Pharmacological effects of lipid-lowering drugs on circulating adipokines

Table 1 Effects of statins on circulating adipokines

Subjects	Treatment	Effects on circulating adipokines	Ref.
Male New Zealand rabbits with hypercholesterolemia	6 wk of 2.5 mg/kg per day atorvastatin	Leptin decreased by 38% from 8.9 ± 2.3 to 5.5 ± 2.8 μg/mL (P < 0.05)	[20]
Humans with T2DMa	8 wk of 40 mg/d atorvastatin	HMW increased by 42.3% while MMW and LMW decreased by 21% and 23% respectively. Total adiponectin did not change. (2009 article) Leptin decreased by 40% from 20.7 ± 2.3 to 12.5 ± 1.1 ng/mL. Resistin decreased by 20% from 3.5 ± 0.4 to 2.9 ± 0.4 μg/mL	[95]
Healthy humans	12 wk of pravastatin (40 mg/d)	No changes in adiponectin or leptin	[21]
Humans with hypercholesterolemia	4 mo of pravastatin or atorvastatin (10 mg/d)	Adiponectin increased from 10.7 ± 4.7 to 11.0 ± 5.1 μg/mL in response to atorvastatin (P < 0.05). No change in leptin or resistin. Atorvastatin reduced TNF-α from 2.0 ± 1.0 to 1.7 ± 0.6 (P < 0.05)	[22]
Humans with hyperlipidemia	6 mo of simvastatin (10 mg/d) or pitavastatin (2 mg/d)	Adiponectin increased in response to pitavastatin but not in response to simvastatin	[74]
Humans with increased cardiovascular risk	12 wk of 10-80 mg/d atorvastatin	Adiponectin increased by 10% with maximal increase (25%) observed at 80 mg/d (P < 0.05)	[75]
Humans with hypercholesterolemia and CADb	6 mo of 10-20 mg/d pravastatin	Adiponectin increased by 16.8% from 7.2 to 7.8 μg/mL (P < 0.001)	[76]
Humans with hypercholesterolemia and ischemic heart disease	3 mo of 10 mg/d atorvastatin	Adiponectin increased from 9.7 ± 7.4 to 13.9 ± 9.98 μg/mL (P < 0.005)	[77]
C57BL/6J mice	0-15 wk of 0.06% of diet as pravastatin	Adiponectin increased (P < 0.01)	[78]
Men with hypercholesterolemia	1 year of 40 mg/d pravastatin	Adiponectin increased by 1.47 ± 0.33 μg/mL (P < 0.05)	[78]
Humans with CADb and IGTc	6 mo of 20 mg/d pravastatin	Adiponectin increased by 35% from 5.2 to 6.1 μg/mL (P < 0.001)	[79]
Humans with stable CADb, hypercholesterolemia and hypertriglyceridemia	6 mo of 10 mg/d atorvastatin	Adiponectin increased by 4 wk (P < 0.05), with further increases by 6 mo (P < 0.01). Atorvastatin decreased TNF-α (P < 0.01)	[80]
Humans with MetS	40 mg/d simvastatin for 8 wk	No change in adiponectin	[81]
Humans at cardiovascular risk	3 mo of 40 mg simvastatin	Adiponectin decreased from 15.5 ± 12.7 to 11.6 ± 7.0 μg/mL (P < 0.05)	[82]
Nondiabetic humans with increased cardiovascular risk	3 mo of simvastatin (40 mg/d)	Adiponectin decreased. No change in RBP4	[83]
Humans with hypercholesterolemia	2 mo of 10-80 mg/d simvastatin	Adiponectin decreased with maximal decrease (10%) observed at 80 mg/d (P < 0.05)	[84]
Humans with hypercholesterolemia	2 mo of simvastatin (20 mg/d) or pravastatin (40 mg/d)	Simvastatin decreased adiponectin (5.8 ± 0.8 to 5.2 ± 0.6 μg/mL); pravastatin increased adiponectin (5.6 ± 0.6 to 6.1 ± 0.6 μg/mL)	[85]
Humans with hypercholesterolemia on fluvastatin plus TLCe and 19 humans with normal cholesterol on TLC alone	12 wk of 80 mg/d fluvastatin plus TLC (n = 24) or 12 wk of TLC alone (n = 19)	Adiponectin increased from 5.3 ± 1.5 to 6.2 ± 2.2 μg/mL in response to TLC (P < 0.05), but was unchanged in response to fluvastatin	[91]
Humans with T2DMa and mixed hyperlipoproteinemia	6 wk of 10 mg/d atorvastatin	No change in adiponectin or resistin	[92]
Kidney transplant recipients	12 wk of atorvastatin (10 mg/d)	No change in adiponectin or TNF-α	[93]
Humans with T2DM or at high risk for T2DM	12 wk of atorvastatin (20 mg/d)	No effect on adiponectin, resistin or TNF-α	[94]
Humans with T2DMa	6 mo of 10 mg/d atorvastatin	Resistin tended to decrease, although not significant (P = 0.11)	[131]

