Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

Figures & data

Figure 1. Pharmacological changes of LDL-C and CRP. Modified from Kinlay S et al. [6]. CETP: Cholesteryl ester transfer protein; PCSK9: Proprotein convertase subtilisin/kexin 9.

Table 1. Percentage changes of hsCRP and LDL-C upon drug treatments.

	Clinical study	hsCRP (mg/L)			LDL-C (mg/dL)
		pre	post	Δ	pre	post	Δ
Monoclonal antibody anti IL-1β
Canakinumab [52]	CANTOS	4.3	2.0	−37% vs placebo	82.4	84.7	+3.1% vs placebo
Statins
Pravastatin [215,216]	CARE	2.3	1.9	−17.4% vs baseline	139.2	98.0	−32% vs baseline
Pravastatin [217]	PRINCE	2.4	2.0	−16.6% vs baseline	142.9	97.5	−31.8% vs baseline
Lovastatin [2,218]	AFCAPS/TexCAPS	1.6	1.3	−14.8% vs baseline	156.0	115.0	−27% vs baseline
Atorvastatin [219,220]	MIRACL	11.5	2.9	−75.0% vs placebo	135.0	72.0	−40% vs placebo
Pravastatin [76]	REVERSAL	3.0	2.9	−5.2% vs baseline	150.2	110.4	−25.2% vs baseline
Atorvastatin [76]	REVERSAL	3.0	1.8	−36.4% vs baseline	150.2	78.9	−46.3% vs baseline
Pravastatin [73,221]	PROVE IT–TIMI 22	11.9	2.1	−82.4% vs baseline	106.0	95.0	−10.4% vs baseline
Atorvastatin [73,221]	PROVE IT–TIMI 22	12.2	1.3	−89.3% vs baseline	106.0	62.0	−41.5% vs baseline
Simvastatin [222]	A-to-Z Trial	2.01	0.17	−91.5% vs baseline	112.0	62.0	−44.6% vs baseline
Rosuvastatin [74]	JUPITER	4.2	2.2	−47.6% vs baseline	108.0	55.0	−49.1% vs baseline
Simvastatin [223]	Heart Protection Study	3.07	2.24	−27% vs baseline	127.9	95.9	−25% vs baseline
Atorvastatin [224]	ASCOT	2.4	1.8	−25.8% vs baseline	136.8	85.6	−38.7% vs baseline
Atorvastatin [225]	CARDS	1.3	1.2	−9.8% vs baseline	121.0	60.0	−50.4% vs baseline
Ezetimibe
Ezetimibe + atorvastatin [226]		2.19	1.98	−10% vs atorvastatin	101.8	89.5	−12.1% vs atorvastatin
Ezetimibe + rosuvastatin [227]	EXPLORER	1.7	1.2	−17.8% vs rosuvastatin	81.5	56.9	−30.2% vs rosuvastatin
Ezetimibe + Simvastatin [88]	SHARP	1.1	0.99	−21% vs placebo	106.0	68.9	−35% vs placebo
Ezetimibe + Simvastatin [87]	IMPROVE-IT	1.9	1.6	−14% vs simvastatin	67.7	49.9	−20% vs simvastatin
Fibrates
Fenofibrate [105]	FIELD	1.8	2.5	+38.9% vs baseline	120	103	−14.2% vs baseline
Fenofibrate + Simvastatin [108]	DIACOR	2.2	2.1	−15.9% vs baseline	136.9	92.0	−29.1% vs baseline
Fenofibrate + Ezetimibe [111]		2.5	1.9	−25.3% vs baseline	159.7	124.6	−22.0% vs baseline
Monoclonal antibody anti PCSK9
Evolocumab [143,228]	FOURIER	1.7	1.4	0% vs placebo	92.0	30.0	−59% vs placebo
Bococizumab [149]	SPIRE-1 and -2	1.88	1.84	+6.6% vs placebo§	96.5	34.7	−60.5% vs placebo§
Alirocumab [140]	ODYSSEY COMBOII	3.58	3.51	−2% vs baseline	108.0	53.3	−49.5% vs baseline
Bile acid sequestrants
Colesevelam HCl + statins [163]		2.0	1.3	−23.3% vs statins	132.6	111.3	−21% vs statins
Colestimide [164]		10.16	5.86	−42.3%	151.2	127.3	−14.4% vs baseline
MTP inhibitor
Lomitapide [168]	NCT00943306	2.0	1.1	−45% vs baseline#	356.0	189.0	−45.5 % vs baseline#
Bempedoic acid
Bempedoic acid + ezetimibe [181]	CLEAR Tranquility	2.2	1.3	−33% vs placebo	129.8	96.2	−28.5% vs placebo
CETP inhibitor
Torcetrapib [187]	ILLUMINATE	1.30	1.34	+1% vs placebo	79.7	60.5	−24% vs placebo
Dalcetrapib [190,191]	dal-OUTCOMES	1.5	1.6	+18% vs placebo	76.4	76.4	no changes
	dal-OUTCOMES (analyzed for carriers of ADCY9 AA genotype)	1.71	1.61	−1.0 % vs placebo	76.0	–	–
Evacetrapib [188]	ACCELERATE	1.52	1.65	+8.6% vs baseline	81.6	54.7	−37.1% vs placebo
Nicotinic acid
Niacin [203]	NCT01216956	2.7	1.6	−40% vs baseline	125	103	−17% vs baseline

#Data available at week 126; §Data available at week 14; –, not available.

Figure 2. Data from a secondary analysis of CANTOS study: Hazard ratios for major CV events, cardiovascular mortality and all-cause mortality were stratified according toon-treatment hsCRP concentrations at 3 months [59].

