Effects of Acipimox on Insulin Action, Vascular Function, and Muscle Function in Type 1 Diabetes

Phase 3

Completed

• Conditions: Type 1 Diabetes
• Interventions: Drug: Placebo; Drug: Acipimox

• Registration Number: NCT01816165
• Lead Sponsor: University of Colorado, Denver

Brief Summary

Insulin resistance (IR) is an important contributor to increased cardiovascular disease risk in type 1 diabetes (T1D). Non-esterified fatty acid elevation is a significant contributor to IR in T1D and may be a target of intervention. The hypothesis of the study is that isolated fatty acid lowering with acipimox will improve insulin action and blood vessel function and have the benefit of reducing mitochondrial oxidant generation and improving mitochondrial function in T1D. Targeting IR through fatty acid lowering is a novel approach to T1D treatment that may significantly improve current management of TID and of cardiovascular disease (CVD) risk in this high risk population.

Detailed Description

Not available

Study Timeline

• Study Start: 2011-06
• Study First Submitted: 2012-06-13
• Study First Submitted QC: 2013-03-18
• Study First Posted: 2013-03-22
• Primary Completion: 2015-06-24
• Study Completion: 2015-06-24
• Results First Submitted: 2021-11-09
• Status Verified: 2021-12
• Results First Submitted QC: 2021-12-21
• Last Update Submitted: 2021-12-21
• Results First Posted: 2022-01-21
• Last Update Posted: 2022-01-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

Inclusion Criteria

1. Men and women, with and without type 1 diabetes between 25-59 years of age,

2. HbA1c 6.0-9.5 (T1D only),

3. Subjects who are willing to commit to:

   • 14 days of prescribed diet,
   • two 44 hour inpatient stays, and
   • two muscle biopsies.

Exclusion Criteria

1. Any comorbid condition associated with inflammation, insulin resistance, or dyslipidemia,
2. Tobacco use,
3. Pregnancy,
4. Steroid use,
5. Scheduled physical activity >3 days a week,
6. Angina or any other cardiovascular or pulmonary disease,
7. History of chronic obstructive pulmonary disease or asthma,
8. Systolic blood pressure >190 at rest or >250 with exercise, or
9. Diastolic pressure >95 at rest, or >105 with exercise,
10. Proteinuria (urine protein >200 mg/dl), or
11. Creatinine > 2 mg/dl, suggestive of severe renal disease,
12. Severe Proliferative retinopathy,
13. Niacin treatment,
14. History of peptic ulcers,
15. History of hereditary angioedema, and
16. C1 esterase deficiency.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Drug: Placebo
Acipimox	Acipimox	Drug: acipimox

Primary Outcome Measures

Name	Time	Method
Insulin Sensitivity: M-value From Hyperinsulinemic Euglycemia Clamp Study	day 8 of each of the 2 random order intervention phases; max 16 weeks post enrollment	Evaluate the impact of Non esterified fatty acid (NEFA)-lowering on insulin sensitivity in T1D versus non-DM. Glucose infusion rate is reported normalized to lean body weight in kg and to final insulin concentration.; The unit of measure reflects the rate at which glucose needs to be infused to maintain a normal blood sugar in the setting of a given serum insulin level from an insulin infusion. As such, a higher number means more glucose was needed and indicates greater sensitivity to insulin.
24 Hour Mean Fatty Acid Levels	day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	Assesses whether fatty acid level is consistently lowered by acipimox. Mean of fatty acid levels measured 22 times over 24 hours (hourly except 0100 and 0300 hours).
Percent Flow-mediated Brachial Artery Dilation	day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	To determine the effects of NEFA lowering and insulin sensitization on endothelial function. Measures percent change in brachial artery diameter with hyperemia after occlusion.
State 3 Mitochondrial Oxygen Consumption	muscle biopsy on day 7 of each weeklong intervention period; max 16 weeks post enrollment	Measures skeletal muscle mitochondrial function and effects of acipimox thereon, carbohydrate \& lipid substrates. State 3 is fully active coupled oxygen flux using PMG or PMGS (pyruvate, malate, glutamate, +/- succinate) or OCMS (octanyl carnitine, malate, +/- succinate) as substrates. FCCP is added as an uncoupler to measure maximum possible O2 flux. Higher values reflect better mitochondrial function.

Secondary Outcome Measures

Name	Time	Method
Oxidative Stress and Inflammatory Markers: Plasminogen Activator Inhibitor (PAI-1)	day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	Plasminogen activator inhibitor (PAI-1)
Heart Rate Variability	day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	Measure of autonomic function; ratio of fastest to slowest heart rate during valsalva maneuver.
Arterial Stiffness (PWV)	day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec. Higher values reflect a stiffer vasculature.
Metabolic Markers: Continuous Glucose Monitoring Measures	day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	Continuous glucose monitoring measures for 3 days before clamp. Collected for participants with T1 Diabetes only.
Arterial Stiffness (AI)	day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	Augmentation index by Sphygmacor is a measure of aortic arterial stiffness. AI@75 is the ratio of augmented pressure/pulse pressure adjusted to a heart rate of 75.; Higher values indicate stiffer vessels
Oxidative Stress and Inflammatory Markers: Adiponectin	day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	adiponectin
Oxidative Stress and Inflammatory Markers: TNFalpha	day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	TNFalpha
Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels	day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	mean glucose and triglycerides for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300).
Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6)	day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	Interleukin 6 (IL6)
Metabolic Markers: Insulin	day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	mean insulin for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300).
Metabolic Markers: Glycerol	day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	mean glycerol for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300).
Oxidative Stress and Inflammatory Markers: High-sensitivity C-reactive Protein (hsCRP)	day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	high-sensitivity C-reactive protein (hsCRP)
Vascular Markers	day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment	endothelin 1 measured as a marker of vascular damage

Trial Locations

Locations (1)

University of Colorado Denver; 🇺🇸 Aurora, Colorado, United States