^aType 2 diabetes mellitus;

^bCoronary artery disease;

^cImpaired glucose tolerance; ^dLipopolysaccharide;

^eTherapeutic lifestyle changes. TNF-α: Tumor necrosis-factor-α; RBP4: Retinol binding protein 4; HMW: High-molecular weight; LMW: Low-molecular weight; MMW: Middle-molecular weight; T2DM: Type 2 diabetes; Ref: Reference.

Table 2 Effects of fibrates on circulating adipokines

Subjects	Treatment	Effects on circulating adipokines	Ref.
Male Wistar rats on standard diet or HFDd	28 d of 75 mg/kg per day gemfibrozil	Leptin decreased in rats on HFDd (P < 0.01). No change in leptin in rats on standard diet.	[32]
Wistar rats on high-fat, high-glucose diet	8 wk of fenofibrate (50 mg/kg/d)	Fenofibrate reduced plasma leptin levels; no effect on plasma adiponectin. Fenofibrate reduced leptin mRNA levels; and increased adiponectin mRNA levels in epididymal fat	[33]
Rats	14 d of clofibrate	No effect on leptin mRNA levels in brown or white adipose tissue	[34]
Obese humans with T2DM and hypertriglycer-idemia	3 mo of fenofibrate (250 mg/d)	Serum leptin levels decreased from 266 ± 205 to 157 ± 122 pg/mL (P = 0.003)	[35]
Humans with hypertriglycer-idemia, central obesity, other characteristics of MetS	12 wk of fenofibrate (160 mg/d)	Adiponectin increased 7.7% from 4.10 to 4.50 μg/mL	[97]
Humans with stable CADb, hypercholester-olemia and hypertriglyceridemia	6 mo of bezafibrate (400 mg/d)	Adiponectin increased by 4 wk (P < 0.05), with further increases by 6 mo (P < 0.01). Bezafibrate reduced TNF-α	[80]
Nondiabetic men with insulin resistance and dyslipidemia; Male sprague-dawley rats on HFD; 3T3-L1 adipocytes	8 wk of fenofibrate (200 mg/d) in humans. 2 wk of fenofibrate (200 mg/kg per day) in rats. 24 h of fenofibrate (10, 50, 100 μmol/L) in 3T3-L1 adipocytes.	Fenofibrate decreased serum RBP4 (34.8 ± 4.0 to 24.4 ± 2.1 μg/mL) and increased adiponectin (11.3 ± 6.7 to 16.5 ± 7.2 μg/mL) in humans. Fenofibrate reduced the HFD-induced increase in RBP4 in rats. Fenofibrate reduced HFD-induced increase in RBP4 mRNA in adipose tissue of rats. Fenofibrate attenuated the HFD-induced decrease in adiponectin mRNA in adipose tissue of rats. Fenofibrate suppressed RBP4 mRNA levels by 22% at highest concentration and increased adiponectin mRNA levels by 46% at highest concentration in 3T3-L1 adipocytes	[100]
Humans with MetSc	Longitudinal study over a period of ~6.2 year of 400 mg/d bezafibrate	After 2 year of treatment, adiponectin increased, with the median percentage change being +9.8% (P < 0.0001)	[98]
Humans with hypertriglyceridemia; some with MetSc	8 wk of fenofibrate (200 mg/d)	Adiponectin increased by 14% ± 5% (P = 0.008)	[99]
Men with hypertriglyceridemia	12 wk of 150 mg/d (n = 7) or 4 wk of 150 mg/d then 8 wk of 300 mg/d (n = 4) fenofibrate	HMWb adiponectin increased from 3.0 ± 1.5 to 3.4 ± 1.7 μg/mL (P < 0.05). No change in total adiponectin	[101]
Humans with T2DMa and mixed hyperlipoproteinemia	6 wk of fenofibrate (200 mg/d)	No change in adiponectin or resistin	[92]
Humans with insulin-resistant MetSc	12 wk of fenofibrate (200 mg/d)	No change in plasma leptin, adiponectin or TNF-α concentrations	[36]
Obese women with T2DMa	3 mo of fenofibrate (200 mg/d)	No effect on adiponectin or resistin	[102]
Hypercholesterolemic rabbits and adipocytes from these rabbits	4 wk of fenofibrate (30 mg/kg per day or 10-100 μmol/L)	Fenofibrate decreased high cholesterol diet-induced increases in TNF-α by 44.7%. Fenofibrate reduced TNF-α release by adipocytes (P < 0.05) compared to the high cholesterol group (10.45 ± 0.33 vs 17.23 ± 0.26 pg/mL, P < 0.05)	[123]

