance (IGT) in a series of Asian population.
Methods
A total of 65,686 consecutive patients who visited cardiovascular center of Korea University Guro Hospital (KUGH) from January 2004 to February 2010 were retrospectively enrolled using the electronic database of KUGH. All patients did lipid profiles, fasting glucose, Hemoglobin (Hb) A1c level, and glucose tolerance tests before statin treatment. Inclusion criteria included both HbA1c ≤5.7% and fasting glucose level ≤100 (mg/dl). Finally, a total of 10,994 patients without DM and IGT were analyzed. The study protocol was approved by the Institutional Review Board of KUGH.
New-onset DM was defined as fasting blood glucose ≥126 (mg/dl), HbA1c ≥6.5%, or the current use of hypoglycemic agents depending on the physician’s discretion. Major adverse cardiac and cerebral events (MACCEs) were defined as the composite of total death, nonfatal myocardial infarction, and cerebrovascular accidents. New-onset DM–related MACCE was defined as both new-onset DM and MACCE occurring at the same follow-up period. The primary study end point was the cumulative incidence of new-onset DM during 3-year clinical follow-up.
For continuous variables, differences between 2 groups were evaluated by unpaired t test or Mann–Whitney rank test. Data are expressed as mean ± SD. For discrete variables, differences were expressed as counts and percentages and analyzed with chi-square or Fisher’s exact test between the groups as appropriate. To adjust for potential confounders, propensity score–matched analysis was performed using the logistic regression model. We tested all available variables that could be of potential relevance: age, men, cardiovascular risk factors (hypertension, diabetes, heart failure, chronic kidney disease, coronary artery disease, and cerebrovascular accidents), comedication treatment (angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, β blockers, diuretics, and warfarin), and laboratory findings (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride). The logistic model by which the propensity scores were estimated showed good predictive value (C statistic = 0.859). Patients in the statin group were then one-to-one matched to those in the nonstatin group according to propensity scores with the nearest available pair matching method. Subjects were matched with a caliper width equal to 0.05. The procedure yielded 1,699 well-matched pairs. A 2-tailed p value of <0.05 was considered to be statistically significant. Various 3-year clinical outcomes were estimated with the Kaplan–Meier method, and differences between groups were compared with the log-rank test. All the statistical analyses were performed using SPSS 20.0 (SPSS Inc., Chicago, Illinois).
Results
In the present study, a total of 10,994 patients were finally enrolled. The patients were divided into 2 groups according to the use of statins (the statin group, n = 2,324 and the nonstatin group, n = 8,670). After propensity score matching (PSM), baseline characteristics of 2 propensity-matched groups (1,699 pairs, n = 3,398, C statistic = 0.859) were balanced except that the statin group were older and had a higher rate of coronary artery disease compared with the nonstatin group. The mean treatment days were 1,456 ± 791 days in the statin group (after PSM, 1,402 ± 782 days; Table 1 ).
| Variables, N (%) or mean ± SD | Overall Patients | Matched Patients | ||||
|---|---|---|---|---|---|---|
| Statin Use (n = 2324) | No Use (n = 8670) | p Value | Statin Use (n = 1699) | No Use (n = 1699) | P Value | |
