In this population-based T1D cohort study, we evaluated the risk of CVD according to statin treatment. The number of 11,483 adult T1D patients is in line with the estimate of the registry study conducted in Korea [11]. In patients with T1D, treatment with statins was associated with a 25% lower risk of CVD. The association between statin use and fewer cardiovascular events was consistent in sensitivity analysis with a nested case-control design, and we also observed that fewer cardiovascular events occurred over a longer period of statin treatment.
It is well known that cardiovascular risk is increased in T1D patients [18]. Indeed, in our cohort study with 11,009 T1D patients, approximately 1 in 14 without previous CVD experienced a stroke or MI during the 10-year follow-up period. Several studies have demonstrated that development of cardiovascular complications is common in T1D patients, and the risk of CVD in T1D is greater than that in T2D patients [19, 20]. A cohort study conducted in the United Kingdom reported a 3.6- to 7.7-fold increase in major CVD in T1D patients compared to the general population [21]. Cardiovascular mortality in T1D patients is higher than that both in the general population and in T2D patients [19, 22]. Currently, CVD remains the leading cause of morbidity and mortality in T1D patients [23–25]. Considering the relatively early onset of T1D patients compared to T2D patients, development of CVD in T1D patients leads to more life-years lost [26].
The mechanism of high CVD risk in T1D is not fully understood, but long-term exposure to hyperglycemia, oxidative stress, and low-grade inflammation are characteristics of T1D and can contribute to the development and progression of vascular complications [27]. T1D is associated with a higher prevalence and more rapid progression of coronary atherosclerosis [28, 29]. Furthermore, the presence of both traditional and non-traditional cardiovascular risk factors is frequently confirmed in T1D patients, and metabolic syndrome is also commonly observed [30, 31]. Hyperglycemia due to a defect in insulin secretion in T1D also contributes to an increased risk of cardiovascular events [32].
Statins have been established to be beneficial for preventing cardiovascular events, which are major complications in T2D patients [33]. Based on the cumulative evidence, statin therapy is recommended for primary and secondary prevention of CVD in diabetic patients who are at greater risk [7]. Evidence from multiple large-scale randomized controlled trials of statin treatment suggests that the beneficial effect of statins on CVD is largely attributable to decrease of low-density lipoprotein cholesterol (LDL-C) [34]. In a study using Swedish national diabetes registry data, LDL-C was a significant predictor of death and CVD in patients with T1D [32]. For each 1-mmol/L increase of LDL-C level in T1D, there was a 35–50% greater CVD risk. Meanwhile, a low level of LDL-C in T1D was negatively associated with coronary atherosclerosis [35]. The relationship between the LDL-C–lowering effect of statins and a proportional reduction in CVD events is consistent between patients with T1D or T2D and non-diabetic individuals [36, 37]. In addition to lowering the LDL-C level, statins have multiple pleiotropic effects such as improving endothelial dysfunction, increasing nitric oxide bioavailability, inhibiting inflammatory responses, and stabilizing atherosclerotic plaques [38]. T1D patients have elevated levels of plasma markers, which reflect inflammation and endothelial dysfunction even before the clinical manifestation of macroangiopathy [39]. Elevated markers of inflammation and endothelial dysfunction are associated with a high risk of CVD in T1D patients [40, 41]. Administration of statins reduces the levels of inflammatory markers and improves endothelial dysfunction, although it is unclear whether statins have a similar effect in T1D [42].
There is a concern that the use of statins in T1D patients may adversely affect diabetes itself [43]. Concerns about impaired glycemic control and increased risk of diabetes with statin treatments are major discourages of adherent use of statins in clinical practice. In a study of T1D patients, statin use was associated with an increased level of HbA1c, reflecting the presence of impaired glycemic control [44]. A report also suggests that statins deteriorate insulin sensitivity in T1D patients [45]. Therefore, it is unclear whether regular statin use for the primary prevention of CVD is beneficial for T1D patients. In the current study, we demonstrated that statin use, particularly longer cumulative use, is associated with a lower risk of CVD. Our study suggests that the use of statins would assist with primary cardiovascular prevention in T1D patients at high risk. Whether the use of statins can promote hemorrhagic stroke is also a concern that inhibits statin use [46]. However, we did not find a significant relationship between the use of statins and hemorrhagic stroke in T1D patients.
In the subgroup analysis of the current study, the cardiovascular preventive effect of statins in T1D was more prominent in females than males. Currently, we did not have a clear answer whether this finding is coincidental or whether there is a notable sex difference in the effect of statins on T1D. One hypothesis is that the more prevalent risk factors, unhealthy lifestyles, and poor drug adherence in males might interrupt the beneficial effect of statins. Further study is needed for this topic. Statin treatment led to fewer cardiovascular events in both those ≥ 40 years and 20–39 years of age. However, this relationship was only significant in the ≥ 40 years age group. We suppose that this trend is due to a lack of statistical power in the younger age group, as most cardiovascular events occurred in participants ≥ 40 years of age. The current guideline for statin use in T1D patients is in accordance with the guidelines established for T2D patients, and it is recommended to use statins in T1D patients > 40 years of age and selectively use statins in those 20–39 years old according to cardiovascular risk [47]. However, the evaluation of individual cardiovascular risk is challenging [48, 49]. The role of statins for primary prevention in T1D patients aged 20–39 years is unclear; further studies are needed to establish whether statin therapy is beneficial in this patient group. In the current study, although the use of statins in T1D patients has increased over time, only one-third of patients were receiving statins at the time of the cardiovascular event. In patients with T1D, the use of statins was substantially less common than the guidelines suggested, and the difference is greater in view of primary prevention compared to secondary prevention for CVD [50, 51]. Given this low statin usage rate, clinicians need to more actively consider the use of statins for T1D patients and increase patient adherence to statins.
Our study has several limitations. First, because this was a retrospective study, there may be bias. Also, this study used a cohort derived from a single ethnic group. Since the characteristics of CVD and T1D may vary by country or ethnicity, caution is needed in generalizing the results. The use of health care claims data also produces limitations. We could not get clinical data such as the degree of control of diabetes (including HbA1c and glucose level) or the lipid profile of individual patients. We also did not know the indications for statin use; there is a possibility of statins being used only in patients with poor lipid profiles, but this could not be verified. Although strict criteria were used to accurately identify T1D patients, our dataset may include misdiagnosis or inadequate information due to the inherent limitation of health claims data. Finally, there might be a difference between the prescription records issued by physicians and the patients’ actual medication intake. However, several strengths highlight the significance of this study. Unlike many Western countries, Korea has a very low prevalence of T1D patients [11]. Therefore, we had to conduct this study using nationwide healthcare claims data. Using a population-based cohort, we were able to include a relatively large number of patients with T1D and evaluate long-term data to reveal the relationship between the development of CVD and statin treatment in T1D in real-life practice. In addition, to increase the strength of the research results, we reconfirmed the association between statin use and CVD in T1D patients by performing additional sensitivity analysis using a nested case-control study. We also identified a trend toward reduced CVD risk in T1D patients with a longer duration of statin treatment. In addition, we performed a subgroup analysis according to insurance status, which can indirectly reflect economic status, and confirmed that statin use is related to CVD risk regardless of insurance status. Our research data from an Asian T1D population consistently showed that statin treatment could contribute to CVD risk reduction in the high-risk group. In addition to the existing evidence that statin administration in T1D patients can contribute to CVD risk reduction,[9] the present study provides supporting evidence for the current guideline recommending statin administration in T1D patients.