The effect of angiotensin receptor blockers on C-reactive protein and other circulating inflammatory indices in man

Figures & data

Figure 1 The renin–angiotensin system and cascade of bioactive angiotensins.

Abbreviations: ACE₂, ACE-related carboxypeptidase; AMP-A, aminopeptidase A; AMP-B, aminopeptidase B; AMP-N, aminopeptidase N; N-EP, neutral endopeptidase; P-EP, prolylen-dopeptidase.

Figure 2 Schematic representation of the classical renin–angiotensin system (RAS) and of the emerging concept integrating the (pro)renin receptor and the blocking of the system at different steps by pharmacological compounds.

Abbreviations: Ri, renin inhibitor; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; (P)RRB, (pro)renin receptor blocker.⁴

Table 1 Main pharmacokinetic characteristics of the available ARBs

Drug	Tmax(h)	Dose range (mg)	Bioavailability (%)	Half-life(h)	Vd (L)	Elimination (feces/urine)	Antagonism
Losartan*	1 (3–4)	50–100	33	2 (6–9)	34 (12)	60/35	Competitive
Valsartan	2	80–160	23	6	17	83/13	Competitive
Irbesartan	1–2	150–300	60–80	11–15	53–93	80/20	Insurmountable
Candesartan	3–5	8–32	42	9–12	9	67/33	Insurmountable
Eprosartan	2–6	400–800	13	5–7	13	90/10	Insurmountable
Telmisartan	1	20–80	43	24	500	98% fecal	Insurmountable
Olmesartan	1.4–2.8	20–40	26	13	17	35%–49% urine	Insurmountable

Abbreviations: ARBs, angiotensin II receptor blockers; Tmax, time to reach peak serum concentration; Vd, distribution volume.

Note: *Values in parentheses refer to EXP3174, the active metabolite of losartan.

Table 2 Acronyms of completed and ongoing randomized controlled clinical trials with ARBs

Drug	HT	Stroke	Diabetes/renal	CHF	MI	AF
Candesartan	SCOPE^Citation15	ACCESS^Citation16	ALPINE^Citation19 DIRECT^Citation27	CHARM^Citation17
Eprosartan		MOSES^Citation22
Irbesartan			IDNT^Citation8, IRMAII^Citation10	I-PRESERVE^Citation28		ACTIVE^Citation31
Losartan	LIFE^Citation12		RENAAL^Citation9	ELITE^Citation7, HEAAL^Citation32	OPTIMAL^Citation14
Olmesartan			ROADMAP^Citation29
Telmisartan	ONTARGET^Citation24 TRANSCEND^Citation26	PROFESS^Citation25	DETAIL^Citation21
Valsartan	VALUE^Citation20 JIKEI^Citation23		MARVAL^Citation13 NAVIGATOR	VALHEFT^Citation11	VALIANT^Citation18	GISSI-AF^Citation30

Abbreviations: AF, atrial fibrillation; ARBs, angiotensin II receptor blockers; CHF, congestive heart failure; HT, hypertension; MI, myocardial infarction.

Figure 3 Effects of angiotensin II on vascular cellular biology.

Abbreviations: LDL, low-density lipoprotein; MMP, matrix metallo proteinases; PAI, plasminogen activator inhibitor; VSMC, vascular smooth muscle cells.

Table 3 Percent changes in high sensitivity (hs) C-reactive protein (CRP) during ARB treatment

Author	Type of ARB	Dose and duration of treatment	Clinical condition (n. patients)	Hs-CRP baseline (mg/L)	% Change
Wassmann^Citation42	C	16 mg × 6 wk	HC (17)	7.6 ± 2.7	−24%^ns vs P
Dohi^Citation46	C	8 mg × 3 mo	HT (67)	0.7 ± 0.4	−14%* vs B
Koh^Citation47	C	16 mg × 3 mo	HT (45)	1.7 (0.11–2.6)	NS vs B
Rosei^Citation60	C	8–16 mg × 3 mo	HT (61)	3.1 ± 2.75	+5%^ns vs B
Schram^Citation63	C	8 mg × 6–12 mo	HT + D (24)	1.97 (1.14–3.65)	NS vs B
White^Citation75	C	4–32 mg × 6 mo	CHF (41)	7 mg/L	−26%* vs P
Schieffer^Citation54	I	300 mg × 3 mo	CAD/HT (21)	NR	−2.5 mg/L* vs B
Biasucci^Citation57	I	300 mg × 1 mo	CAD (13)	3.1 (0.7–17.7)	−61%* vs P
Andersen^Citation34	L	50–100 mg × 2 mo	Type 1D (16)	1.0 (0.5–1.82)	+16%^ns vs P
Prasad^Citation38	L	25–50 mg × 2 mo	CAD (31)	4.5 ± 1.1	+10%^ns vs B
Koh^Citation52	L	100 mg × 2 mo	HT/HC (47)	0.85 (0.3–1.3)	+6%^ns vs B
Fliser^Citation50	O	20 mg × 3 mo	HT/MS (100)	3.56 ± 3.17	−15%* vs B
Miura^Citation59	T	40 mg × 3 mo	Type 2D (18)	1.54 ± 1.55	−29%* vs B
Koulouris^Citation62	T	40 mg × 3 mo	Type2D (37)	1.38 ± 1.0	−38%* vs P
Link^Citation65	T	40 mg × 3 mo	CAD/HT (21)	2.5 ± 0.6	−44%* vs B
Nagel^Citation66	T	40 mg × 3 mo	HT/MS (20)	5.3 ± 3.77	+8%^ns vs B
Yano^Citation74	T	40 mg × 3 mo	HT/MS (30)	0.77	−22%* vs B
Galle^Citation77	T	40–80 mg × 1 yr	Type2D + HT (255)	2.1 (0.28–15.8)	−3%^ns vs B
Nakayama^Citation78	T	40 mg/2 mo	HT/DIAB (20)	0.76 ± 0.6	+90% vs B
Dandona^Citation45	V	160 mg × 1 wk	NS (8)	1.27 ± 1.54	−23%* vs B
Yasunari^Citation55	V	80 mg × 8 mo	HT (52)	NR	−29%* vs B
Anand^Citation56	V	160 mg × 1 yr	CHF (106)	3.23	−9.3%* vs B
Manabe^Citation58	V	40–80 × 1 mo	HT (29)	1.5 ± 1.1	−13%^ns vs B
Ruilope^Citation61	V	160 mg × 6 mo	HT (720)	NR	−13%* vs B
Ridker^Citation69	V	80–160 mg × 6 wk	HT (836)	2.11	−8.9%* vs B
Rajagopalan^Citation73	V	160 mg × 4 mo	HT (107)	3	−5.3%^ns vs B
Galle^Citation77	V	80–160 mg × 1 yr	DIAB + T (255)	1.88 (0.28–12.59)	−3%^ns vs B

