Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis

doi:10.1016/j.jhep.2007.04.013

Journal of Hepatology

Volume 47, Issue 4, October 2007, Pages 565-570

https://doi.org/10.1016/j.jhep.2007.04.013 Get rights and content

Background/Aims

Non-Alcoholic Steatohepatitis (NASH) is a chronic liver disease frequently associated with insulin resistance and type 2 diabetes mellitus (T2DM). Pioglitazone reverses the metabolic and histological abnormalities of patients with impaired glucose tolerance or T2DM and NASH, but also leads to weight gain. To understand the nature of weight gain associated with pioglitazone treatment in NASH we analyzed 35 patients who completed tests for determination of whole body fat (WBF) and total body water (TBW).

Methods

Twenty-one patients received pioglitazone and 14 placebo in a double-blind, randomized fashion for a period of 6 months. WBF and TBW were measured before and after treatment using DXA, a water dilution technique and bioimpedance.

Results

Pioglitazone increased body weight (from 93.6 ± 4.2 to 96.1 ± 4.5 kg, p < 0.003) and WBF measured with DXA (from 32.9 ± 2.1 to 35.4 ± 2.5 kg, p < 0.002) while no changes were seen with placebo. Total body water was not altered significantly either after pioglitazone (from 45.4 ± 2.3 to 45.6 ± 2.7 l, p = NS) or placebo. Muscle hydration and extracellular water were unchanged both by pioglitazone and placebo treatments.

Conclusions

Six months of pioglitazone treatment in patients with NASH is associated with weight gain that is attributable to an increase in adipose tissue mass and not to water retention.

Introduction

Non-alcoholic steatohepatitis (NASH) is a chronic liver condition in which hepatic fat accumulation is associated with lobular necroinflammation, with or without fibrosis. Insulin resistance syndrome is almost always associated with NASH [1]. It is believed that the incidence of NASH is on the rise, considering the growing incidence of states associated with insulin resistance: fatty liver disease, obesity and type 2 diabetes [2]. Studies have shown that NASH can progress to cirrhosis, although the real rate of progression is still undetermined [3].

Pilot studies using insulin-sensitizers such as metformin [4] and thiazolidinediones [5], [6] suggested benefit in patients with NASH. Recently, our group reported that pioglitazone improves the metabolic and histologic abnormalities of patients with NASH in the first randomized, placebo-controlled study using an insulin-sensitizer in this population [7].

However, a limitation of thiazolidinedione use may be excessive weight gain and the development of lower extremity edema observed in some patients [8]. Weight gain is a well-recognized effect of thiazolidinediones [9], [10], it seems to be class related and it is still uncertain whether it is due to an increase in body fat, body water or both. The mechanisms remain poorly understood. Weight gain most frequently develops within the first few months of treatment [11], [12], [13], [14] and appears to plateau thereafter although there can be additional weight gain over time [15]. Occasionally, the use of thiazolidindiones is associated with lower extremity edema [15], [16], [17], [18], although rarely with the development of congestive heart failure [19], [20]. Interestingly, previous studies have reported total body water (TBW) either unchanged [21], [22], [23] or increased [24].

Given the clinical benefit reported with TZDs, it is likely that their use in patients with NASH (and perhaps in other obesity-related conditions) may become more common. Because of this we felt it to be important to explore the impact pioglitazone has on whole body fat (WBF) and total body water (TBW) during treatment of patients with NASH.

Section snippets

Subjects

Participants were recruited from the University of Texas H.S.C. at San Antonio, the Audie L. Murphy VAMC, and Brooke Army Medical Center (BAMC), San Antonio, TX. All patients had biopsy-proven NASH. Thirty-five subjects with impaired glucose tolerance (n = 15) or newly diagnosed type 2 diabetes (n = 20) were enrolled. The study population has been previously described [7]. We are here reporting the results on the subgroup of subjects who agreed to complete all tests for body fat and body water

Baseline patient characteristics

At baseline, NASH patients had similar weight, BMI, body fat and total body water; all these parameters were increased when compared to the control group (Table 1). Our cohort of patients with NASH was composed of subjects with either IGT or T2DM, and many patients with T2DM were newly diagnosed, hence the HbA_1c was only modestly increased. Although the fasting plasma glucose was slightly higher in the placebo group, the difference between the two intervention groups was not significantly

Discussion

NASH is a potentially severe liver condition that may progress to fibrosis and cirrhosis. Amongst the many drugs tested for treatment of NASH [31] TZDs have been the most promising with pioglitazone significantly reducing steatosis and necro-inflammation (and with a trend towards less fibrosis) in this cohort of NASH patients [7].

Weight gain and/or edema (which in rare occasions may lead to CHF) may be associated with TZD utilization in T2DM patients. Consequently, we thought it important to

Acknowledgements

We would like to thank all volunteers and the invaluable efforts of the GCRC nursing staff and associated personnel, and the skilled nursing assistance of James King, John Kincade, Norma Diaz, Rose Kaminski-Graham and Tricia Wolff, who performed the metabolic studies. We are grateful to Kathy Camp, Pengou Zuo, Sheila Taylor and Phyllis Eagan for their skilled laboratory work. Elva Gonzales and Lorrie Albarado contributed with outstanding secretarial support. This work was supported by a General

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Indices of NAFLD improved after pioglitazone, but not after sulphonylureas; differences between changes (1-year minus baseline) were respectively: -1.76 ± 3.84 vs. 0.28 ± 3.75 for LFE; -1.35 ± 2.78 vs. -0.27 ± 2.63 for HSI; -9.75 ± 43 vs. 3.24 ± 31 for ION; p < 0.05 for all. Indices of insulin resistance decreased after pioglitazone, but not after sulphonylureas: -0.95 ± 4.57 vs. 0.37 ± 3.34 for HOMA-IR, p = 0.032; -1.25 ± 4.11 vs. 1.36 ± 5.43 for ADIPO-IR, p = 0.001; -0.53 ± 1.88 vs. 0.03 ± 2.36 for VAI, p = 0.074. Changes in NAFLD indices were similar with different doses of pioglitazone (15, 30, or 45 mg/day), and were independent of blood glucose control.
One-year treatment with pioglitazone even at low dosage significantly improved liver steatosis and inflammation, systemic and adipose tissue insulin resistance in patients with T2D. The beneficial effects of pioglitazone on NAFLD were independent of blood glucose control.
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^☆: The authors who have taken part in this study have declared a relationship with the manufacturers of the drugs involved and they received partial funding from the manufacturers to carry out their research. They received partial funding from Takeda which enabled them to carry out their study.

^☆☆: Disclaimer statement (Dr. Harrison): The opinion of assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the view of the Department of the Army or the Department of Defense.

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Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis☆,☆☆

Background/Aims

Methods

Results

Conclusions

Introduction

Section snippets

Subjects

Baseline patient characteristics

Discussion

Acknowledgements

Hepatology

Lancet

Hepatology

Clin Ther

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Control Clin Trials

Nutrition

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