The impact of a short course of three lipid lowering drugs on fat oxidation during exercise in healthy volunteers

Abstract

UK Summary:We examined the impact ofthree lipid lowering drugs on fat oxidation during a 120 minute treadmill walk, at an exercise intensity of 50% maximal oxygen uptake (Vo2 max). Subjects (N = 24) were healthy male volunteers with normal serum chemistry, assigned to three groups (n = 8). Group A received simvastatin 20 mg twice daily, Group B received gemfibrozil 600 mg twice daily, Group C received acipimox 600 mg twice daily. Each subject performed two 120 minute walks, once with drug, and once with placebo (4 days treatment plus a final dose on the morning ofthe exercise trial). Treatment order was reversed for half of each group.Compared to placebo, simvastatin treatment, had no impact on fat oxidation (40.9 ± 8.6% vs 40.9 ± 9.7%), or on plasma concentration of free fatty acids (FFA), glycerol or glucose. Treatment with gemfibrozil, showed lower fat oxidation (32.3 ± 13.9% vs 39.7 ± 7.9%), and lower plasma concentrations of FFA and glycerol, but differences did not reach significance at the 0.05 level. Acipimox treatment, produced significantly lower fat oxidation (36.9 ± 12.8% vs 50.2 ± 16.1%, P = 0.011), and lower plasma concentrations of FFA and glycerol (P = <0.0001 and P = <0.0001, respectively). Plasma glucose showed a trend toward lower values with acipimox (P = 0.088). These data demonstrate that selective lipid lowering drugs can reduce fat availability for exercise metabolism, placing increased demands on carbohydrates which may reduce exercise tolerance.

Statin therapy depresses total body fat oxidation in the absence of genetic limitations to fat oxidation

“…The decrease in total body fat oxidation associated with lipid-lowering drugs observed in the statin-tolerant group in the present study and previous studies (Head et al 1993;Phillips et al 2002Phillips et al , 2004 may be due to the impairment in the availability of substrate, substrate transport or mitochondrial dysfunction. Patients with mutations in the CPT2 gene demonstrate reduced fat oxidation due to transport limitations (Vladutiu et al 2002), as do patients with rhabdomyolysis (Lofberg et al 1998); however, CPT2 gene deficiencies were not observed in the patients in the present study, suggesting substrate availability or mitochondrial factors as the mechanism of low fat oxidation in the tolerant group.…”

“…Their fat oxidation was normal during this study while they were symptom free. A previous study (Head et al 1993) demonstrated that simvastatin had no impact on fat oxidation or plasma concentration of free fatty acids and glycerol or glucose in tolerant subjects, while gemfibrozil decreased fat oxidation and lowered plasma concentrations of FFA and glycerol (32%). Acipimox reduced fat oxidation and lowered plasma concentrations of FFA and glycerol, thus reducing fat availability for exercise metabolism (Head et al 1993).…”

“…Muscle pathology and abnormal excretion of urinary organic acids in patients intolerant of lipid-lowering drugs suggest altered fat metabolism (Phillips et al 2002). The increased RER and low fat oxidation in patients, along with the supporting biochemical data, have prompted investigators to suggest that abnormal lipid oxidation may predispose some patients to myotoxicity caused by lipid-lowering therapies (Head et al 1993;Phillips et al 2002Phillips et al , 2004. If there is a statin-associated fat oxidation impairment that is evident at rest, it would be more limiting during exercise and lead to increased carbohydrate use, which could limit sustained submaximal exercise tolerance and cause the observed symptoms.…”

A Randomized Clinical Trial to Assess the Effect of Statins on Skeletal Muscle Function and Performance: Rationale and Study Design

“…14 Interestingly, in the latter study, the resting respiratory exchange ratio (RER; an index of fat and carbohydrate metabolism) increased with statin therapy in both asymptomatic and symptomatic statin users, consistent with other reports suggesting that statins decrease or impair fat oxidation. [15][16][17] An altered RER attributable to statins could alter exercise metabolism and diminish aerobic exercise performance.…”

Statins Do Not Impair Whole-body Fat Oxidation During Moderate-intensity Exercise in Dyslipidemic Adults

“…Hormone-sensitive lipase (HSL), an intracellular enzyme in adipose tissue, and lipoprotein lipase (LPL), an enzyme which hydrolyzes the triglyceride core of circulating chylomicrons, both liberate free fatty acids (FFA) for use by exercising muscle. Any drugs acting at these sites, could potentially alter FFA availability, which may result in increasing dependence on muscle glycogen stores and possible earlier fatigue [5]. An early study examining muscle biopsies of quadriceps femoris has documented glycogen depletion in healthy males while cycling in the presence of the lipid-lowering drug acipimox, also known as nicotinic acid [6].…”