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Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial.
Ann Intern Med 2016; 165(5):305-15AIM

Abstract

BACKGROUND

The metabolic defects of nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes mellitus (T2DM) seem to be specifically targeted by pioglitazone. However, information about its long-term use in this population is limited.

OBJECTIVE

To determine the efficacy and safety of long-term pioglitazone treatment in patients with NASH and prediabetes or T2DM.

DESIGN

Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT00994682).

SETTING

University hospital.

PARTICIPANTS

Patients (n = 101) with prediabetes or T2DM and biopsy-proven NASH were recruited from the general population and outpatient clinics.

INTERVENTION

All patients were prescribed a hypocaloric diet (500-kcal/d deficit from weight-maintaining caloric intake) and then randomly assigned to pioglitazone, 45 mg/d, or placebo for 18 months, followed by an 18-month open-label phase with pioglitazone treatment.

MEASUREMENTS

The primary outcome was a reduction of at least 2 points in the nonalcoholic fatty liver disease activity score in 2 histologic categories without worsening of fibrosis. Secondary outcomes included other histologic outcomes, hepatic triglyceride content measured by magnetic resonance and proton spectroscopy, and metabolic parameters.

RESULTS

Among patients randomly assigned to pioglitazone, 58% achieved the primary outcome (treatment difference, 41 percentage points [95% CI, 23 to 59 percentage points]) and 51% had resolution of NASH (treatment difference, 32 percentage points [CI, 13 to 51 percentage points]) (P < 0.001 for each). Pioglitazone treatment also was associated with improvement in individual histologic scores, including the fibrosis score (treatment difference, -0.5 [CI, -0.9 to 0.0]; P = 0.039); reduced hepatic triglyceride content from 19% to 7% (treatment difference, -7 percentage points [CI, -10 to -4 percentage points]; P < 0.001); and improved adipose tissue, hepatic, and muscle insulin sensitivity (P < 0.001 vs. placebo for all). All 18-month metabolic and histologic improvements persisted over 36 months of therapy. The overall rate of adverse events did not differ between groups, although weight gain was greater with pioglitazone (2.5 kg vs. placebo).

LIMITATION

Single-center study.

CONCLUSION

Long-term pioglitazone treatment is safe and effective in patients with prediabetes or T2DM and NASH.

PRIMARY FUNDING SOURCE

Burroughs Wellcome Fund and American Diabetes Association.

Authors

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

27322798

Citation

Cusi, Kenneth, et al. "Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: a Randomized Trial." Annals of Internal Medicine, vol. 165, no. 5, 2016, pp. 305-15.
Cusi K, Orsak B, Bril F, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med. 2016;165(5):305-15.
Cusi, K., Orsak, B., Bril, F., Lomonaco, R., Hecht, J., Ortiz-Lopez, C., ... Portillo-Sanchez, P. (2016). Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Annals of Internal Medicine, 165(5), pp. 305-15. doi:10.7326/M15-1774.
Cusi K, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: a Randomized Trial. Ann Intern Med. 2016 Sep 6;165(5):305-15. PubMed PMID: 27322798.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. AU - Cusi,Kenneth, AU - Orsak,Beverly, AU - Bril,Fernando, AU - Lomonaco,Romina, AU - Hecht,Joan, AU - Ortiz-Lopez,Carolina, AU - Tio,Fermin, AU - Hardies,Jean, AU - Darland,Celia, AU - Musi,Nicolas, AU - Webb,Amy, AU - Portillo-Sanchez,Paola, Y1 - 2016/06/21/ PY - 2016/6/21/entrez PY - 2016/6/21/pubmed PY - 2017/5/5/medline SP - 305 EP - 15 JF - Annals of internal medicine JO - Ann. Intern. Med. VL - 165 IS - 5 N2 - BACKGROUND: The metabolic defects of nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes mellitus (T2DM) seem to be specifically targeted by pioglitazone. However, information about its long-term use in this population is limited. OBJECTIVE: To determine the efficacy and safety of long-term pioglitazone treatment in patients with NASH and prediabetes or T2DM. DESIGN: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT00994682). SETTING: University hospital. PARTICIPANTS: Patients (n = 101) with prediabetes or T2DM and biopsy-proven NASH were recruited from the general population and outpatient clinics. INTERVENTION: All patients were prescribed a hypocaloric diet (500-kcal/d deficit from weight-maintaining caloric intake) and then randomly assigned to pioglitazone, 45 mg/d, or placebo for 18 months, followed by an 18-month open-label phase with pioglitazone treatment. MEASUREMENTS: The primary outcome was a reduction of at least 2 points in the nonalcoholic fatty liver disease activity score in 2 histologic categories without worsening of fibrosis. Secondary outcomes included other histologic outcomes, hepatic triglyceride content measured by magnetic resonance and proton spectroscopy, and metabolic parameters. RESULTS: Among patients randomly assigned to pioglitazone, 58% achieved the primary outcome (treatment difference, 41 percentage points [95% CI, 23 to 59 percentage points]) and 51% had resolution of NASH (treatment difference, 32 percentage points [CI, 13 to 51 percentage points]) (P < 0.001 for each). Pioglitazone treatment also was associated with improvement in individual histologic scores, including the fibrosis score (treatment difference, -0.5 [CI, -0.9 to 0.0]; P = 0.039); reduced hepatic triglyceride content from 19% to 7% (treatment difference, -7 percentage points [CI, -10 to -4 percentage points]; P < 0.001); and improved adipose tissue, hepatic, and muscle insulin sensitivity (P < 0.001 vs. placebo for all). All 18-month metabolic and histologic improvements persisted over 36 months of therapy. The overall rate of adverse events did not differ between groups, although weight gain was greater with pioglitazone (2.5 kg vs. placebo). LIMITATION: Single-center study. CONCLUSION: Long-term pioglitazone treatment is safe and effective in patients with prediabetes or T2DM and NASH. PRIMARY FUNDING SOURCE: Burroughs Wellcome Fund and American Diabetes Association. SN - 1539-3704 UR - https://www.unboundmedicine.com/medline/citation/27322798/Long_Term_Pioglitazone_Treatment_for_Patients_With_Nonalcoholic_Steatohepatitis_and_Prediabetes_or_Type_2_Diabetes_Mellitus:_A_Randomized_Trial_ L2 - https://www.annals.org/aim/fullarticle/doi/10.7326/M15-1774 DB - PRIME DP - Unbound Medicine ER -