Effects of Pitavastatin on Insulin Sensitivity and Liver Fat

• ClinicalTrials.gov Identifier: NCT02290106
• Recruitment Status: Completed
• First Posted: November 13, 2014
• Results First Posted: July 2, 2019
• Last Update Posted: July 2, 2019
• Sponsor: Massachusetts General Hospital
• Information provided by (Responsible Party): Takara Stanley, Massachusetts General Hospital

Study Description

Brief Summary:

HMG co-A reductase inhibitors, commonly called statins, are an effective treatment for dyslipidemia and atherosclerotic heart disease with proven mortality benefit. While the lipid-lowering effects of statins are well-known, other metabolic effects, including effects on glucose tolerance and ectopic fat distribution, are less completely understood. Recent studies have shown that some statins may increase the risk of diabetes. Further, research has suggested that statins may have some benefit in nonalcoholic fatty liver disease (NAFLD), a condition associated with obesity that includes increased fat in the liver (steatosis) and, in some cases, inflammation and hepatocellular damage (steatohepatitis). Pitavastatin, approved by the United States Food and Drug Administration (FDA) in 2009, is the most recent statin to enter the market. Unlike most statins, pitavastatin is not primarily metabolized through cytochrome P450 (CYP450), and thus has reduced potential for interactions with other medications that are metabolized by CYP450. Previous studies have suggested that pitavastatin may be neutral to glucose homeostasis and may improve hepatic lipid. Neither of these effects has been proven definitively, however, and the current proposal aims to characterize in detail the effects of pitavastatin on glucose homeostasis, hepatic steatosis, and steatohepatitis.

Condition or disease	Intervention/treatment	Phase
Obesity; Fatty Liver, Nonalcoholic	Drug: pitavastatin; Other: PLACEBO	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effects of Pitavastatin on Insulin Sensitivity and Liver Fat
• Actual Study Start Date: March 2, 2015
• Actual Primary Completion Date: April 30, 2018
• Actual Study Completion Date: April 30, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pitavastatin; pitavastatin 4mg daily by mouth for 6 months	Drug: pitavastatin; Other Name: Livalo
Placebo Comparator: Placebo; Identical placebo 4mg by mouth daily for 6 months	Other: PLACEBO

Outcome Measures

Primary Outcome Measures :

1. Insulin-stimulated Glucose Uptake [ Time Frame: 6 months ]
   insulin-stimulated glucose uptake measured by euglycemic hyperinsulinemic clamp
2. Liver Fat [ Time Frame: 6 months ]
   liver fat content as measured by 1H-magnetic resonance spectroscopy

Secondary Outcome Measures :

1. Alanine Aminotransferase (ALT) [ Time Frame: 6 months ]
   alanine aminotransferase at the 6 month timepoint
2. Aspartate Aminotransferase (AST) [ Time Frame: 6 months ]
   aspartate aminotransferase at 6 month timepoint
3. Hepatic Insulin Sensitivity [ Time Frame: 6 months ]
   hepatic insulin sensitivity assessed by glucose infusion rate corrected for fluctuations in serum glucose ("M") during low-dose insulin clamp
4. Hemoglobin A1c (HbA1c) [ Time Frame: 6 months ]
5. Quantitative Insulin Sensitivity Check Index (QUICKI) [ Time Frame: 6 months ]
   quantitative insulin sensitivity check index (QUICKI) at 6 months. Measure = 1/((log(glucose in mg/dL) + log(insulin in uU/mL))

Eligibility Criteria

• Ages Eligible for Study: 40 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Men age 40-65yo
2. BMI ≥ 27kg/m2 and waist circumference ≥102cm, high probability risk factors for NAFLD
3. At least one of the following indicating insulin resistance: Fasting glucose ≥100mg/dL and <126mg/dL, HOMA-IR >2.0, and/or 2 hour glucose ≥140mg/dL and <200mg/dL following standard glucose tolerance test.
4. 10-year cardiovascular disease risk ≥5% by American Heart Association(AHA)/American College of Cardiology (ACC) Pooled Cohort Equations CV Risk Calculator or LDL ≥ 100mg/dL
5. No use of any statin within 1 year of study entry and not being actively considered for statin therapy by a treating provider.

Exclusion Criteria:

1. Diagnosis of diabetes or use of anti-diabetic medications.
2. Use of erythromycin, rifampin, cyclosporin, colchicine, or gemfibrozil.
3. Use of statin therapy within 1 year prior to study entry as above. Use of any other lipid-modifying therapy (including fish oil, fibrates, niacin, gemfibrozil) within 6 months of study entry.
4. Contraindication to statin therapy.
5. Creatinine > upper limit of normal or known renal disease
6. AST or ALT > 3 times the upper limit of normal
7. hemoglobin < 10g/dL
8. Contraindication to undergoing a magnetic resonance scan.
9. Atherosclerotic cardiovascular disease or low-density lipoprotein cholesterol (LDL-C) ≥ 190mg/dL.
10. Triglyceride ≥500mg/dL

Contacts and Locations

Locations

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Sponsors and Collaborators

Massachusetts General Hospital

Investigators

• Principal Investigator: Steven K Grinspoon, MD; Massachusetts General Hospital
• Principal Investigator: Takara L Stanley, MD; Massachusetts General Hospital

  Study Documents (Full-Text)

Documents provided by Takara Stanley, Massachusetts General Hospital:

Study Protocol and Statistical Analysis Plan  [PDF] August 17, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Braun LR, Feldpausch MN, Czerwonka N, Weiss J, Branch K, Lee H, Martinez-Salazar EL, Torriani M, Sponseller CA, Grinspoon SK, Stanley TL. Effects of Pitavastatin on Insulin Sensitivity and Liver Fat: A Randomized Clinical Trial. J Clin Endocrinol Metab. 2018 Nov 1;103(11):4176-4186. doi: 10.1210/jc.2018-01446.

• Responsible Party: Takara Stanley, Assistant Professor of Pediatrics, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT02290106
• Other Study ID Numbers: 2014p-002117
• First Posted: November 13, 2014
• Results First Posted: July 2, 2019
• Last Update Posted: July 2, 2019
• Last Verified: June 2019

Keywords provided by Takara Stanley, Massachusetts General Hospital:

obesity; insulin sensitivity; statin (HMG-CoA Reductase Inhibitor); fatty liver

Additional relevant MeSH terms:

Fatty Liver; Non-alcoholic Fatty Liver Disease; Insulin Resistance; Hypersensitivity; Immune System Diseases; Liver Diseases; Digestive System Diseases; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Pitavastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Lipid Regulating Agents