Rosuvastatin, inflammation, C-reactive protein, JUPITER, and primary prevention of cardiovascular disease – a perspective

Figures & data

Figure 1 A picture of C-reactive protein (CRP) from 1B09.pdb made using pymol.¹⁰ CRP is a pentameric molecule containing a recognition face that binds phosphocholine and calcium ions, and on the opposite side, an effector face that contains a C1q-binding site. Function depends upon Ca²⁺-dependent ligand binding. See text for details. Reproduced by permission of Skolstoe through Wikipedia commons.

Figure 3 The structure of rosuvastatin, uniquely containing sulfur, a fluorophenyl group, and a modified hydroxyglutaric acid moiety. The IUPAC name of rosuvastatin is (E,3R,5R)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan- 2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid.

Table 1 Rough equivalent doses of rosuvastatin

% Reduction in LDL	Rosuvastatin	Atorvastatin	Simvastatin	Fluvastatin	Lovastatin	Pravastatin
30–40	5 mg	10 mg	20 mg	80 mg	40 mg	40 mg
40–45	5–10 mg	20 mg	40 mg	N/A	80 mg	80 mg
46–50	10–20 mg	40 mg	80 mg	N/A	N/A	N/A
50–55	20 mg	80 mg	N/A	N/A	N/A	N/A
56–60	40 mg	N/A	N/A	N/A	N/A	N/A

Abbreviation: LDL, low-density lipoprotein.

Table 2 Baseline clinical data in the JUPITER trial

Characteristic	Treated group	Placebo group
Age, years (%)	66 (median)	66
Female sex, number (%)	3426 (38.5)	3375 (37.9)
Ethnicity
White, number (%)	6358 (71.4)	6325 (71.1)
Black, number (%)	1100 (12.4)	1124 (12.6)
Hispanic, number (%)	1121 (12.6)	1140 (12.8)
Body mass index, kg/m^2	28.3 (median)	28.4
Family history, number (%)	997 (11.2)	1048 (11.8)
Tobacco use number (%)	1400 (15.7)	1420 (16.0)
Systolic blood pressure, mm Hg	134 (median)	134
Diastolic blood pressure, mm Hg	80	80
CRP
mg/L	4.2 (2.8–7.1)a	4.3 (2.8–7.2)
nmol/L	40.0 (median)	40.9
Triglycerides
mg/dL	118 (median)	118
mmol/L	1.33	1.33
Total cholesterol
mg/dL	186	185
mmol/L	4.82	4.79
LDL cholesterol
mg/dL	108	108
mmol/L	2.8	2.8
HDL cholesterol
mg/dL	49	49
mol/L	1.27	1.27
Glucose
mg/dL	94	94
mol/L	5.22	5.22
HbA1c %	5.7 (5.4–5.9)	5.7 (5.5–5.9)
Metabolic syndrome (%)b	3652 (41.0)	3723 (41.8)

a Notes: Interquartile range;

b Metabolic syndrome was defined according to the National Heart, Lung, and Blood Institute definition or American Heart Association consensus criteria.

Abbreviations: HbA_1c, glycated hemoglobin; LDL, low-density lipoprotein.

Table 3 JUPITER trial: comparison of outcomes between treated and nontreated patients

End point	Patients in subgroup rosuvastatin (n = 8901)	Patients in subgroup placebo (n = 8901)	Hazard ratio (95% CI)
Primary end pointa	142	251	0.56 (0.46–0.69)
Any MI	31	68	0.46 (0.30–0.70)
Nonfatal MI	22	62	0.35 (0.22–0.58)
Any stroke	33	64	0.52 (0.34–0.79)
Nonfatal stroke	30	58	0.52 (0.33–0.80)
Revascularization	71	131	0.54 (0.41–0.72)
Hospitalization for unstable angina	16	27	0.59 (0.32–1.10)
Revascularization or hospitalization for unstable angina	76	143	0.53 (0.40–0.70)
MI, stroke, or death from cardiovascular causes	83	157	0.53 (0.40–0.69)
Any death	198	247	0.80 (0.67–0.97)

a Notes: Primary end point: composite of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, revascularization, and death from cardiovascular causes.

