Discussion
This is one of the first studies to utilize a real-world retrospective claims-based analysis to associate observed LLT modification(s) (if any) with possible treatment intolerance and/or ineffectiveness among patients with type 2 diabetes with high CVD risk. Our study showed that more than 70% of patients initiating statin and/or ezetimibe treatment had at least one treatment modification and more than 35% had at least two treatment modifications, implying that many patients initiating statin and/or ezetimibe experienced issues with their index and first treatment modification during the study period. As defined and categorized in our study, these treatment modification(s) are associated with >23% of patients having possible statin intolerance and possible statin intolerance and/or ineffectiveness issues after accounting for the second treatment modification (if any).
ADA 2015 Standards of Care position statement recommended the need for high-intensity statin treatment for patients with type 2 diabetes with history of overt CVD.8 Although patients diagnosed with type 2 diabetes represent a high-risk group (including all 3 cohorts in the present study), <26% across all three study cohorts were prescribed high-intensity index statins from 2007 to 2011. The low initiation rate of high-intensity statin among high CVD risk patients with type 2 diabetes suggests the need for better LLT management within this patient population. Additional research should utilize contemporary data to further understand the effects of the introduction of current guidelines.
Our study showed that 21–25% of patients with type 2 diabetes permanently discontinued all LLTs during the follow-up period. In a retrospective study conducted by Caspard et al,21 26% of patients discontinued treatment during the first year, and the probability of resuming statin treatment was 51% within 2 years after the last prescription fill. Simpson et al22 reported 46.9% of the patients in their study discontinued LLT 3 months after drug initiation during the 12 months follow-up period. Although the discontinuation rates vary among these studies, primarily due to the varying definitions of discontinuation and follow-up periods, these studies corroborate with other published studies that discontinuation was common among statin users.23–25 For some patients, adverse events associated with statin use (eg, musculoskeletal issues, peripheral neuropathy, insomnia, creatine kinase, and liver function test elevation) influence therapy decisions, thereby increasing the likelihood of statin therapy discontinuation.11 ,26–28 In a recent survey of self-reported former and current statin users, nearly two-thirds of patients (62%) discontinued statin use primarily because of side effects, most commonly muscle-related.29 Also, among current statin users who switched treatment, 28% said they switched due to the side effects, and 22% switched due to the lack of efficacy. These results suggest that treatment modifications may be associated with possible statin intolerance and/or ineffectiveness. Patient registries along with observational studies showed a 7–29% prevalence of statin intolerance.22 ,24 ,28–31 After accounting for the second treatment modification (if any), our study showed that 23–28% of patients were identified with possible statin intolerance. The differences between previous studies and our study may be attributed to a number of factors, including statin intensity prescribed (high intensity vs any intensity),28 differences in patient selection (general population vs hyperlipidemic patients)31 and differences in possible statin intolerance identification (patient reported vs observed treatment modification).29
Previous studies of statin treatment patterns have focused on monotherapy, adherence or post-therapeutic substitution.32–34 Simpson et al22 concluded that high CVD risk patients were usually initiated on moderate-intensity statin which was similar to our findings, but, unlike our study which included combination treatment, Simpson's study was based on initiation of statin monotherapy. Harley et al34 followed patients after they were switched from simvastatin to other statins or combination of simvastatin and ezetimibe and found that most patients switching from higher doses of simvastatin switched to fixed-dose combination of simvastatin plus ezetimibe. However, none of these studies have put treatment modifications into perspective by critically analyzing and providing detailed classification of treatment modification and possible associated statin intolerance and/or ineffectiveness issues.
To our knowledge, there is currently no existing validated claims-based algorithm to identify statin intolerance and/or ineffectiveness issues among patients. Nevertheless, statin intolerance management, based on LLT modifications, have been mentioned in national and international guidelines.11–14 The National Lipid Association defines statin intolerance as a clinical syndrome characterized by the inability of a patient to tolerate statin therapy with statin challenge of ≥2 different statins.35 As part of the 2015 comprehensive diabetes management algorithm, the American Association of Clinical Endocrinologists/American College of Endocrinology recommends ‘try(ing) alternate statins, lowering statin dose or frequency, or adding non-statin LDL-C lowering therapies’ for statin intolerant patients.15 For patients showing symptoms of statin intolerance, the ACC/AHA,12 European Atherosclerosis Society,11 and Canadian Working Group Consensus14 also recommended similar LLT modification (eg, rechallenge, dose reduction, switch to other LLT). Based on these guideline definitions/recommendations, the present study utilized treatment modifications (eg, dose reduction, reinitiation) to connote possible statin intolerance and ineffectiveness. While adapting the mentioned statin intolerance treatment management recommendations, our claims-based analyses precluded us from providing definite reasons regarding treatment modifications. However, while accounting for up to two treatment modifications, our study results are indicative of possible associated statin intolerance and/or ineffectiveness among patients included in study. We acknowledge that treatment modifications (or the lack of modification) may also be due to unobserved factors (eg, health system changes, modification in health plan formulary coverage, physician/clinical inertia). Further research (eg, the clinical chart review) is warranted to confirm our findings and explore causal links between statin intolerance and/or ineffectiveness with specific LLT modifications to provide more definite conclusions.
Additional study limitations are due to the use of claims data, subject to potential coding, billing, and recording errors. The dispensed LLT prescription claims do not guarantee that patients actually took their medications as prescribed. The requirement for commercially insured patients with continuous medical and pharmacy coverage for 12 months before and after index date may have resulted in selection bias by eliminating patients who had <24 months of data. Therefore, the results of this study may not be generalizable to other patient populations. Specific LDL-C levels data were not available in the data set to assess their impact on treatment modifications. Some treatment modifications may be indicative of patients achieving LDL-C targets, but this may represent a small proportion of patients36 since the study focused on patients with type 2 diabetes at high CVD risk. Nonetheless, previous studies that utilized specific LDL levels are limited in size or generalizability.7 ,21