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Legacy effect of fibrate add-on therapy in diabetic patients with dyslipidemia: a secondary analysis of the ACCORDION study



The Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid study found no evidence of a beneficial effect of statin-fibrate combined treatment, compared to statins alone, on cardiovascular outcomes and mortality in type 2 diabetes mellitus after 5 years of active treatment. However, a beneficial reduction in major CVD events was shown in a pre-specified sub-group of participants with dyslipidemia. The extended follow-up of this trial provides the opportunity to further investigate possible beneficial effects of fibrates in this group of patients. We aimed to evaluate possible “legacy effects” of fibrate add-on therapy on mortality and major cardiovascular outcomes in patients with dyslipidemia.


The ACCORD-lipid study was a randomized controlled trial of 5518 participants assigned to receive simvastatin plus fenofibrate vs simvastatin plus placebo. After randomized treatment allocation had finished at the end of the trial, all surviving participants were invited to attend an extended follow-up study (ACCORDION) to continue prospective collection of clinical outcomes. We undertook a secondary analysis of trial and post-trial data in patients who had dyslipidemia. The primary outcome was all-cause and cardiovascular mortality, and secondary outcomes were nonfatal myocardial infarction, stroke, congestive heart failure and major coronary heart disease. We used an intention-to-treat approach to analysis to make comparisons between the original randomized treatment groups.


853 participants with dyslipidemia had survived at the end of the trial. Most participants continued to use statins, but few used fibrates in either group during the post-trial period. The incidence rates in the fenofibrate group were lower with respect to all-cause mortality, CVD mortality, nonfatal myocardial infarction, congestive heart failure and major coronary heart disease than those in the placebo group over a post-trial follow-up. Allocation to the combined fibrate-statin treatment arm during the trial period had a beneficial legacy effect on all-cause mortality (adjusted HR = 0.65, 95% CI 0.45–0.94; P = 0.02).


Fibrate treatment during the initial trial period was associated with a legacy benefit of improved survival over a post-trial follow-up. These findings support re-evaluation of fibrates as an add-on strategy to statins in order to reduce cardiovascular risk in diabetic patients with dyslipidemia.

Trial registration, Identifier: NCT00000620


Dyslipidemia is a major contributor to the increased risk of cardiovascular disease (CVD) among patients with type 2 diabetes mellitus (T2DM). While other types of lipid abnormalities can be found in people with diabetes, the typical diabetic dyslipidemia (also called atherogenic dyslipidemia) is characterized by elevated triglycerides, small dense low-density lipoproteins (LDL) particles, and low levels of high-density lipoproteins (HDL) cholesterol [1]. Recommended first line measures for CVD prevention in people with diabetes who have dyslipidemia include non-drug interventions (dietary regulation, exercise, moderation of alcohol intake and weight loss) and LDL-cholesterol lowering with statin drug therapy [2, 3]. The use of statins as the primary drug treatment option is supported by a large body of evidence. For example, a meta-analysis of 14 randomized trials which included more than 18,000 people with diabetes, found that for every mmol/L reduction in LDL cholesterol there was a 21% proportional reduction in the risk of a major vascular event [4]. This proportional risk reduction is similar to that observed in people without diabetes [5], but because the baseline absolute risk is on average higher in people with diabetes, the absolute benefits are greater. However, the trial data also show substantial “residual risk” in people with T2DM who are on statin treatment [6,7,8], and often the absolute risk is still higher than that in people without diabetes who are not on statin treatment [9,10,11]. This indicates that preventative treatment with statins alone may not be enough in people with T2DM and additional therapies may need to be considered. There is also evidence from Mendelian randomization studies that high triglycerides are causally related to CVD, and so drug therapy targeting this lipid abnormality could help to further reduce CVD risk in people with T2DM [12,13,14].

Fibrates are an example of such a drug therapy, as they both decrease triglyceride levels and increase HDL-C [15]. To investigate if these effects on lipid biomarkers translates into a reduction in CVD, the Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid study randomized 5518 people with T2DM to combined statin-fibrate therapy vs statin therapy alone. Although the ACCORD-Lipid study found no benefit between randomized groups overall, a beneficial reduction in major CVD events was found in a pre-specified sub-group analysis of study participants with dyslipidemia (triglyceride greater than 204 mg/dl and high-density lipoprotein less 34 mg/dl) [16, 17]. The authors hypothesized that fibrate therapy, offered as an add-on to statin therapy, may be beneficial for people with diabetes who are found have hypertriglyceridemia and/or reduced HDL-C. This hypothesis is supported by the findings of several systematic reviews of RCTs of fibrate therapy [18,19,20,21].

