Effectiveness of icosapent ethyl on first and total cardiovascular events in patients with metabolic syndrome, but without diabetes: REDUCE-IT MetSyn

Abstract

Aims

Metabolic syndrome (MetSyn) is associated with high risk of cardiovascular (CV) events, irrespective of statin therapy. In the overall REDUCE-IT study of statin-treated patients, icosapent ethyl (IPE) reduced the risk of the primary composite endpoint (CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or unstable angina requiring hospitalization) and the key secondary composite endpoint (CV death, non-fatal myocardial infarction, or non-fatal stroke).

Methods and results

REDUCE-IT was an international, double-blind trial that randomized 8179 high CV risk statin-treated patients with controlled LDL cholesterol and elevated triglycerides to IPE 4 g/day or placebo. The current study evaluated the pre-specified patient subgroup with a history of MetSyn, but without diabetes at baseline. Among patients with MetSyn but without diabetes at baseline (n = 2866), the majority (99.8%) of this subgroup was secondary prevention patients. Icosapent ethyl use was associated with a 29% relative risk reduction for the first occurrence of the primary composite endpoint [hazard ratio: 0.71; 95% confidence interval (CI): 0.59–0.84; P < 0.0001, absolute risk reduction (ARR) = 5.9%; number needed to treat = 17] and a 41% reduction in total (first plus subsequent) events [rate ratio: 0.59; (95% CI: 0.48–0.72); P < 0.0001] compared with placebo. The risk for the key secondary composite endpoint was reduced by 20% (P = 0.05) and a 27% reduction in fatal/non-fatal MI (P = 0.03), 47% reduction in urgent/emergent revascularization (P < 0.0001), and 58% reduction in hospitalization for unstable angina (P < 0.0001). Non-statistically significant reductions were observed in cardiac arrest (44%) and sudden cardiac death (34%).

Conclusion

In statin-treated patients with a history of MetSyn, IPE significantly reduced the risk of first and total CV events in REDUCE-IT. The large relative and ARRs observed supports IPE as a potential therapeutic consideration for patients with MetSyn at high CV risk.

Registration REDUCE-IT ClinicalTrials.gov number: NCT01492361

Graphical Abstract

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Introduction

More than one of every three adult Americans have the metabolic syndrome (MetSyn),¹ a cluster of three or more of the following five risk factors: (i) waist circumference ≥40 inches (102 cm) in men and ≥35 inches (88 cm) in women, (ii) blood pressure ≥130/85 mmHg, (iii) fasting glucose ≥100 mg/dL, (iv) triglycerides (TGs) ≥150 mg/dL, and (v) HDL-C <40 mg/dL in men and <50 mg/dL in women.² Metabolic syndrome is not only a recognized risk factor for incident diabetes but also raises the risk of adverse cardiovascular disease (CVD) outcomes [e.g. myocardial infarction, stroke, and cardiovascular (CV) mortality] by at least two-fold, even in the absence of diabetes.³ In recent years, MetSyn has also been linked to a variety of pathologic phenotypes including heart failure⁴ and renal insufficiency.⁵ While intensive lifestyle changes that result in significant weight loss invariably improve the risk-factor profile associated with MetSyn,⁶ there are surprisingly few data evaluating either lifestyle and/or pharmacologic therapy aimed at reducing CVD risk in patients with MetSyn. Recently, icosapent ethyl (IPE), a purified formulation of eicosapentaenoic acid (EPA), was demonstrated in the Reduction of Cardiovascular Events with Icosapent Ethyl Trial (REDUCE-IT) to reduce CVD events in men and women with hypertriglyceridaemia (HTG) and established CVD or elevated CVD risk.⁷ However, evaluation of IPE in patients with MetSyn was not a primary analysis in the REDUCE-IT study. Consequently, the rationale for the current study, of Metsyn as a pre-specified subgroup analysis in REDUCE-IT, was two-fold: (i) examine the extent to which IPE may be beneficial in patients with MetSyn who did not have diabetes at baseline and (ii) determine whether IPE had any impact on the risk of new-onset diabetes in patients with MetSyn.

Methods

REDUCE-IT was a randomized double-blind, placebo-controlled Phase 3b trial of statin-treated patients with HTG [150–499 mg/dL (1.69–5.63 mmol/L)] and LDL cholesterol, 41–100 mg/dL (1.06–2.59 mmol/L), assigned to either IPE or placebo (4 g daily) after dietary counselling. The study design and results have been reported in the past.^6,7 Efficacy analyses were conducted using the intention-to-treat (ITT) approach. All study sites were approved by the respective ethics committee or institutional review board. A composite of CV death, non-fatal myocardial infarction (MI), non-fatal stroke, coronary revascularization, or unstable angina resulting in hospitalization represented the primary endpoint, whereas CV death, non-fatal MI, or non-fatal stroke comprised the key secondary composite endpoint. Other endpoints included CV death or non-fatal MI, fatal or non-fatal MI, urgent or emergent revascularization, CV death, hospitalization for unstable angina, fatal or non-fatal stroke, the combination of total mortality, non-fatal MI and non-fatal stroke, total mortality, cardiac arrest, and sudden cardiac death. The current analysis evaluated hazard ratios (HRs) and 95% confidence intervals (CIs) in patients distinguished by a history of MetSyn as characterized by three or more criteria noted above but without diabetes at baseline. Diabetes was defined by a history of elevated blood glucose [fasting levels exceeding 125 mg/dL (6.9 mmol/L)] requiring medication with new-onset diabetes similarly defined during interval history and/or follow-up visits.