| Gender (men) | 1318 (56.7 %) | 4033 (46.5 %) | < 0.001 | 883 (51.9 %) | 879 (51.7 %) | 0.891 |
| Age, (years) | 60.6 ± 10.8 | 51.1 ± 14.9 | < 0.001 | 59.8 ± 10.8 | 60.7 ± 12.4 | 0.027 |
| Body mass index, kg/m 2 | 24.4 ± 3.0 | 24.3 ± 3.4 | 0.091 | 24.5 ± 3.1 | 24.4 ± 3.6 | 0.576 |
| Hypertension | 1273 (54.7 %) | 3149 (36.3 %) | < 0.001 | 888 (52.2 %) | 904 (53.2 %) | 0.582 |
| Dyslipidemia | 597 (25.6 %) | 1125 (12.9 %) | < 0.001 | 388 (22.8 %) | 408 (24 %) | 0.418 |
| Coronary artery disease | 693 (29.8 %) | 386 (4.4 %) | < 0.001 | 253 (14.8 %) | 178 (10.4 %) | < 0.001 |
| Myocardial infarction | 208 (8.9 %) | 40 (0.4 %) | < 0.001 | 44 (2.5 %) | 31 (1.8 %) | 0.129 |
| Coronary revascularizations | 436 (18.7 %) | 63 (0.7 %) | < 0.001 | 73 (4.2 %) | 53 (3.1 %) | 0.069 |
| Coronary spasm | 101 (4.3 %) | 280 (3.2 %) | 0.009 | 79 (4.6 %) | 92 (5.4 %) | 0.308 |
| Cerebrovascular accidents | 438 (18.8 %) | 670 (7.7 %) | < 0.001 | 311 (18.3 %) | 329 (19.3 %) | 0.430 |
| Heart failure | 93 (4.0 %) | 259 (2.9 %) | 0.014 | 68 (4.0 %) | 69 (4.0 %) | 0.931 |
| Angina pectoris | 634 (27.2 %) | 1877 (21.6 %) | < 0.001 | 425 (25 %) | 412 (24.2 %) | 0.605 |
| Chest pain | 131 (5.6 %) | 729 (8.4 %) | < 0.001 | 96 (5.6 %) | 84 (4.9 %) | 0.358 |
| Arrhythmia | 178 (7.6 %) | 520 (5.9 %) | 0.004 | 122 (7.1 %) | 122 (7.1 %) | ns |
| Atrial fibrillation | 119 (5.1 %) | 267 (3.0 %) | < 0.001 | 82 (4.8 %) | 81 (4.7 %) | 0.936 |
| Cardiac arrhythmia | 95 (4.0 %) | 340 (3.9 %) | 0.715 | 64 (3.7 %) | 61 (3.5 %) | 0.785 |
| Fasting glucose, mg/dl | 94.1 ± 8.1 | 93.1 ± 8.0 | < 0.001 | 94.2 ± 7.8 | 94.2 ± 7.9 | 0.900 |
| Hemoglobin A1c, (%) | 5.5 ± 0.2 | 5.4 ± 0.2 | < 0.001 | 5.5 ± 0.2 | 5.5 ± 0.2 | 0.464 |
| Insulin, (ng/ml) | 7.5 ± 4.9 | 7.1 ± 5.3 | 0.072 | 7.6 ± 5.0 | 7.6 ± 5.4 | 0.945 |
| Total cholesterol, (mg/dL) | 179 ± 45 | 178 ± 33 | 0.100 | 181 ± 44 | 182 ± 34 | 0.664 |
| Triglyceride, (mg/dL) | 135 ± 93 | 122 ± 88 | < 0.001 | 135 ± 97 | 136 ± 118 | 0.866 |
| High-density lipoprotein cholesterol, (mg/dL) | 50 ± 13 | 53 ± 13 | < 0.001 | 52 ± 13 | 51 ± 14 | 0.508 |
| Low-density lipoprotein cholesterol, (mg/dL) | 113 ± 41 | 110 ± 29 | 0.008 | 114 ± 41 | 114 ± 30 | 0.733 |
| Medication treatment | ||||||
| Beta blockers | 641 (27.5 %) | 807 (9.3 %) | < 0.001 | 356 (20.9 %) | 350 (20.6 %) | 0.800 |
| Calcium channel blockers | 1160 (49.9 %) | 1816 (20.9 %) | < 0.001 | 794 (46.7 %) | 814 (47.9 %) | 0.492 |
| Angiotensin receptor blockers | 756 (32.5 %) | 1218 (14.0 %) | < 0.001 | 516 (30.3 %) | 511 (30.0 %) | 0.852 |
| Angiotensin converting enzyme inhibitors | 335 (14.4 %) | 279 (3.2 %) | < 0.001 | 137 (8.0 %) | 145 (8.5 %) | 0.619 |
| Diuretics | 534 (22.9 %) | 1039 (11.9 %) | < 0.001 | 383 (22.5 %) | 385 (22.6 %) | 0.935 |
| Nitrates | 974 (41.9 %) | 798 (9.2 %) | < 0.001 | 490 (28.8 %) | 450 (26.4 %) | 0.125 |
| Type of Statins | ||||||
| Atorvastatin | 811 (34.8 %) | – | – | 605 (35.6 %) | – | – |
| Fluvavastatin | 133 (5.7 %) | – | – | 106 (6.2 %) | – | – |
| Pitavastatin | 241 (10.3 %) | – | – | 161 (9.4 %) | – | – |
| Pravastatin | 252 (10.8 %) | – | – | 196 (11.5 %) | – | – |
| Rosuvastatin | 344 (14.8 %) | – | – | 220 (12.9 %) | – | – |
| Simvastatin | 543 (23.3 %) | – | – | 411 (24.1 %) | – | – |
| Fibrates | 29 (1.2 %) | 98 (1.1 %) | 0.638 | 25 (1.4 %) | 34 (2.0 %) | 0.237 |
After PSM, during the 3-year follow-up period, the incidence of new-onset DM was higher in the statin group compared to that in the nonstatin group (4.7% vs 2.4%, p value <0.001). However, the rates of total death and MACCE were lower in the statin group compared with those in the nonstatin group ( Tables 2 and 3 ).