Abbreviations: CI, confidence interval; MI, myocardial infarction.

Table 4 Cardiovascular events fell based on LDL cholesterol and on hs-CRP levels <2 mg/L

LDL cholesterol (mg/dL) and hs-CRP (mg/L) values	Event rate	Hazard ratio (95% CI)
≥70 and ≥2	1.11	1.06 (0.72–1.55)
≥70 and <2	0.54	0.42 (0.18–0.94)
<70 and ≥2	0.62	0.53 (0.38–0.74)
<70 and <2	0.38	0.35 (0.23–0.54)
≥70 or ≥2	0.38	0.64 (0.49–0.84)

Abbreviations: CI, confidence interval; LDL, low-density lipoprotein; hs-CRP, high CRP.

Table 5 Cardiovascular events fell based on LDL cholesterol and on hs-CRP levels <1 mg/L

LDL cholesterol (mg/dL) and hs-CRP (mg/L) values	Event rate	Hazard ratio (95% CI)
≥70 and ≥1	0.95	0.89 (0.62–1.28)
≥70 and <1	0.64	0.46 (0.11–1.85)
<70 and ≥1	0.56	0.49 (0.37–0.66)
<70 and <1	0.24	0.21 (0.09–0.51)
≥70 or ≥1	0.67	0.59 (0.46–0.75)

Abbreviations: CI, confidence interval; LDL, low-density lipoprotein; hs-CRP, high CRP.

Table 6 Event rates and hazard ratios for the primary end point correlated with estimated 10-year Framingham and Reynolds risk scores at baseline

Risk level	Event rate/100-person years, rosuvastatin 20 mg group	Event rate/100-person years, placebo group	Hazard ratio (95% CI)
Framingham 10-year risk score
<5% (n = 2791, 173 men, 2618 women)	0.22	0.34	0.64 (0.23–1.81)
5%–10% (n = 6091, 2525 women, 3566 men)	0.50	0.92	0.55 (0.36–0.84) 5-year NNT = 40a
11%–20% (n = 7340,1404 women, 5936 men)	0.95	1.84	0.51 (0.39–0.68) 5-year NNT = 18b
>20% (n = 1555, 242 women, 1313 men)	1.72	2.41	0.70 (0.43–1.14)
Reynolds 10-year risk score
<5% (n = 3583, 944 men, 2639 women)	0.26	0.41	0.62 (0.27–1.43)
5%–10% (n = 6436, 2651 women, 3785 men)	0.44	1.00	0.45 (0.29–0.68)
11%–20% (n = 5040, 1151 women, 3889 men)	1.07	1.65	0.65 (0.47–0.90)
>20% (n = 2651, 327 women, 2324 men)	1.55	2.84	0.55 (0.38–0.80)

a Notes: Corresponds to estimated absolute risk difference between treated and placebo groups at 5 year of ≈2.5 events/100 person-years;

b Corresponds to estimated absolute risk difference between treated and placebo groups at 5 year of ≈5.7 events/100 person-years.

Abbreviations: CI, confidence interval; NNT, number needed to treat.

Table 7 Components of the primary end point reached in the JUPITER study

End point	Rosuvastatin group	Placebo group	Hazard ratio	95% CI	P value
Primary end point	142	251	0.56	0.46–0.69	<0.00001
Nonfatal MI	22	62	0.35	0.22–0.58	<0.00001
Any MI	31	68	0.46	0.30–0.70	<0.0002
Nonfatal stroke	30	58	0.52	0.33–0.80	0.003
Any stroke	33	64	0.52	0.34–0.79	0.002
Revascularization or Unstable angina	76	143	0.53	0.40–0.70	<0.00001
MI, stroke, CV death	83	157	0.53	0.40–0.69	<0.00001
Total mortality	198	247	0.80	0.67–0.97	0.02
CV death (verified)	35	43	0.82	0.52–1.27	0.37
Sudden death	16	25	0.64	0.34–1.20	0.16

Abbreviations: CI, confidence interval; CV, cardiovascular; MI, myocardial infarction.