^aType 2 diabetes mellitus;

^bHigh molecular weight;

^cMetabolic syndrome;

^dHigh-fat diet. TNF-α: Tumor necrosis-factor-α; RBP4: Retinol binding protein 4; HMW: High-molecular weight; T2DM: Type 2 diabetes; Ref: Reference.

Table 3 Effects of niacin on circulating adipokines

Subjects	Treatment	Effects on circulating adipokines	Ref.
Male sprague-dawley rats	Acute dose of 30 mg/kg niacin (n = 6)	Adiponectin increased by 37% at 10 min, peaked at 1 h and remained elevated for 24 h (P < 0.05). No change in resistin or leptin	[39]
Male New Zealand rabbits on high-cholesterol diet	6 wk of 200 mg/kg per day niacin (n = 6)	Leptin decreased by 22% from 6.87 ± 1.58 to 8.79 ± 1.45 ng/mL (P < 0.05)	[41]
Men with MetSa	6 wk of 1500 mg extended-release niacin	Adiponectin increased by 46% from 5.7 ± 0.5 to 8.4 ± 0.7 μg/mL (P < 0.05)	[104]
Men with MetSa	6 wk of 1500 mg extended-release niacin	Adiponectin increased by 56% from 6.1 ± 2.3 to 10.1 ± 4.0 μg/mL (P < 0.01). Leptin increased by 27% from 19.8 ± 21.4 to 24.6 ± 26.8 ng/mL (P < 0.05). No change in resistin, TNF-α, IL-6	[42]
Men with MetSa	6 wk of 1500 mg extended-release niacin	Low- and medium-molecular weight adiponectin increased by 35% and 33%, respectively, but HMW adiponectin by 88% (all P < 0.05)	[103]
Humans	6 wk of 1500 mg extended-release niacin	Adiponectin increased by 94% from 4.83 ± 2.39 to 9.35 ± 6.06 μg/mL (P < 0.01). No change leptin or resistin	[40]
Humans	4 wk of 1000 mg extended-release niacin	Adiponectin increased by 54% from 4.83 ± 2.39 to 7.45 ± 5.71 μg/mL (P < 0.01). No change in leptin. Resistin decreased by 8.3% from 3.97 ± 2.25 to 3.64 ng/mL (P < 0.05)	[40]
Humans with T2DMb	3 d of 125 mg acipimox every 2 h	Leptin increased by 2.38 ± 0.57 ng/mL (P < 0.005)	[43]

^aMetabolic syndrome;

^bType 2 diabetes mellitus. TNF-α: Tumor necrosis-factor-α; HMW: High-molecular weight; T2DM: Type 2 diabetes; Ref: Reference.