| Variable, N (%) | Overall Patients | Matched Patients | ||||
|---|---|---|---|---|---|---|
| Statin Use (n = 2324) | No Use (n = 8670) | P Value | Statin Use (n = 1699) | No Use (n = 1699) | P Value | |
| New-onset diabetes | 116 (4.9 %) | 111 (1.2 %) | < 0.001 | 80 (4.7 %) | 41 (2.4 %) | < 0.001 |
| Mortality | 18 (0.7 %) | 48 (0.5 %) | 0.221 | 8 (0.4 %) | 23 (1.3 %) | 0.007 |
| Cardiac death | 10 (0.4 %) | 11 (0.1 %) | 0.006 | 3 (0.1 %) | 7 (0.4 %) | 0.205 |
| Myocardial infarction | 14 (1.0 %) | 8 (0.1 %) | < 0.001 | 4 (0.4 %) | 6 (0.6 %) | 0.755 |
| Cerebrovascular accidents | 11 (0.4 %) | 26 (0.2 %) | 0.200 | 6 (0.3 %) | 15 (0.8 %) | 0.049 |
| MACCE | 34 (1.4 %) | 64 (0.7 %) | 0.001 | 15 (0.8 %) | 31 (1.8 %) | 0.018 |
| Description | Patients. No. | New-onset DM | MACCE | ||
|---|---|---|---|---|---|
| HR (95% CI) | P Value | HR (95% CI) | P Value | ||
| Unadjusted HR | 10 994 | 4.05 (3.10-5.27) | < 0.001 | 1.99 (1.31-3.03) | 0.001 |
| Adjusted HR (95% CI) | |||||
| Multivariate | 10 994 | 2.70 (1.99-3.67) | < 0.001 | 0.70 (0.42-1.18) | 0.191 |
| Propensity score | 10 994 | 2.71 (1.94-3.79) | < 0.001 | 0.50 (0.29-0.87) | 0.015 |
| Propensity score matched | 3 398 | 1.99 (1.36-2.92) | < 0.001 | 0.47 (0.25-0.89) | 0.020 |
In the present study, we compared the incidence of new-onset DM–related MACCEs between the 2 groups during the 3-year follow-up period. In the statin group, new-onset DM–related MACCEs occurred in 3 cases (0.18%), accounting for 20% of the total MACCE (hazard ratio (HR) 4.42, 95% CI 1.16 to 16.7, p = 0.029). In the nonstatin group, new-onset DM–related MACCE occurred in 1 case (0.06%), accounting for 3.2% of the total MACCE (HR 0.85, 95% CI 0.10 to 6.95, p = 0.882). The incidence of MACCE between the statin group and the nonstatin group was similar, suggesting the risk of MACCE occurred from chronic statin use is not different from that of patients without statin ( Figure 1 ).
After PSM, multivariate Cox regression analysis showed that elderly, male gender, and drug intake (diuretics, overall statins, and subtype statins) were the independent risk factors for new-onset DM. However, when we analyze the impact of individual statin on the incidence of new-onset DM, the use of simvastatin was not a significant risk factor for new-onset DM ( Table 4 ).
| Description | Patients, N (%) (n = 3,398) | New-onset DM, N (%) (n = 121) | HR (95% CI) | P Value |
|---|---|---|---|---|
| Gender (men) | 1762 (51.8 %) | – | 1.76 (1.19-2.59) | 0.004 |
| Age, [mean ± SD] | 60.2 ± 11.6 | – | 1.01 (1.00-1.03) | 0.025 |
| Hypertension | 1792 (52.7 %) | – | 1.38 (0.94-2.02) | 0.097 |
| Cardiovascular disease | 431 (12.6 %) | – | 0.96 (0.56-1.65) | 0.891 |
| Coronary spasm | 171 (5.0 %) | – | 1.64 (0.80-3.35) | 0.169 |
| Dyslipidemia | 796 (23.4 %) | – | 1.00 (0.63-1.58) | 0.973 |
| Angiotensin receptor blockers | 1027 (30.2 %) | – | 1.34 (0.87-2.05) | 0.173 |
| Angiotensin converting enzyme inhibitors | 282 (8.2 %) | – | 0.80 (0.38-1.67) | 0.559 |
| Calcium channel blockers | 1608 (47.3 %) | – | 0.72 (0.49-1.05) | 0.090 |
| Beta blockers | 706 (20.7 %) | – | 1.30 (0.85-2.01) | 0.218 |
| Diuretics | 768 (22.6 %) | – | 1.61 (1.03-2.52) | 0.035 |
| Nitrates | 940 (27.6 %) | – | 1.07 (0.70-1.64) | 0.735 |
| Statins (overall) | 1699 (50.0 %) | 80/1699 (4.7 %) | 2.06 (1.40-3.04) | < 0.001 |
| Atorvastatin ∗ | 605 (35.6 %) | 28/605 (4.6 %) | 2.09 (1.27-3.44) | 0.003 |
| Simvastatin ∗ | 411 (24.1 %) | 10/411 (2.4 %) | 0.99 (0.49-2.02) | 0.998 |
| Rosuvastatin ∗ | 220 (12.9 %) | 10/220 (4.5 %) | 2.13 (1.04-4.38) | 0.038 |
| Pravastatin ∗ | 196 (11.5 %) | 13/196 (6.6 %) | 2.88 (1.50-5.55) | 0.001 |
| Pitavastatin ∗ | 161 (9.4 %) | 13/161 (8.0 %) | 3.46 (1.79-6.68) | < 0.001 |
| Fluvastatin ∗ | 106 (6.2 %) | 6/106 (5.6 %) | 2.53 (1.03-6.21) | 0.041 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
