December 22, 2015
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Long-term free fatty acid reduction with acipimox improves fasting glucose levels

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Nondiabetic adults with insulin resistance and obesity saw improved fasting glucose levels and decreased free fatty acids after 6 months of treatment with the lipase inhibitor acipimox, according to research in The Journal of Clinical Endocrinology & Metabolism.

Hideo Makimura, MD, of the program in nutritional metabolism and neuroendocrine unit of Massachusetts General Hospital, and colleagues analyzed data from 39 healthy adults with obesity (BMI > 30 kg/m²) and a fasting plasma glucose between 100 mg/dL and 125 mg/dL randomly assigned acipimox 250 mg three times per day (n = 20; 65% men; 60% black; mean age, 47 years; mean BMI, 39.9 kg/m²) or matching placebo for 6 months (n = 18; 68.4% men; 52.6% white; mean age, 45 years; mean BMI, 38.9 kg/m²). Researchers measured insulin sensitivity, homeostatic model assessment of insulin resistance (HOMA-IR), lipid profile, adiponectin and mitochondrial function via the rate of phosphocreatine recovery after exercise on 31P-magnetic resonance spectroscopy, as well as muscle mitochondrial density and relevant muscle gene expression. FPG was measured at baseline and at 1-month intervals.

Fasting free fatty acid levels decreased in the acipimox group vs. placebo at 6 months (–0.29 mmol/L vs. 0.01 mmol/L; P = .02). Researchers found that fasting glucose decreased in adults assigned acipimox vs. placebo (effect size, –6 mg/dL; P = .02), and trends were seen for reduced fasting insulin (effect size, –6.8 µU/mL; P = .07) and HOMA-IR (effect size, –1.96; P = .06) and increased adiponectin (effect size, 668 ng/mL; P = .02).

The researchers did not observe effects on mitochondrial function, mitochondrial density or muscle insulin sensitivity, whereas previous short-term acipimox studies revealed improvements.

In addition, researchers did not observe changes in glucose uptake under hyperinsulinemic-euglycemic clamp conditions, also contradicting several short-term studies showing improved muscle insulin sensitivity.

“One potential explanation is that, although acipimox decreased fasting [free fatty acid] levels in our study, [free fatty acid] levels during the clamp did not differ between groups after suppression by insulin,” the researchers wrote. “Another potential explanation is that [intramyocellular lipid], rather than circulating lipid, may be the relevant determinant of muscle insulin sensitivity.” – by Regina Schaffer

Disclosure: Makimura became an employee of Merck after the study was completed and all data were collected. Please see the full study for the other authors’ relevant financial disclosures.