At the end of the ACCORD-Lipid trial, participants were unblinded from their randomized groups, and passively followed up for an additional 5 years through follow-up clinics and routine data collection methods. The post-trial follow-up data provide a unique opportunity to evaluate the effect of add-on fibrate therapy in the longer-term, and the possibility of the emergence of “legacy effects”. Legacy effects describe intervention effects observed in the post-trial period which are not due to the direct effects observed during the trial period [22]. The finding of a legacy effect would have important clinical implications, including the potential benefits of early initiation of fibrate treatment in the setting of diabetic dyslipidemia. Although potential legacy effects for statin treatment have been investigated in a number of post-trial follow up studies [23], those for combined statin-fibrate treatment remain unexplored [24, 25]. Post-trial data after a statin-fibrate RCT provide the opportunity to investigate potential legacy effects in people with T2DM and dyslipidemia. Therefore, we conducted a secondary analysis of data from the ACCORD-Lipid trial and the ACCORDION post-trial follow-up study, in order to determine whether or not there is evidence for legacy effects for fibrate add-on strategy to statins in diabetic patients with dyslipidemia.


Study participants and setting

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial was a randomized, double 2 × 2 factorial design study, which evaluated the effects of intensive glycemic control, intensive blood pressure control, and combined fibrate statin treatment, on the prevention of cardiovascular disease in people with T2DM [26]. It enrolled 10,251 people (mean age 62 years), who had a history of T2DM for a median duration of 10 years, with mean glycated hemoglobin (HbA1c) level of 8.3%. Participants had either a history of previous cardiovascular disease or had elevated risk factors levels. The lipid sub-study was conducted in 5518 of the trial participants. In addition to fulfilling the overarching ACCORD entry criteria, the LIPID participants needed to meet all of the following additional criteria: (1) 60 mg/dl < LDL-C < 180 mg/dl (1.55 to 4.65 mmol/l) if not on a lipid lowering agent during screening, or, if on a lipid-lowering agent, the LDL-C needed to be between prespecified drug/dose-specific cut points, and (2) HDL-C less than 55 mg/dl (1.42 mmol/l) for women or African-Americans, or HDL-C less than 50 mg/dl (1.29 mmol/l) for all other gender and ethnic groups, and (3) triglycerides < 750 mg/dl (8.47 mmol/l) on no therapy or < 400 mg/dl (4.52 mmol/l) on treatment with lipid lowering drugs. Participants were randomly assigned to either simvastatin plus fenofibrate or simvastatin plus placebo. The starting dose of open-labeled simvastatin were determined by presence of cardiovascular disease and the dose of masked fenofibrate/placebo were determined by calculated glomerular filtration rate at randomization. Further changes to the dose of both drugs were made during the trial in accordance to the trial guidelines [16]. At the end of the trial, all surviving ACCORD participants who could be contacted were invited to enter an observational follow-up study (ACCORDION) [27, 28]. No active trial therapy was provided in this period, and medical care was provided by the participant’s local primary care provider. Data on health outcomes (e.g. hospital records, death certificates, etc.) and medication usage were collected by phone and clinic visits. Physical examinations were conducted at the first and last clinic visits, include the collection of urine and blood samples for analysis [28].

In the ACCORD-Lipid trial, dyslipidemia was pre-specified as the combination of the highest tertile of triglyceride (204 mg/dl) and lowest third of HDL-C (34 mg/dl) at baseline [16]. We used the same definition for dyslipidemia in the current analysis. Our primary outcomes were all-cause mortality and cardiovascular mortality, and our secondary outcomes were nonfatal myocardial infarction, stroke, congestive heart failure and a major coronary heart disease event [16, 28]. Although there was event adjudication during the ACCORD trial, this was done in only a randomly selected 10% of events during the post-trial follow-up period (for the purpose of quality control). For consistency across all follow up data, we used outcomes reported by site investigators during both trial and post-trial period (unadjudicated events).