Kinlay S. Low-density lipoprotein-dependent and -independent effects of cholesterol-lowering therapies on C-reactive protein: a meta-analysis. J Am Coll Cardiol. 2007;49:2003–2009.

 PubMed Web of Science ®Google Scholar

Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–1131.

 PubMed Web of Science ®Google Scholar

Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001–1009.

 PubMed Web of Science ®Google Scholar

Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999;100:230–235.

 PubMed Web of Science ®Google Scholar

Albert MA, Danielson E, Rifai N, et al. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001;286:64–70.

 PubMed Web of Science ®Google Scholar

Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344:1959–1965.

 PubMed Web of Science ®Google Scholar

Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615–1622.

 PubMed Web of Science ®Google Scholar

Kinlay S, Schwartz GG, Olsson AG, et al. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation. 2003;108:1560–1566.

 PubMed Web of Science ®Google Scholar

Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711–1718.

 PubMed Web of Science ®Google Scholar

Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071–1080.

 PubMed Web of Science ®Google Scholar

Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–28.

 PubMed Web of Science ®Google Scholar

Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–1504.

 PubMed Web of Science ®Google Scholar

de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292:1307–1316.

 PubMed Web of Science ®Google Scholar

Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–2207.

 PubMed Web of Science ®Google Scholar

Heart Protection Study Collaborative G, Jonathan E, Derrick B, Emma L, et al. C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20,536 patients in the Heart Protection Study. Lancet. 2011;377:9764469–9764476.

 Web of Science ®Google Scholar

Sever PS, Poulter NR, Chang CL, et al. Evaluation of C-reactive protein before and on-treatment as a predictor of benefit of atorvastatin: a cohort analysis from the Anglo-Scandinavian Cardiac Outcomes Trial lipid-lowering arm. J Am Coll Cardiol. 2013;62:717–729.

 PubMed Web of Science ®Google Scholar

Soedamah-Muthu SS, Livingstone SJ, Charlton-Menys V, et al. Effect of atorvastatin on C-reactive protein and benefits for cardiovascular disease in patients with type 2 diabetes: analyses from the Collaborative Atorvastatin Diabetes Trial. Diabetologia. 2015;58:1494–1502.

 PubMed Web of Science ®Google Scholar

Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003;107:2409–2415.

 PubMed Web of Science ®Google Scholar

Ballantyne CM, Weiss R, Moccetti T, et al. Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (results from the EXPLORER study). Am J Cardiol. 2007;99:673–680.

 PubMed Web of Science ®Google Scholar

Storey BC, Staplin N, Haynes R, et al. Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation. Kidney Int. 2018;93:1000–1007.

 PubMed Web of Science ®Google Scholar

Bohula EA, Giugliano RP, Cannon CP, et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation. 2015;132:1224–1233.

 PubMed Web of Science ®Google Scholar

Hiukka A, Westerbacka J, Leinonen ES, et al. Long-term effects of fenofibrate on carotid intima-media thickness and augmentation index in subjects with type 2 diabetes mellitus. J Am Coll Cardiol. 2008;52:2190–2197.

 PubMed Web of Science ®Google Scholar

Muhlestein JB, May HT, Jensen JR, et al. The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia: the DIACOR (Diabetes and Combined Lipid Therapy Regimen) study. J Am Coll Cardiol. 2006;48:396–401.

 PubMed Web of Science ®Google Scholar

McKenney JM, Farnier M, Lo KW, et al. Safety and efficacy of long-term co-administration of fenofibrate and ezetimibe in patients with mixed hyperlipidemia. J Am College Cardiol. 2006;47:1584–1587.

 PubMed Web of Science ®Google Scholar

Bohula EA, Giugliano RP, Leiter LA, et al. Inflammatory and Cholesterol Risk in the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk). Circulation 2018;138:131–140.

 PubMed Web of Science ®Google Scholar

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376:1713–1722.

 PubMed Web of Science ®Google Scholar

Pradhan AD, Aday AW, Rose LM, et al. Residual Inflammatory Risk On Treatment with PCSK9 Inhibition and Statin Therapy. Circulation. 2018;138:141–149.

 PubMed Web of Science ®Google Scholar

Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36:1186–1194.

 PubMed Web of Science ®Google Scholar

Bays HE, Davidson M, Jones MR, et al. Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia. Am J Cardiol. 2006;97:1198–1205.

 PubMed Web of Science ®Google Scholar

Kato T, Inagaki K, Sawai Y, et al. Comparison of efficacy of pitavastatin and colestimide in Japanese patients with diabetes mellitus complicated by hyperlipidemia and metabolic syndrome. Exp Clin Endocrinol Diabetes. 2011;119:554–558.

 PubMed Web of Science ®Google Scholar

Blom DJ, Averna MR, Meagher EA, et al. Long-term efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in patients with homozygous familial hypercholesterolemia. Circulation. 2017;136:332–335.

 PubMed Web of Science ®Google Scholar

Ballantyne CM, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study. Atherosclerosis. 2018; Available online 12 June 2018.

 Google Scholar

Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357:1301–1310.

 PubMed Web of Science ®Google Scholar

Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–2099.

 PubMed Web of Science ®Google Scholar

Tardif JC, Rhainds D, Brodeur M, et al. Genotype-dependent effects of dalcetrapib on cholesterol efflux and inflammation: concordance with clinical outcomes. Circulation Cardiovascular Genetics 2016;9:340–348.

 PubMed Web of Science ®Google Scholar

Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017;376:1933–1942.

 PubMed Web of Science ®Google Scholar

Adiels M, Chapman MJ, Robillard P, et al. Niacin action in the atherogenic mixed dyslipidemia of metabolic syndrome: Insights from metabolic biomarker profiling and network analysis. J Clin Lipidol. 2018;12:810–821.e1.

 PubMed Web of Science ®Google Scholar