Statistical analysis

Baseline characteristics were examined between treatment groups with categorical and continuous variables compared using the χ² test and Wilcoxon rank-sum test, respectively. The time to the initial occurrences of both primary and secondary composite endpoints was assessed by Kaplan–Meier analysis based upon CV risk category, geographic region, and prescribed use of ezetimibe at baseline. Initial and recurrent (total) events were analysed using a negative binomial regression model as previously conducted.⁸ Hazard ratios and 95% CIs were generated from a corresponding stratified Cox proportional-hazards regression model. P-values presented are nominal and exploratory with no adjustment for multiple comparisons. Statistical analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC, USA).

Results

Baseline characteristics

Of the 8179 patients enrolled in REDUCE-IT, 35% (n = 2866) of the ITT population had MetSyn (≥3 factors) without diabetes at baseline. The majority (99.8%) of this subgroup was secondary prevention patients. As shown in Table 1, baseline characteristics included the median age of 62 years with women comprising 19.9% (n = 569). In addition to HTG (TG ≥ 150 mg/dL), which served as an entry criterion for REDUCE-IT, the other MetSyn factors with prevalence were increased waist circumference (men, 66.3%; women 87.9%), hypertension (82%), impaired fasting glucose (100–125 mg/dL; 57.9%), and low HDL-C (men, 60.3%; women, 74.5%), with assignment to IPE associated with higher prevalence of low HDL-C for women (P = 0.01). Patients taking medications commonly prescribed with MetSyn (Table 2) did not demonstrate differences at baseline whether assigned to IPE or placebo.

Clinical outcomes

Over a median follow-up time of 4.9 years, IPE-treated patients with MetSyn but without diabetes experienced a 29% relative risk reduction (RRR) for the time to first primary composite endpoint [HR: 0.71; 95% CI: 0.59–0.84; P < 0.0001; absolute risk reduction (ARR) = 5.9%; number needed to treat = 17] and a 41% reduction in total (first plus subsequent) events [rate ratio (RR): 0.59; (95% CI: 0.48–0.72); P < 0.0001], compared with placebo (Figure 1).

Similarly, IPE use in patients with MetSyn who did not have diabetes at baseline was associated with a 20% reduction in the key secondary composite endpoint (HR: 0.80; 95% CI: 0.64–1.00; P = 0.05) and a 27% reduction in total events (RR: 0.73; 95% CI: 0.57–0.93; P = 0.01; Figure 2). No appreciable differences were observed in the primary or key secondary composite endpoint in IPE-treated patients with MetSyn who had pre-existing diabetes (see Supplementary material online, Figure S1).

Similarly, subgroup analysis for individual MetSyn components, except for high TGs, with IPE treatment effects on the primary endpoint is illustrated in Supplementary material online, Figure S2. Across these four MetSyn criteria, IPE significantly reduced the risk of primary endpoint events regardless of the presence or absence of each criterion in the ITT population with two exceptions—patients without elevated blood pressure and those without reduced HDL-C—although there was a non-statistically significant trend towards benefit with IPE (P = 0.07). Efficacy endpoints were further stratified in primary and secondary prevention patients with MetSyn (see Supplementary material online, Figure S3). Consistent with the main REDUCE-IT study results, IPE significantly reduced the risk of the primary and key secondary endpoints in the secondary prevention subgroup, with a trend towards benefit in the smaller primary prevention subgroup.

A forest plot of primary and key secondary composite endpoints and development of new-onset diabetes based on treatment assignment and stratified by the presence or absence of MetSyn is shown in Figure 3. Icosapent ethyl use was associated with statistically significant reductions in CVD events only with MetSyn for patients without diabetes at baseline; however, there were no significant differences in primary or key secondary composite endpoints between the MetSyn groups (interaction P-values of 0.45 and 0.95, respectively). Treatment with IPE vs. placebo did not increase the risk of new-onset diabetes, irrespective of baseline MetSyn status (with MetSyn 4.3 vs. 4.0%, log-rank P = 0.74; and without MetSyn 1.2 vs. 2.1%, log-rank P = 0.40).