Statistical methods

Participants’ characteristics at baseline of trial and first post-trial visit were summarized for the two randomized groups using means, standard deviations, and percentages. The measured lipid levels at each study visit, including total cholesterol, triglycerides, HDL-C, LDL-C and VLDL-C, were compared between randomized groups. VLDL-C was obtained by subtracting HDL-C and LDL-C from total cholesterol. Primary and secondary outcomes were analyzed according to the intention-to-treat principle. Hazard ratios (HRs) and 95% confidential intervals were estimated using Cox proportional hazards models. Kaplan–Meier estimates were used to obtain the proportion of patients who had an event during follow-up. The direct effects of treatment were estimated by fitting models for the trial period (short term effects), and the entire study period (from baseline of trial through to end of post-trial, long term effects). The legacy effects of treatment were estimated by fitting models for the post-trial period alone. This analysis was based on survivors who consented to additional follow-up, and their follow-up times were calculated by the difference between full follow-up time and censoring time for the trial. These analyses were adjusted for age, sex, ethnicity, network, education status, CVD history, blood glucose trial treatment assignment and years of diabetes. To examine the robustness of these findings, sensitivity analyses were undertaken to (i) account for effects of medications taken in the post-trial follow-up period, and (ii) to account for possible imbalance in confounders between the two groups at the start of post-trial follow-up (using inverse probability weighting). All analyses were performed with R (version 3.5.1).


Characteristics of the participants at baseline and 1st post-trial visit

Of a total of 5518 patients enrolled in the ACCORD Lipid trial, 940 (17.0%) were identified as having dyslipidemia. 484 of them were assigned to fenofibrate and simvastatin therapy, and 456 participants received simvastatin and placebo. Of these participants, 853 had survived at the end of the trial, and 765 (90.0%) consented to enter the post-trial follow-up study. The median follow-up time in the post-trial period was 4.9 years. Table 1 shows characteristics of the participants at the trial baseline and at the first post-trial visit. The mean age at baseline was 61.8 years, and the fenofibrate group was slightly younger than the placebo group. Most of the patients were male and about forty percent of patients had a history of CVD disease. The HbA1c, blood pressure and lipid levels were well matched across treatment groups both at baseline and 1st post-trial visit.

Table 1 Characteristics of the participants at baseline and 1st post-trial visit

Trial adherence and use of lipid-modifying medication after trial

Participants’ adherence during the trial and the use of statin/fibrate post-trial is shown in Table 2. The adherence for both simvastatin and fenofibrate/placebo during the trial period was high. In the post-trial period, most participants continued to use statin therapy, while few used fibrates in either group (likely due to the finding of no benefit overall in the ACCORD-Lipid study).

Table 2 Trial adherence and use of lipid-modifying medication post-trial

Efficacy of fenofibrate in lipid-modifying

Figure 1 compares the plasma lipids of the two groups at each study visit during the within trial and post-trial periods. During the trial, allocation to fenofibrate resulted in improvements in almost all lipids compared with placebo, but the largest differences were seen for plasma triglyceride concentrations and VLDL-C levels. Further, although the differences in HDL-C and LDL-C levels between randomized groups decreased over time, they were maintained for levels of triglycerides (P = 0.01) and VLDL-C (P = 0.006) through to the end of the trial. At the first post-trial visit there were minimal differences between randomized groups for any of the lipids, and this remained the case through to the last clinic visit.

Fig. 1
figure 1

Plasma lipid levels of patients with dyslipidemia at each study visit. The line charts show the means of lipid levels and corresponding 95% CI at 1/2/3/4 year, exit visit, 1st post-trial visit and last post-trial visit. HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, VLDL-C very low-density lipoprotein cholesterol, PT1 first post-trial clinic visit, PT3 last post-trial clinic visit

