The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence

Table 5

Effect of mTOR inhibitors on components of metabolic syndrome.

	NODM (% recipients)	Hypertension; (% recipients)	Lipid levels; (% recipients)	Weight gain; (% recipients)
Sirolimus
Maintenance dosing
Kazimi et al. Transplantation. 2010; 90 (2S): 697 (Abstract 1950) [66]	32 versus 10 (SRL versus CNI, 𝑃=0.005)
De novo dosing
Chinnakotla et al. Liver Transpl. 2009; 15: 1834–42 [55]	12.26 versus 0 (TAC versus SRL, 𝑃<0.001)
Levy et al. Liver Transpl. 2006; 12: 1640–8 [52]			Hypercholesterolemia: 3.3, 7.1, 10.0, 9.7
Dunkelberg et al. Liver Transpl. 2003; 9: 463–8 [61]	26 versus 30 (SRL versus SRL-free, 𝑃=NS)			Obesity (BMI > 28): 20 versus 31 (SRL versus SRL-free, 𝑃<0.05)
Early conversion (≤3 months after conversion)
Rogers et al. Clin Transplant. 2009; 23: 887–96 [48]			Hypertriglyceridemia (>200 mg/dL): 22 versus 15 (SRL versus CNI, 𝑃=NS); Hypertriglyceridemia (>500 mg/dL): 13 versus 0 (𝑃=0.003)
Schleicher et al. Transplant Proc. 2010; 42: 2572–5 [49]			Hyperlipidemia: 42
Late conversion (>3 months after conversion)
Herlenius et al. Transplant Proc. 2010; 42: 4441–8 [73]			Hypertriglyceridemia: 58.3 versus 16.7 (SRL versus MMF, 𝑃=0.002)
Lam et al. Dig Dis Sci. 2004; 49: 1029–35 [74]			Increase in serum cholesterol: 30.5 (𝑃=0.003)
Shenoy et al. Transpl. 2007; 83: 1389–92 [76]			Hyperlipidemia requiring treatment: 15 (SRL and CNI)
Uhlmann et al. Exp Clin Transplant. 2012; 10: 30–8 [77]		In 12 hypertensive patients who converted to SRL: systolic BP decreased from 151.5±20.2 mmHg to 132.1±19.4 mmHg, and diastolic BP decreased from 89.7±11.2 mmHg to 82.1±9.1 mmHg
Morard et al. Liver Transpl. 2007; 13: 658–64 [75]	Incidence of diabetes did not change after conversion (32 versus 30, before versus after conversion)	Incidence of hypertension did not change after conversion (70 versus 74, before versus after conversion)	Hypercholesterolemia: 49 (𝑃=NS)
Watson et al. Liver Transpl. 2007; 13: 1694–702 [78]		Hypertension treatment increased: 15.4 versus 21.4 (SRL versus CNI, 𝑃=NS); Hypertension treatment reduced: 23.1 versus 0 (SRL versus CNI, 𝑃=NS)	Statin treatment required: 35.7 versus 0 (SRL versus CNI)	Weight gain: 7.7 versus 0 (SRL versus CNI, 𝑃=NS)
Vivarelli. Transplant Proc. 2010; 42: 2579–84 [80]			Hyperlipidemia: 51.1
Abdelmalek et al. Am J Transplant. 2012; 12: 694–705 [45]			Hyperlipidemia: 41 versus 10 (SRL versus CNI, 𝑃<0.001); Hypercholesterolemia: 28 versus 4 (SRL versus CNI, 𝑃<0.001)
Di Benedetto et al. Transplant. Proc. 2009; 41: 1297–9 [81]			Hypertriglyceridemia: 35.4; Hypercholesterolemia: 25.8
McKenna et al. Hepatology. 2009; 50; 590A: Abstract 602 [101]				Median weight 2 years: 75.3 versus 84.1 (SRL versus non-SRL, 𝑃=0.05); 5 years: 79.5 versus 88.6 (SRL versus non-SRL, 𝑃=0.04)
Everolimus
Early conversion (≤3 months after conversion)
De Simone et al. Am J Transplant. 2012; 12: 3008–20 [87]	Incidence of NODM in non-diabetics at randomization in EVR + TAC-RD: 32.0% (𝑛=48/150) versus TAC-SD: 28.6% (𝑛=40/140)(𝑃=0.609)	17.1 versus 15.8 (EVR + TAC-RD versus TAC-SD, RR 1.09, 95% CI 0.73, 1.62)	Total cholesterol: mean (SD) values at month 12 (EVR + TAC-RD versus TAC-SD): 209 (43) mg/dL versus 175 (44) mg/dL (𝑃<0.001); Triglycerides: 197 (136) mg/dL versus 141 (78) mg/dL (𝑃<0.001)
Fischer et al. Am J Transplant. 2012; 12: 1855–65 [50]	Diabetes mellitus: 4.0 versus 7.8 (EVR versus CNI, 𝑃=NS)	Hypertension: 19.8 versus 13.7 (EVR versus CNI, 𝑃=NS)	Hypercholesterolemia: 22.8 versus 10.8*; Hyperlipidemia: 11.9 versus 2.0* (EVR versus CNI)
Masetti et al. Am J Transplant. 2010; 10: 2252–62 [89]				Significantly higher cholesterol levels in EVR versus CsA: 9.6 versus 7.7 required statin treatment (EVR versus CsA)
Late conversion (>3 months after conversion)
Bilbao et al. Presented at ILTS; 2011 (Abstract P-68) [56]	7/18 recipients who had diabetes mellitus at conversion to EVR showed improvement
Casanovas et al. Transplant Proc. 2011; 43: 2216–9 [93]			Dyslipidemia: 27.3
Castroagudín et al. Liver Transpl. 2009; 15: 1792–7 [94]			Before and after conversion: triglyceride: 144.6±88.9 versus 188.8±121.3 mg/dL (𝑃=0.121); cholesterol: 192.8±34.8 versus 241.8±95.5 mg/dL (𝑃=0.024)
De Simone et al. Transpl Int. 2009; 22: 279–86 [95]			Hyperlipemia: 42.5
De Simone et al. Liver Transpl. 2009; 15: 1262–9 [96]			Hypercholesterolemia: 13.9 versus 2.7 (𝑃=0.017)
Vallin et al. Clin Transplant. 2011; 25: 660–9 [99]	Incidence of diabetes did not significantly vary after EVR introduction (before versus after: 30 versus 31)	Incidence of arterial hypertension did not significantly vary after EVR introduction (before versus after: 59 versus 53)	Hyperlipidemia: 37
Saliba et al. Liver Transpl. 2011; 17: 905–13 [98]			Hypertriglyceridemia: 14.6; Hypercholesterolemia: 13.3

BMI: body mass index; CNI: calcineurin inhibitor; EVR: everolimus; ILTS: 2011 Joint International Congress of the International Liver Transplantation Society; NODM: new-onset diabetes mellitus; NS: nonsignificant; SD: standard deviation; SRL: sirolimus; TAC: tacrolimus; TAC-RD: reduced-dose tacrolimus (C0: 3–5 ng/mL); TAC-SD: standard-dose tacrolimus (C0: 6–10 ng/mL).
𝑃 values are included where available.
∗Treatment group differences with an exploratory 𝑃 value ≤ 0.05.