Abbreviations: C, candesartan; I, irbesartan; L, losartan; O, olmesartan; T, telmisartan; V, valsartan; CHF, congestive heart failure; HC, hypercholesterolemia; HT, hypertension; CAD, coronary artery disease; T2D, type 2 diabetes; T1D, type 1 diabetes; NS, normal subjects; MS, metabolic syndrome; B, baseline; P, concurrent placebo; ns, not significant.

Note: *denotes statistical significance (p < 0.05 or less) of changes from either baseline or concurrent placebo.

Table 4 Percent changes in circulating e-selectin (SEL), intercellular cellular adhesion molecule (ICAM)-1, vascular cellular adhesion molecule (VCAM)-1, interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1 during ARB treatment

Author	Type of ARB	Clinical condition (n. patients)	e-SEL	sICAM-1	sVCAM-1	IL-6	TNF-α	MCP-1
Tsutamoto^Citation35	C	CHF (14)	N/A	↓	↓	↓	↓	N/A
Wassmann^Citation42	C	HC (17)	N/A	−22.6%*	N/A	N/A	+6.8%^ns	−18.1%*
Koh^Citation47	C	HT (47)	N/A	N/A	N/A	N/A	−24%*	−7%*
Rosei^Citation60	C	HT (61)	−5%*	−4.1%*	N/A	N/A	N/A	N/A
Schram^Citation63	C	HT (22)	N/A	ns	↓	N/A	N/A	N/A
Ogawa^Citation68	C/V	HT/T2D (33)	N/A	N/A	N/A	−29.4%	N/A	−25.7%
White^Citation75	C	CHF (41)	ns	ns	N/A	ns	N/A	Ns
Rahman^Citation40	E	HT (19)	N/A	N/A	−35%	N/A	N/A	−34%*
Lauten^Citation48	I	CAD (37)	N/A	N/A	N/A	↓	N/A	N/A
Schieffer^Citation54	I	CAD/HT (21)	N/A	N/A	N/A	↓	N/A	N/A
De Rosa^Citation64	I/T	T2D/MS (188)	N/A	N/A	N/A	↓	N/A	N/A
Andersen^Citation34	L	T1D (29)	−1%^ns	+2%^ns	−5%*	N/A	N/A	N/A
Prasad^Citation38	L	CAD (31)	+2%^ns	+5%^ns	+3%^ns	N/A	N/A	N/A
Jilma^Citation39	L	HT (15)	−3%^ns	−5%^ns	−8%^ns	N/A	+1%^ns	+2%^ns
Rajagopalan^Citation41	L	NS (18)	ns	−50%*	−24%*	N/A	N/A	−30%*
Graninger^Citation51	L	NS (7)	0%^ns	−11%*	−11%*	N/A	N/A	N/A
Koh^Citation52	L	HT (47)	N/A	N/A	N/A	N/A	N/A	−7%*
Sardo^Citation53	L	HT (20)	N/A	−3%^ns	N/A	N/A	−8%^ns	N/A
Fliser^Citation50	o	HT (100)	N/A	N/A	N/A	−18%*	−14%*	−4%*
Link^Citation65	T	HT (21)	N/A	N/A	−14%^ns	−38%^ns	−39%^ns	N/A
Nagel^Citation66	T	HT/MS (20)	N/A	N/A	N/A	−8%^ns	N/A	N/A
Manabe^Citation58	V	HT (39)	N/A	N/A	N/A	−4%*	−33%*	N/A
Nomura^Citation67	V	HT/DIAB (28)	−6.1%*	−3.6%	N/A	N/A	−6.6%*	−4.7%*
Rajagopalan^Citation73	V	HT (107)	N/A	N/A	N/A	N/A	N/A	−15.6%*

Abbreviations: C, candesartan; I, irbesartan; L, losartan; O, olmesartan; T, telmisartan; V, valsartan; CHF, congestive heart failure; HC, hypercholesterolemia; HT, hypertension; CAD, coronary artery disease; T2D, type 2 diabetes; T1D, type 1 diabetes; NS, normal subjects; MS, metabolic syndrome; B, baseline; P, concurrent placebo; ns, not significant; N/A, not assessed.

Notes: ↓ Indicates significant reductions in absence of precise figures retrievable from the publication.

*Denotes statistical significance (p < 0.05 or less).

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