Clinical outcomes

The incidence rate of the primary and secondary outcomes and the hazard ratios of allocation to the fenofibrate plus simvastatin versus simvastatin alone during the ACCORD-lipid trial, ACCORDION and the full follow-up period are shown in Table 3. We found that the incidence rates in the fenofibrate group were lower with respect to all-cause mortality, CVD mortality, nonfatal myocardial infarction, congestive heart failure and major coronary heart disease than those in the placebo group over the post-trial follow-up. Allocation to the combined fibrate-statin treatment arm during the trial period resulted in a statistically significant beneficial legacy effect on all-cause mortality observed in the post-trial period (adjusted HR = 0.65, 95% CI 0.45–0.94; P = 0.02, other effects not statistically significant). Long-term beneficial effects were also found when trial and follow up periods were combined (9.7 years follow-up from time of randomization) for all-cause mortality, CVD mortality and major coronary heart disease events (effects on CVD mortality and all-cause mortality were statistically significant). Kaplan–Meier cumulative event curves for primary outcome and selected secondary outcomes are consistent with findings from the Cox models and are presented in Fig. 2. Sensitivity analyses adjusting for medication use of post-trial follow-up and for other potential confounders, using inverse probability weighting, resulted in similar findings (Additional file 1: Table S1).

Table 3 Clinical outcomes by randomized treatment during ACCORD-lipid trial, ACCORDION and full follow-up period
Fig. 2
figure 2

Kaplan–Meier cumulative event curves for primary and secondary outcomes. The Kaplan–Meier curves display the time to event for the all-cause mortality (a) and cardiovascular mortality (b), nonfatal myocardial infarction (c), stroke (d), congestive heart failure (e) and a major coronary heart disease event (f) during trial period, post-trial and the entire study period. The numbers of individuals at risk are shown for each time point


We found that patients with dyslipidemia who were randomized to statin-fibrate treatment during the trial had higher survival in the 5 years after the trial than those randomized to statin-placebo. This effect was observed despite similar achieved lipid profile during the extended observational follow-up, which suggests a legacy effect of fibrate add-on therapy on all-cause mortality. Although estimated legacy effects on all other outcomes were not statistically significant, the effect estimates suggest that improved survival is likely to be largely explained through effects on CVD. No information was available on non-CVD causes of death, which meant we were not able to explore other possible explanations for the all-cause mortality reduction. The overall long-term benefits for CVD mortality appeared to be driven by both within-trial treatment effects and legacy effects emerging post-trial. Other studies suggest that fibrates may also have beneficial effects on microvascular outcomes, including on renal and liver function [29], but we didn’t have data to explore this.

During the trial period, fibrate add-on therapy reduced triglycerides and VLDL-C beyond that achieved with statins only, but HDL-C was increased by only a limited amount. These findings have been observed in other clinical trials of fibrate—for example in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, allocation to fenofibrate resulted in a 20% reduction of baseline TG, but HDL-C remained almost unchanged at study close [30,31,32]. The improvement of the triglyceride-rich environment may explain the reduced risk of CVD observed during the trial period in these patients [15, 33]. As most of participants in active arm discontinued the use of fibrate in post-trial, between group differences in triglycerides and VLDL-C soon disappeared. This suggests continuous treatment is necessary to maintenance a lower TRIG/VLDL-C.

Our findings on potential beneficial effects on CVD mortality reduction are supported by a recent report of a large propensity matched cohort study that found a (non-statistically significant) reduction in CVD mortality associated with fibrate use [23]. Results from the ongoing Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study will also provide evidence regarding short term effectiveness; further follow up studies are needed for longer term legacy effects [34, 35].

Our study has several limitations. First, our analysis examined a relatively small subset of the full trial and the power to detect smaller effects is limited [36]. The findings for this prespecified subgroup with dyslipidemia must be interpreted with caution, and further larger studies in people with dyslipidemia are needed. Second, as in ACCORD, the diabetic dyslipidemia was defined in a data-driven manner, however the thresholds used are similar to other definitions of dyslipidemia [3, 37]. Third, we used the investigators reported (unadjudicated) cause of death data for both trial and post-trial periods. A previous report from ACCORD study group has shown the CVD mortality was under-reported by the investigators compared to the adjudicated Committee [28], suggesting potential misclassification of cause of death using these data. Fourth, although we adjusted analyses for potential imbalance between randomized groups in confounders during the post-trial period, measurement error in these, and the presence of other unmeasured confounders could bias our estimates [22].


