Effects of Pitavastatin on Insulin Sensitivity and Liver Fat

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT02290106
• Collaborator: (none)
• Enrollment: 50
• Location: 1
• Arms: 2
• Actual Duration (Months): 37.9
• Patients Per Site Per Month: 1.3

Study Details

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	N/A

Study Design

• Study Type: Interventional
• 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: Mar 2, 2015
• Actual Primary Completion Date: Apr 30, 2018
• Actual Study Completion Date: Apr 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pitavastatin pitavastatin 4mg daily by mouth for 6 months	Drug: pitavastatin; Other Names: 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 [6 months]

   insulin-stimulated glucose uptake measured by euglycemic hyperinsulinemic clamp

2. Liver Fat [6 months]

   liver fat content as measured by 1H-magnetic resonance spectroscopy

Secondary Outcome Measures

1. Alanine Aminotransferase (ALT) [6 months]

   alanine aminotransferase at the 6 month timepoint

2. Aspartate Aminotransferase (AST) [6 months]

   aspartate aminotransferase at 6 month timepoint

3. Hepatic Insulin Sensitivity [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) [6 months]

5. Quantitative Insulin Sensitivity Check Index (QUICKI) [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

Criteria

• Ages Eligible for Study: 40 Years to 65 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	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)

• Study Protocol and Statistical Analysis Plan - Aug 17, 2017

More Information

Publications

None provided.

• Responsible Party: Takara Stanley, Assistant Professor of Pediatrics, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT02290106
• Other Study ID Numbers: 2014p-002117
• First Posted: Nov 13, 2014
• Last Update Posted: Jul 2, 2019
• Last Verified: Jun 1, 2019

• Keywords provided by Takara Stanley, Assistant Professor of Pediatrics, 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; Pitavastatin

Study Results

Participant Flow

Arm/Group Title	Pitavastatin	Placebo
Arm/Group Description	pitavastatin 4mg daily by mouth for 6 months pitavastatin	Identical placebo 4mg by mouth daily for 6 months PLACEBO
Period Title: Overall Study
STARTED	25	25
COMPLETED	24	23
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Pitavastatin	Placebo	Total
Arm/Group Description	pitavastatin 4mg daily by mouth for 6 months pitavastatin	Identical placebo 4mg by mouth daily for 6 months PLACEBO	Total of all reporting groups
Overall Participants	25	25	50
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.8 (6.5)	52.9 (7)	52.8 (6.7)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	25 100%	25 100%	50 100%
Race/Ethnicity, Customized (Count of Participants)
White	24 96%	21 84%	45 90%
Non-white	1 4%	3 12%	4 8%
Not Reported	0 0%	1 4%	1 2%
Region of Enrollment (participants) [Number]
United States	25 100%	25 100%	50 100%
Low density lipoprotein cholesterol (LDL-C, mg/dL) (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	116 (18)	125 (22)	120 (20)
Fasting glucose (mg/dL) (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	98 (9)	97 (9)	97 (9)
Homeostasis model of insulin resistance (HOMA-IR) (HOMA-IR Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [HOMA-IR Score]	2.1 (1.9)	1.6 (1.0)	1.8 (1.5)
Liver fat content (hepatic fat fraction, %) (%) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%]	17 (11)	14 (11)	16 (11)

Outcome Measures

1. Primary Outcome

Title	Insulin-stimulated Glucose Uptake
Description	insulin-stimulated glucose uptake measured by euglycemic hyperinsulinemic clamp
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All patients with results for baseline and final. In addition to 3 participants who did not finish the study, 2 participants were unable to undergo clamp.

Arm/Group Title	Pitavastatin	Placebo
Arm/Group Description	pitavastatin 4mg daily by mouth for 6 months pitavastatin	Identical placebo 4mg by mouth daily for 6 months PLACEBO
Measure Participants	22	23
Mean (Standard Deviation) [mg/kg/minute]	5.9 (2.1)	5.9 (1.6)

2. Primary Outcome

Title	Liver Fat
Description	liver fat content as measured by 1H-magnetic resonance spectroscopy
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All participants with baseline and final data were analyzed. In addition to patients who discontinued from the study, some patients were unable to have MRI scan due to inability to fit in the scanner or unanticipated claustrophobia.