Figure 2 Cholesterol is synthesized via the mevalonate pathway. Acetyl-CoA forms 3-hydroxyl-3-methylglutaryl CoA (HMG-CoA) in several steps. The conversion of 3-hydroxy-3-methylglutaryl (HMG)-CoA to mevalonate, the rate-limiting step in cholesterol synthesis, is catalyzed by HMG-CoA reductase (HMGR), an enzyme within the endoplasmic reticulum. Rosuvastatin is an efficient competitive inhibitor of HMGR, reducing not only mevalonate levels, but also prenylated downstream products. The post-translational process of prenylation is needed for the function of small G proteins, including geranylgeranylation of Rho, Ras, and Rab, necessary for cellular signaling, transduction, and intermembrane translocation. As beneficial as statins are, there are obligatory molecular consequences inherent in their use, some related to their beneficial pleiotropic actions, but also to their side effects. Many steps and enzymes are omitted for clarity.

Table 8 Effect of coadministered drugs on rosuvastatin systemic exposure

Coadministered drug and dosing regimen	Rosuvastatin
	Dose (mg)a	Change in AUCb	Change in Cmaxb
Cyclosporine – stable dose required (75–200 mg twice daily)	10 mg daily for 10 days	↑ 7-foldc	↑ 11-foldc
Gemfibrozil 600 mg twice daily for 7 days	80 mg	↑ 1.9-foldc	↑ 2.2-foldc
Lopinavir/ritonavir combination 400 mg/100 mg twice daily for 10 days	20 mg daily for 7 days	↑ 2-foldc	↑ 5-foldc
Atazanavir/ritonavir combination 300 mg/100 mg daily for 7 days	10 mg	↑ 3-foldc	↑ 7-foldc
Tipranavir/ritonavir combination 500 mg/200 mg twice daily for 11 days	10 mg	↑ 26%	↑ 2-fold
Fosamprenavir/ritonavir 700 mg/100 mg twice daily for 7 days	10 mg	↑ 8%	↑ 45%
Fenofibrate 67 mg 3 times daily for 7 days	10 mg	↑ 7%	↑ 21%
Aluminum and magnesium hydroxide combination antacid, administered simultaneously	40 mg	↓ 54%c	↓ 50%c
The above, administered 2 hours apart	40 mg	↓ 22%	↓ 16%
Erythromycin 500 mg 4 times daily for 7 days	80 mg	↓ 20%	↓ 31%
Ketoconazole 200 mg twice daily for 7 days	80 mg	↑ 2%	↓ 5%
Itraconazole 200 mg daily for 5 days	10 mg 80 mg	↑ 39% ↑ 28%	↑ 36% ↑ 15%
Fluconazole 200 mg daily for 11 days	80 mg	↑ 14%	↑ 9%

a Notes: Single dose unless otherwise noted;

b Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively;

c Clinically significant.

Abbreviations: AUC, area under the plasma concentration-time curve; C_max, peak plasma concentration.

Table 9 Effect of rosuvastatin coadministration with warfarin, digoxin, and an oral contraceptive

Rosuvastatin dosage regimen	Coadministered drug
	Name and dose	Change in AUC	Change in Cmax
40 mg daily for 10 days	Warfarin 25 mg, single dose	R-Warfarin ↑ 4% S-Warfarin ↑ 6%	R-Warfarin ↓ 1% S-Warfarin 0%
40 mg daily for 12 days	Digoxin 0.5 mg, single dose	↑ 4%	↑ 4%
40 mg daily for 28 days	Oral contraceptive (EE 0.035 mg and NG 0.180, 0.215, and 0.250 mg) daily for 21 days	EE ↑ 26% NG ↑ 34%	EE ↑ 25% NG ↑ 23%

Abbreviations: AUC, area under the plasma concentration-time curve; C_max, peak plasma concentration; EE, ethinyl estradiol; NG, norgestrel; R-warfarin and S-warfarin, referring to the stereoisomers.

ThompsonDPepysMBWoodSPThe physiological structure of human C-reactive protein and its complex with phosphocholineStructure1999716917710368284

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