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Macrovascular Residual Risk Studies

15 April 2016
VOYAGER highlights need for additional therapy targeting elevated triglycerides in statin-treated patients
Despite high-intensity statin therapy, about 50% of hypertriglyceridaemic patients do not attain desirable triglyceride levels (<150 mg/dl or 1.7 mmol/L).
Karlson BW, Palmer MK, Nicholls SJ et al. A VOYAGER meta-analysis of the impact of statin therapy on low-density lipoprotein cholesterol and triglyceride levels in patients with hypertriglyceridemia. Am J Cardiol 2016 [Epub ahead of print].
Objective: To evaluate changes in low-density lipoprotein cholesterol (LDL-C) and triglycerides in patients with elevated triglycerides (≥177 mg/dl or 2.0 mmol/L) on statin treatment, as part of the VOYAGER (indiVidual patient meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin and simvastatin) database.
Study design: VOYAGER was a meta-analysis of 32,258 patients in 37 randomized, fixed-dose trials directly comparing changes in lipid levels observed during treatment with rosuvastatin, atorvastatin, and simvastatin.
Study population: This analysis included data from 15,800 patients (mean age 59.8 years, 59% men, 32% with diabetes) with baseline triglycerides ≥177 mg/dl or 2.0 mmol/L.  Patients were allocated treatment with 5, 10, 20 or 40 mg rosuvastatin; 5, 10, 20 or 40 mg atorvastatin; and 10, 20, 40 or 80 mg simvastatin.
Efficacity measures

·      Least squares mean percentage change from baseline in LDL-C and triglycerides

·       Percentage of patients attaining triglycerides level of <150 mg/dl or <1.7 mmol/L on statin treatment alone

Methods: Least squares mean percentage change from baseline in LDL-C and triglycerides was compared using 15,800 patient exposures to rosuvastatin, atorvastatin and simvastatin (see above for doses). A mixed-effects model with fixed effect for treatment and a random effect for trial was used to compare the two key efficacy outcomes on rosuvastatin and atorvastatin or simvastatin. 
Results: • Rosuvastatin 10 to 40 mg resulted in significantly greater reduction in LDL-C than equal or double doses of atorvastatin and simvastatin
• While rosuvastatin 10 mg resulted in greater reduction in triglycerides than atorvastatin 10 mg, at higher doses, the triglyceride lowering effect of the two statins was comparable. Both rosuvastatin and atorvastatin were significantly more effective than simvastatin.
• Despite high-intensity statin therapy, 45% of patients on atorvastatin 80 mg and 51% on rosuvastatin 40 mg did not attain desirable triglyceride levels (<150 mg/dl or <1.7 mmol/L).
Authors’ conclusion: In patients with hypertriglyceridaemia, LDL-C reduction was substantial and dependent on the choice and dose of statin. Triglyceride reduction was numerically less than for LDL-C, and additional TG-lowering therapy may be considered to further reduce residual cardiovascular risk.


Despite intensive statin therapy to lower elevated LDL-C levels a high residual cardiovascular risk persists. There is now accumulating evidence to support elevated triglycerides (a marker for triglyceride-rich lipoproteins and their remnants) as an important contributor to this residual risk,1,2 as discussed in Call to Action statements from the Residual Risk Reduction Initiative (R3i).3,4  As shown in this VOYAGER analysis, while high-intensity statin monotherapy was effective in reducing LDL-C levels by up to 56%, about 50% of hypertriglyceridaemic patients do not attain desirable triglyceride levels (<1.7 mmol/L or 150 mg/dl). This is an important unmet clinical need; indeed, data from the EUROASPIRE survey of secondary prevention care in Europe showed that about one-third of patients with previous coronary events had persistently elevated triglycerides (>1.7 mmol/l) despite statin treatment.5 Moreover, residual hypertriglyceridaemia is not restricted to Europe, with studies from other regions showing a similar or higher proportion of patients with elevated triglycerides despite statin treatment.6,7

The key question is what is the most appropriate therapy for targeting residual elevated triglycerides in statin-treated patients. Evidence, albeit from post hoc analyses, support the value of combination therapy with statin plus a fibrate,8 although definitive outcomes data are not yet available. Other therapeutic approaches under investigation include combination with n-3 fatty acids (as in REDUCE-IT and STRENGTH).9,10 Most recently, there is interest in the potential of selective peroxisome proliferator-activated receptor modulators (SPPARMs), given evidence from a murine model which showed that treatment with the SPPARM K-877, not only decreased atherogenic lipoproteins but also reduced atherosclerotic lesion progression.11 Such findings provide a rationale for the landmark PROMINENT trial with K-877 (pemfibrate) in patients with type 2 diabetes and atherogenic dyslipidaemia (high triglycerides and low HDL-C).


1. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.

2. Schwartz GG, Abt M, Bao W et al. Fasting triglycerides predict recurrent ischemic

events in patients with acute coronary syndrome treated with statins. J Am Coll Cardiol 2015;65:2267-75.

3. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319-35.

4. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.

5. Reiner , De Bacquer D, Kotseva K et al. Treatment potential for dyslipidaemia management in patients with coronary heart disease across Europe: findings from the EUROASPIRE III survey. Atherosclerosis 2013;231:300-7.

6. Raal FJ, Blom DJ, Naidoo S, Bramlage P, Brudi P. Prevalence of dyslipidaemia in statin-treated patients in South Africa: results of the DYSlipidaemia International Study (DYSIS). Cardiovasc J Afr 2013;24:330-8.

7. Zhao S, Wang Y, Mu Y et al. Prevalence of dyslipidaemia in patients treated with lipid-lowering agents in China: results of the DYSlipidemia International Study (DYSIS). Atherosclerosis 2014;235:463-9.

8. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-4.

9. A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. (REDUCE-IT). Identifier: NCT01492361.

10. Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH). Identifier: NCT02104817.

11. Hennuyer N, Duplan I, Paquet C et al. The novel selective PPARα modulator (SPPARMα) K-877 improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis. Atherosclerosis 2016 (in press).

Key words  triglycerides; statins; VOYAGER meta-analysis; residual cardiovascular risk