Use of non‐LDL‐C lipid‐lowering medications in patients with type 2 diabetes

Abstract Background A number of non‐low‐density lipoprotein cholesterol lipid abnormalities are associated with type 2 diabetes and insulin resistance, which may lead practitioners to use medications targeting these abnormal lipid fractions despite a lack of evidence or guideline recommendations. Methods and Results Among 382 921 US patients with type 2 diabetes (69% with cardiovascular disease, 76% on a statin), 95 995 (26%) were on some nonstatin lipid‐lowering medication—19 265 (5%) on niacin, 32 919 (9%) on a fibrate and 69 513 (18%) on fish oil. Use of all three medications was stable over time and higher in patients with cardiovascular disease and with higher triglyceride levels, although even among patients with triglyceride levels <2.3 mmol/L, 6% were on a fibrate and 17% were on fish oil. Conclusion As clinical trials demonstrate little to no cardiovascular benefit from taking these medications, greater attention is needed to focus the use of lipid‐lowering medications to those with proven benefit.


Funding information
The Diabetes Collaborative Registry is funded by AstraZeneca (founding sponsor) and Boehringer Ingelheim. Corporate sponsors had no role in data analysis or interpretation, manuscript development or in publication review or approval for this study.

Abstract
Background: A number of non-low-density lipoprotein cholesterol lipid abnormalities are associated with type 2 diabetes and insulin resistance, which may lead practitioners to use medications targeting these abnormal lipid fractions despite a lack of evidence or guideline recommendations.

Methods and Results:
Among 382 921 US patients with type 2 diabetes (69% with cardiovascular disease, 76% on a statin), 95 995 (26%) were on some nonstatin lipidlowering medication-19 265 (5%) on niacin, 32 919 (9%) on a fibrate and 69 513 (18%) on fish oil. Use of all three medications was stable over time and higher in patients with cardiovascular disease and with higher triglyceride levels, although even among patients with triglyceride levels <2.3 mmol/L, 6% were on a fibrate and 17% were on fish oil.

Conclusion:
As clinical trials demonstrate little to no cardiovascular benefit from taking these medications, greater attention is needed to focus the use of lipid-lowering medications to those with proven benefit.

K E Y W O R D S
diabetes mellitus, lipids, quality of care, triglycerides trial results for fibrates 6,7 and fish oil. 8,12 Furthermore, niacin as a treatment for low HDL-C is no longer recommended given the negative results of two large clinical trials. 13,14 It is unknown how these medications are currently used in patients with T2D-both for primary and secondary prevention of ASCVD. Given the unique aspects to diabetic dyslipidaemia and the underlying atherosclerotic risk of patients with diabetes, exploring the contemporary use of non-LDL-C lipid medications in these patients may provide important insights.

| Patient population
The data source for this analysis was the Diabetes Collaborative Registry (DCR), a US quality improvement registry designed to describe the outpatient care of diabetes through the spectrum of primary and specialty care. 15 Patient data, including laboratory data, are extracted from electronic health records from 2014 to 2016 with the most recent visit used. We restricted the analysis to patients with T2D and available lipid levels. Because registry participation requires no data collection beyond that of the routine clinical care and due to the de-identified nature of the collected information, waiver of written informed consent and authorization for this study was granted by Chesapeake Research Review Incorporated.

| Statistical analysis
We examined the use of fibrates, niacin and fish oil (documented in the health record) in the following groups: overall, ASCVD (coronary artery disease, peripheral artery disease, cerebrovascular disease) versus no ASCVD, statin versus no statin, according to different triglyceride levels, and over time. The last patient visit was used for analysis. To examine use over time, the last patient visit in each quarter was used. We compared demographics, comorbidities and lipid levels for those patients on versus not on each of the medications using standardized differences (>10% difference is considered clinically relevant). All analyses were performed with SAS version 9.4 (SAS Institute).

| D ISCUSS I ON
In a large cohort of patients with T2D, we found that lipid levels were not markedly abnormal. Non-LDL-C lipid-lowering medications were not infrequently used in patients with T2D, with an even greater use in those with established atherosclerosis. Furthermore, in patients with triglyceride levels <1.7 mmol/L, we found that 5% were on a fibrate and 16% were on fish oil and 5% of all patients were on niacin.
Finally, we found general stability in these rates over time, indicating that practice patterns do not appear to be rapidly changing. Greater attention is needed to focus lipid-lowering strategies to those with proven cardiovascular benefit.
A prior analysis examined use of nonstatin lipid-lowering medications in elderly patients with coronary artery disease from 2007 to 2011 and found that 5% of patients were on fibrates and 3% were on niacin. 16 Patients with diabetes were more likely to be treated There are limitations to our analysis that merit further discussion. First, we do not have pretreatment lipid levels to know whether a patient's triglycerides were markedly elevated, making treatment with fish oil and/or fibrates appropriate. Second, while over-the-counter fish oil and niacin are often documented in electronic health records, we cannot know whether a patient was taking these supplements without the knowledge of the physician.
Third, fibrates appear to have some benefit in reducing nonfatal cardiovascular events in statin-intolerant patients, and fish oil has previously been recommended in cardiology guidelines for secondary prevention of coronary artery disease. As such, some patients with established ASCVD were likely given these medications for these reasons. Furthermore, with publication of the trial with high-dose icosapent ethyl 9 and ongoing studies of fibrates with statins in high-risk patients, guidelines may again change for patients with ASCVD and elevated triglycerides. Fourth, our cohort had a high prevalence of ASCVD, which was associated with higher use of all 3 classes of non-LDL-C lipid-lowering medications. As such, overall use numbers would be expected to be lower in a general T2D population. Finally, we cannot document harm from any apparent overtreatment with nonstatin lipid-lowering medications.
In conclusion, we found that medications that target non-LDL-C lipid fractions are commonly used in patients with T2D, which likely reflects the underlying lipid abnormalities associated with T2D/insulin resistance. As clinical trials have thus far demonstrated little cardiovascular benefit from taking these medications, greater attention is needed to focus the use of lipid-lowering medications to those with proven benefit.

ACK N OWLED G M ENTS
None.

CO N FLI C T O F I NTE R E S T
NDW received research support through institution from Amgen, Boehringer Ingelheim, Amarin, Novo Nordisk; advisory board from Novaris, Amarin; speaker fees from Sanofi, Amarin; and consulting

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the Diabetes Collaborative Registry, which is managed by the American College of Cardiology. Restrictions apply to the availability of these data.