Arm/Group Title	Pitavastatin	Placebo
Arm/Group Description	pitavastatin 4mg daily by mouth for 6 months pitavastatin	Identical placebo 4mg by mouth daily for 6 months PLACEBO
Measure Participants	21	18
Mean (Standard Deviation) [% liver fat (hepatic fat fraction)]	17 (11)	14 (10)

3. Secondary Outcome

Title	Alanine Aminotransferase (ALT)
Description	alanine aminotransferase at the 6 month timepoint
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

all patients with available data at baseline and final

Arm/Group Title	Pitavastatin	Placebo
Arm/Group Description	pitavastatin 4mg daily by mouth for 6 months pitavastatin	Identical placebo 4mg by mouth daily for 6 months PLACEBO
Measure Participants	24	23
Mean (Standard Deviation) [U/L]	37 (38)	27 (17)

4. Secondary Outcome

Title	Aspartate Aminotransferase (AST)
Description	aspartate aminotransferase at 6 month timepoint
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

all patients with available data at baseline and final

Arm/Group Title	Pitavastatin	Placebo
Arm/Group Description	pitavastatin 4mg daily by mouth for 6 months pitavastatin	Identical placebo 4mg by mouth daily for 6 months PLACEBO
Measure Participants	24	23
Mean (Standard Deviation) [U/L]	31 (23)	26 (12)

5. Secondary Outcome

Title	Hepatic Insulin Sensitivity
Description	hepatic insulin sensitivity assessed by glucose infusion rate corrected for fluctuations in serum glucose ("M") during low-dose insulin clamp
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

all patients with available data at baseline and final (note, in addition to 3 patients who discontinued, some patients were unable to undergo clamp procedure)

Arm/Group Title	Pitavastatin	Placebo
Arm/Group Description	pitavastatin 4mg daily by mouth for 6 months pitavastatin	Identical placebo 4mg by mouth daily for 6 months PLACEBO
Measure Participants	20	22
Mean (Standard Deviation) [mg/kg/minute]	1.5 (1.0)	1.6 (0.7)

6. Secondary Outcome

Title	Hemoglobin A1c (HbA1c)
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pitavastatin	Placebo
Arm/Group Description	pitavastatin 4mg daily by mouth for 6 months pitavastatin	Identical placebo 4mg by mouth daily for 6 months PLACEBO
Measure Participants	24	23
Mean (Standard Deviation) [% (hemoglobin A1c)]	5.7 (0.5)	5.7 (0.3)

7. Secondary Outcome

Title	Quantitative Insulin Sensitivity Check Index (QUICKI)
Description	quantitative insulin sensitivity check index (QUICKI) at 6 months. Measure = 1/((log(glucose in mg/dL) + log(insulin in uU/mL))
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pitavastatin	Placebo
Arm/Group Description	pitavastatin 4mg daily by mouth for 6 months pitavastatin	Identical placebo 4mg by mouth daily for 6 months PLACEBO
Measure Participants	21	23
Mean (Standard Deviation) [QUICKI index]	0.16 (0.02)	0.15 (0.02)

Adverse Events

Time Frame	6 months (during study period)
Adverse Event Reporting Description	Patients were asked at every study visit to recall any adverse events. (Patients were not contacted following study completion.)
Arm/Group Title	Pitavastatin		Placebo
Arm/Group Description	pitavastatin 4mg daily by mouth for 6 months pitavastatin		Identical placebo 4mg by mouth daily for 6 months PLACEBO
All Cause Mortality
	Pitavastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)
Serious Adverse Events
	Pitavastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/25 (8%)		1/25 (4%)
Gastrointestinal disorders
Pancreatic Cancer	1/25 (4%)	1	0/25 (0%)	0
Acute appendicitis	0/25 (0%)	0	1/25 (4%)	1
General disorders
Chest Pain	1/25 (4%)	1	0/25 (0%)	0
Other (Not Including Serious) Adverse Events
	Pitavastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/25 (64%)		25/25 (100%)
Gastrointestinal disorders
Diarrhea or Loose Stools	3/25 (12%)		7/25 (28%)
Any Gastrointestinal Symptoms	5/25 (20%)		8/25 (32%)
General disorders
Fatigue	2/25 (8%)		5/25 (20%)
Musculoskeletal and connective tissue disorders
Any Musculoskeletal Symptoms	4/25 (16%)		6/25 (24%)
Muscle Cramps	4/25 (16%)		4/25 (16%)
Nervous system disorders
Headache	0/25 (0%)		2/25 (8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.