In conclusion, this secondary analysis found evidence of legacy effects of fenofibrate-statin combined therapy on all-cause mortality in diabetic patients with dyslipidemia. This finding suggests fibrate treatment may be an effective means of reducing residual cardiovascular risk in these patients.

Availability of data and materials

The datasets analyzed during the current study are available from the National Heart, Lung, and Blood Institute on reasonable request.



Cardiovascular disease


Type 2 diabetes mellitus


Action to Control Cardiovascular Risk in Diabetes


Action to Control Cardiovascular Risk in Diabetes Follow-On




High-density lipoprotein


Low-density lipoprotein


Very low-density lipoprotein


Myocardial infarction


Congestive heart failure


Major coronary heart disease


  1. Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Rev Endocrinol. 2009;5:150–9.

    Article  CAS  Google Scholar 

  2. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol. 2019;73:e285–350.

    Article  PubMed  Google Scholar 

  3. Alexopoulos A-S, Qamar A, Hutchins K, Crowley MJ, Batch BC, Guyton JR. Triglycerides: emerging targets in diabetes care? Review of moderate hypertriglyceridemia in diabetes. Curr Diabetes Rep. 2019;19:13.

    Article  CAS  Google Scholar 

  4. Trialists CT. Efficacy of cholesterol-lowering therapy in 18 686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117–25.

    Article  Google Scholar 

  5. Trialists CT. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–78.

    Article  Google Scholar 

  6. Ridker PM, Genest J, Boekholdt SM, Libby P, Gotto AM, Nordestgaard BG, et al. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet. 2010;376:333–9.

    Article  CAS  PubMed  Google Scholar 

  7. Fruchart J-C, Sacks F, Hermans MP, Assmann G, Brown WV, Ceska R, et al. The residual risk reduction initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102:1K–34K.

    Article  PubMed  Google Scholar 

  8. Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep. 2012;14:1–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hague WE, Simes J, Kirby A, Keech AC, White HD, Hunt D, et al. Long-term effectiveness and safety of pravastatin in patients with coronary heart disease. Circulation. 2016;133:1851–60.

    Article  CAS  PubMed  Google Scholar 

  10. Shepherd J, Blauw GJ, Murphy MB, Bollen ELEM, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–30.

    Article  CAS  PubMed  Google Scholar 

  11. Collins R, Armitage J, Parish S, Sleight P, Peto R. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebocontrolled trial. Lancet. 2002;360:7–22.

    Article  Google Scholar 

  12. Varbo A, Benn M, Tybjærg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation. 2013;128:1298–309.

    Article  CAS  PubMed  Google Scholar 

  13. Thomsen M, Varbo A, Tybjaerg-Hansen A, Nordestgaard BG. Low nonfasting triglycerides and reduced all-cause mortality: a mendelian randomization study. Clin Chem. 2014;60:737–46.

    Article  CAS  PubMed  Google Scholar 

  14. Holmes MV, Asselbergs FW, Palmer TM, Drenos F, Lanktree MB, Nelson CP, et al. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J. 2015;36:539–50.

    Article  CAS  PubMed  Google Scholar 

  15. Keating GM. Fenofibrate. Am J Cardiovasc Drugs. 2011;11:227–47.

    Article  CAS  PubMed  Google Scholar 

  16. Pisano E, Gatsonis C, Boineau R, Domanski M, Troutman C, Anderson J, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74.

    Article  Google Scholar 

  17. Margolis KL, O’Connor PJ, Morgan TM, Buse JB, Cohen RM, Cushman WC, et al. Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial. Diabetes Care. 2014;37:1721–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bruckert E, Labreuche J, Deplanque D, Touboul P-J, Amarenco P. Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic review and meta-analysis. J Cardiovasc Pharmacol. 2011;57:267–72.

    Article  CAS  PubMed  Google Scholar 

  19. Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375:1875–84.

    Article  CAS  PubMed  Google Scholar 

  20. Lee M, Saver JL, Towfighi A, Chow J, Ovbiagele B. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis. 2011;217:492–8.

    Article  CAS  PubMed  Google Scholar 

  21. Koopal C, Visseren FLJ, Westerink J, van der Graaf Y, Ginsberg HN, Keech AC. Predicting the effect of fenofibrate on cardiovascular risk for individual patients with type 2 diabetes. Diabetes Care. 2018;41:1244–50.