Further evaluation of efficacy endpoints in patients with MetSyn but without diabetes at baseline is illustrated in Figure 4. There was a 27% RRR in fatal/non-fatal MI (P = 0.03), 47% RRR in urgent/emergent revascularization (P < 0.0001), and 58% RRR in hospitalization for unstable angina (P < 0.0001), with associated ARRs of 2.1, 3.9, and 2.8%, respectively. Non-statistically significant reductions were observed in CV death or non-fatal MI (16%), fatal or non-fatal stroke (27%), the combination of total mortality, non-fatal MI and non-fatal stroke (17%), cardiac arrest (44%), and sudden cardiac death (34%).

Two medically significant adverse experiences associated with use of omega-3 fatty acids include atrial fibrillation/flutter and bleeding. In the subgroup of patients with MetSyn but without diabetes at baseline, hospitalization for positively adjudicated atrial fibrillation or flutter events was higher in participants assigned to IPE than placebo (2.9 vs. 1.8%; log-rank P = 0.06; Supplementary material online, Figure S4). Bleeding treatment-emergent adverse events (TEAEs) or haemorrhagic stroke endpoints trended higher with IPE vs. placebo (10.0 vs. 9.1%; Fisher’s exact P = 0.37), albeit with no significant differences for either bleeding TEAEs (9.8 vs. 8.9%; Fisher’s exact P = 0.41) or haemorrhagic stroke endpoints (0.2 vs. 0.3%; Fisher’s exact P = 0.72; Supplementary material online, Figure S5).

Discussion

In this pre-specified analysis of REDUCE-IT, assignment to IPE with pre-existing MetSyn (based on ≥3 factors) but no history of diabetes at baseline resulted in significant reductions in the first event and also in total events (29 and 41%, respectively) of the primary composite endpoint compared with placebo; these results compared favourably with the overall REDUCE-IT results (25 and 30% reductions, respectively^7,9). The risk of primary composite endpoint events in placebo-treated patients with MetSyn aligns with the overall REDUCE-IT placebo cohort (21.7 vs. 22.0%⁷) over the median 4.9-year follow-up period.

Even in the absence of diabetes at baseline, these data are consistent with the notion that secondary prevention patients with MetSyn pose higher CVD risk than comparably risk-defined patients without MetSyn,^2,10 and reflects in part, an atherothrombotic milieu characterized by chronic inflammation, oxidative stress and endothelial dysfunction.^11,12 That IPE appreciably offsets the excessive risk inherent in CVD patients with MetSyn is supported by investigational studies demonstrating the anti-inflammatory, antithrombotic, and membrane stabilizing effects of highly purified EPA.¹³ In contrast, other therapies added to statins have failed to effectively lower CVD risk in high-risk patients with MetSyn or with at least two MetSyn criteria (e.g. low HDL-C and high TG).^14–17

As the prevalence of MetSyn continues to rise beyond the approximate one in four adults currently afflicted worldwide, owing in part to the growing epidemic of obesity and diabetes,¹⁸ treatment considerations include lifestyle interventions, notably weight reduction and/or improvement in associated cardiometabolic factors identified in small-scaled trials.^19–22 We await the initiation of larger randomized clinical trials that specifically address these measures, although the Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) trial²³ may provide insight on the effectiveness of this GLP-1 receptor agonist in the cohort with MetSyn but without diabetes at baseline. In the meantime, IPE represents one of only a handful of therapies^24,25 that may effectively reduce CVD risk in MetSyn patients without exhibiting robust effects on other MetSyn parameters.

Study limitations

Limitations of this pre-specified analysis were its exploratory nature and relatively small number of events in certain subgroups or for certain endpoints, including cardiac arrest and sudden cardiac death. Nevertheless, the trends observed were consistent with the favourable results identified in the primary and key secondary composite endpoints. In addition, variation in subjective measures (e.g. waist circumference) may have affected the classification of MetSyn.

Conclusions

In this pre-specified analysis of patients with MetSyn from REDUCE-IT, patients with MetSyn but without diabetes at baseline who were assigned to IPE treatment experienced significantly fewer first and total events compared with placebo. These data expand the growing list of benefits attributable to IPE, including prior MI, percutaneous coronary intervention or coronary bypass grafting, chronic kidney disease, heart failure, and history of cigarette smoking.^26–31 Taken together, IPE is effective in a variety of clinical settings including patients with MetSyn at high CV risk.

Lead author biography

Michael Miller, MD, is a cardiologist and Professor of Medicine at the Hospital of the University of Pennsylvania and Chief of Medicine at the Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA. Dr Miller has had a longstanding interest in triglyceride metabolism. He and his collaborators were the first to show optimal fasting triglyceride levels to be <100 mg/dL (1.13 mmol/L) and higher levels [e.g. >150 mg/dL (1.7 mmol/L)] to predict recurrent cardiovascular events despite low on-treatment LDL-C [<70 mg/dL (1.8 mmol/L)]. His studies on fatty acids, including EPA, have spanned multiple decades.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Supplementary material

Supplementary material is available at European Heart Journal Open online.

Ethical approval

All sites received approval from their respective institutional review board or ethics committee.

Funding

This work was supported by Amarin Corporation .

References

Author notes