Association Between Triglyceride Lowering and Reduction of Cardiovascular Risk Across Multiple Lipid-Lowering Therapeutic Classes

Abstract

Background: Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events. Methods: We performed a systematic review and trial-level meta-regression analysis of 3 classes of lipid-lowering therapies that reduce triglycerides to a greater extent than they do low-density lipoprotein cholesterol (LDL-C): fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported major vascular events. We also incorporated data from a previous meta-regression of 25 statin trials. The main outcome measure was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters. Results: A total of 197 270 participants from 24 trials of nonstatin therapy with 25 218 major vascular events and 177 088 participants from 25 trials of statin therapy with 20 962 major vascular events were included, for a total of 374 358 patients and 46 180 major cardiovascular events. Starting with non–high-density lipoprotein cholesterol, a surrogate for very-low-density lipoproteins and low-density lipoproteins, the RR per 1-mmol/L reduction in non–high-density lipoprotein cholesterol was 0.79 (95% CI, 0.76–0.82; P <0.0001; 0.78 per 40 mg/dL). In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for low-density lipoproteins and very-low-density lipoproteins, respectively), the RR was 0.80 (95% CI, 0.76–0.85; P <0.0001) per 1-mmol/L (0.79 per 40 mg/dL) reduction in LDL-C and 0.84 (95% CI, 0.75–0.94; P =0.0026) per 1-mmol/L (0.92 per 40 mg/dL) reduction in triglycerides. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (95% CI, 0.76–0.83; P <0.0001) per 1-mmol/L (0.78 per 40 mg/dL) reduction in LDL-C and 0.91 (95% CI, 0.81–1.006; P =0.06) per 1-mmol/L (0.96 per 40 mg/dL) reduction in triglycerides. In regard to omega-3 dose, each 1 g/d eicosapentaenoic acid administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [95% CI, 0.91–0.95]; P <0.0001), whereas there was no significant association between the dose of docosahexaenoic acid and the relative risk reduction in major vascular events (RR 0.96 [95% CI, 0.89–1.03]). Conclusions: In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects.

Clinical relevance between sodium-glucose co-transporter 2 inhibitors and lipid profiles in Asian patients with type 2 diabetes mellitus: a systematic review with a meta-analysis of randomized controlled trials

“…The present meta-analysis showed that SGLT2is decreased TG by 16.4 mg/dL and increased LDL-C by 3.0 mg/dL from placebo values. A recent meta-regression analysis with an average median trial duration of 4.8 years showed that the risk ratio of major vascular events was 0.92 per 40 mg/dL reduction in TG [35]. Another metaanalysis with a mean follow-up of 4.3 years [36] reported a 21% reduction in major vascular events per 1 mmol/L (38.7 mg/dL) reduction in LDL-C. Further RCTs with a longer duration are needed to establish whether the modest changes observed in TG and LDL-C in our meta-analysis are of clinical importance because the maximum duration of RCT in our review was too short (at most 24 weeks).…”

Lipids and Cardiovascular Risk with CKD

“…Finally, the question of whether alteration of triglyceride levels can modify the risk of atherosclerosis can be best answered in adequately powered randomized controlled clinical trials. In a 2019 meta-analysis of 49 randomized controlled clinical trials of lipid-lowering agents which spanned over 43 years, a total of 374,358 patients from 24 trials of nonstatin therapies and 25 trials of statin therapies with a total of 46,180 major cardiovascular events were analyzed (7). Using a multivariable meta-regression model in a pooled analysis, relative risk of major cardiovascular outcome was 0.84 (95% CI, 0.75-0.94; P=0.0026) per each 1 mmol/L (40 mg/dl) reduction in triglycerides.…”

Targeting hypertriglyceridemia to mitigate cardiovascular risk: A review

“…Nonetheless, subgroup analyses from several of these studies have been hypothesis-generating, suggesting potential benefit to TG level reduction in patients with hypertriglyceridemia and providing clinical support for targeting this population, as in REDUCE-IT. In fact, a meta-analysis of 24 TG-lowering clinical trials, which included REDUCE-IT, concluded that lowering TG levels was associated with a lower risk of major vascular events, even after adjusting for lowering LDL-C. 67 The effect of this meta-analysis was mostly powered by the REDUCE-IT trial. Another recent meta-analysis including REDUCE-IT concluded that data support routine dietary supplementation with omega-3 fatty acids to prevent vascular events and mortality and improve cardiometabolic risk factors.…”

“… 60 A recent meta-analysis of omega-3 fatty acid studies including REDUCE-IT supported a reduction in the risk of CVD endpoints 66 ; however, a meta-analysis of TG-lowering treatments suggested that the CVD risk reduction associated with TG level lowering alone was relatively modest after exclusion of REDUCE-IT. 67 While elevated TG levels have been identified in some studies as an independent CVD risk factor, 68 , 69 there is some evidence to the contrary. For example, another recent meta-analysis found that while an elevated TG level in patients with type 2 diabetes was associated with an increased risk of CVD, this association was lost after adjusting for other blood lipid parameters.…”

“… 83 Consistent with data supporting the potential pleiotropic effects of EPA, a recent meta-analysis of 24 TG-lowering clinical trials (including 13 omega-3 fatty acid trials) noted that the magnitude of lipid profile reduction did not fully account for the CV benefit of EPA therapy. 67

Figure 4 Biosynthetic Cascades and Actions of Selected Lipid Mediators Derived From Arachidonic Acid (AA), Eicosapentaenoic Acid (EPA), and Docosahexaenoic Acid (DHA). COX, cyclooxygenase; HDHA, hydroxy-docosahexaenoic acid; HETE, hydroxyeicosatetraenoic acid; LO, lipoxygenase; LT, leukotriene; LX, lipoxin; MaR, maresin; PD, protectin; PG, prostaglandin; Reproduced with permission from Serhan CN, Petasis NA.

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