    Article  CAS  PubMed  Google Scholar 

  22. Zhu L, Bell KJL, Hayen A. Estimated legacy effects from simulated post-trial data were less biased than from combined trial/post-trial data. J Clin Epidemiol. 2019;114:30–7.

    Article  PubMed  Google Scholar 

  23. Kim NH, Han KH, Choi J, Lee J, Kim SG. Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study. BMJ. 2019.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kashef MA, Giugliano G. Legacy effect of statins: 20-year follow up of the West of Scotland Coronary Prevention Study (WOSCOPS). Glob Cardiol Sci Pract. 2017.

    Article  Google Scholar 

  25. Nayak A, Hayen A, Zhu L, McGeechan K, Glasziou P, Irwig L, et al. Legacy effects of statins on cardiovascular and all-cause mortality: a meta-analysis. BMJ Open. 2018;8:e020584.

    Article  PubMed  PubMed Central  Google Scholar 

  26. ACCORD Study Group, Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364:818–28.

    Article  Google Scholar 

  27. ACCORDION: the ACCORD follow-on study. 2011.

  28. Elam MB, Ginsberg HN, Lovato LC, Corson M, Largay J, Leiter LA, et al. Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes. JAMA Cardiol. 2017;2:370.

    Article  PubMed  Google Scholar 

  29. Malur P, Menezes A, DiNicolantonio JJ, O’Keefe JH, Lavie CJ. The microvascular and macrovascular benefits of fibrates in diabetes and the metabolic syndrome: a review. Mo Med. 2017;114:464–71.

    PubMed  PubMed Central  Google Scholar 

  30. Arai H, Yamashita S, Yokote K, Araki E, Suganami H, Ishibashi S. Efficacy and safety of K-877, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), in combination with statin treatment: two randomised, double-blind, placebo-controlled clinical trials in patients with dyslipidaemia. Atherosclerosis. 2017;261:144–52.

    Article  CAS  PubMed  Google Scholar 

  31. Field T. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–61.

    Article  Google Scholar 

  32. Ida S, Kaneko R, Murata K. Efficacy and safety of pemafibrate administration in patients with dyslipidemia: a systematic review and meta-analysis. Cardiovasc Diabetol. 2019;18:38.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Park S, Lee S, Kim Y, Lee Y, Kang MW, Han K, et al. Altered risk for cardiovascular events with changes in the metabolic syndrome status. Ann Intern Med. 2019.

    Article  PubMed  Google Scholar 

  34. Pradhan AD, Paynter NP, Everett BM, Glynn RJ, Amarenco P, Elam M, et al. Rationale and design of the pemafibrate to reduce cardiovascular outcomes by reducing triglycerides in patients with diabetes (PROMINENT) study. Am Heart J. 2018;206:80–93.

    Article  CAS  PubMed  Google Scholar 

  35. Fruchart JC, Santos RD, Salinas CA, Aikawa M, Al Rasadi K, Amarenco P, et al. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential. Cardiovasc Diabetol. 2019.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Rothwell PM. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Lancet. 2005;365:176–86.

    Article  PubMed  Google Scholar 

  37. Expert Panel on Detection, Evaluation and T of HBC in A. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA J Am Med Assoc. 2001;285:2486–97.

    Article  Google Scholar 

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We thank the National Heart, Lung, and Blood Institute for providing us data of ACCORD main study and the ACCORDION ancillary study.


Lin Zhu receives funding support from an Australian Government Research Training Program. Katy Bell is the recipient of an Australian National Health and Medical Research Council Investigator Grant (#1174523).

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AH and KB conceived the study and design, interpreted the data, supervised the study, and revised for important intellectual content. LZ conceived the study and design, analyzed and interpreted the data, drafted and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Lin Zhu.

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Supplementary information

Additional file 1.

Results of the sensitivity analysis.

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Zhu, L., Hayen, A. & Bell, K.J.L. Legacy effect of fibrate add-on therapy in diabetic patients with dyslipidemia: a secondary analysis of the ACCORDION study. Cardiovasc Diabetol 19, 28 (2020).

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