Effects of Exercise Paul D. Thompson,

and Lovastatin

on Serum Creatine Kinase Activity

Patricia A. Gadaleta, Susan Yurgalevitch, Eileen Cullinane, and Peter N. Herbert

Vigorous physical activity and lovastatin (Mevacor) a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, have both been independently associated with elevated creatine kinase (CK) levels. To determine the effect of lovastatin plus exercise on serum CK activity, we measured CK levels before and after maximal treadmill exercise in 14 men (51.6 r?r17.3 years. mean + SD) and 6 women (48.5 r 7.4 years) before and after 4 weeks of lovastatin treatment (20 mg/d). Blood samples were obtained before, immediately after, and 24 hours after exercise. Individual subjects were exercised for the same duration on each test. Preexercise CK levels and the average CK response to treadmill exercise did not differ before and after lovastatin treatment. In two men taking lovastatin, however, CK levels increased by 183% and 242% 24 hours after exercise during lovastatin administration. We conclude that low-dose lovastatin treatment plus exercise does not affect average CK activity but that this combination may markedly increase CK levels in certain individuals. Copyright gb1991 by W.B. Saunders Company

L

OVASTATIN (Mevacor; Merck Sharp & Dohme, Rahway, NJ) reduces low-density lipoprotein (LDL)cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in cholesterol synthesis.’ One side effect of this medication is a~ increase in serum activity of the muscle enzyme creatine kinase (CK).” In addition, rhabdomyolysis with renal failure has been reported in subjects using lovastatin in combination with cyclosporine,’ nicotinic acid,4 erythromycin.5 and gemfibrozil.” Vigorous exercise can also injure muscle, and CK elevations of 13% to 24% have been reported in sedentary subjects after as little exertion as an exercise stress test.‘.” This increase in CK activity after mild exercise has been limited to the CK-MM isoenzyme, but increases in the CK-MB have been documented after extreme exertion.“.“’ Despite the fact that both exercise and lovastatin can increase serum CK activity, the effect of exercise on CK activity during lovastatin therapy has not been examined. The present

study

tested

the hypothesis

that

lovastatin

plus

CK activity more than exercise alone. Clarification of this issue is relevant to the clinical interpretation of CK levels and to recommendations regarding extreme exertion during lovastatin therapy. exercise

increases

METHODS Subjects Written informed consent was obtained from 14 men (51.6 ? 17.3 years. mean + SD) and 6 women (48.5 -C 7.4 years). Subjects had LDL-cholesterol concentrations above 159 mg/dL, and plasma triglycerides below 251 mg/dL, while ostensibly consuming the American Heart Association Phase I diet, National Cholesterol Education Program Step One diet, or a similar diet for 16 weeks prior to lovastatin treatment.

Lovastatin at a dose of 20 mg/d was initiated after the first exercise test. Subjects performed a repeat maximal exercise test 4 weeks later. The second test was stopped at the same duration and work rate as the first test to ensure identical exercise sessions. Measurements Venous blood samples were obtained after a l4-hour fast before each exercise test, as well as immediately and 24 hours following exercise. Total CK activity was analyzed using the S.V.R. creatine kinase reagent test (Boehring Diagnostics, La Jolla, CA). based on the method of Oliver” and Rosalki.” CK isoenzyme activity was determined by electrophoresis on cellulose acetate using the CPK-US isoenzyme electrophoresis procedure (Helena Laboratories, Beaumont, TX), based on Trainer and Gruenig’s method.” Total cholesterol was determined by enzymatic techniques.” High-density lipoprotein (HDL)-cholesterol was measured in the supernate after heparin manganese chloride precipitation. Triglycerides were measured by direct enzymatic measurement of glycerides in serum after blanking for free glycerol.” LDL-cholesterol was calculated using the Friedewald formula.‘” Hemoglobin and hematocrit were measured on each blood sample to estimate changes in plasma volume. Statistical AnaJvsis CK values before. immediately after, and 24 hours after the treadmill test were analyzed using Friedman’s nonparametric ANOVA. Differences between the no-drug and lovastatin preexercise values as well as the change immediately and 24 hours after exercise were tested for significance using Wilcoxon’s signed rank test for pair-wise comparisons and Bonferroni’s correction.” An overall level of P < .05 was required for statistical significance or P < ,017 for the three comparisons. Lipid and lipoprotein values before and during drug treatment were also tested using Wilcoxon’s signed rank test. Student’s t test was used to compare maximal heart rates between treadmill tests.

Protocol Cholesterol-lowering medications were withdrawn 6 weeks before the initial treadmill test. Other medications and the patients’ activity levels remained constant throughout the study. Exercise testing was performed using a modified Naughton protocol. Speed was initially held constant at 2.0 mph, and grade was increased by 2.5% every 2 minutes. Depending on exercise tolerance, speed was either held constant at 2.0 mph or increased to 3.0 mph after the first 15 minutes, while grade continued to increase by 2.5%. The pretreatment test was terminated at volitional fatigue after maxirn:d effort. Merabolism, Vol40, No 12 (December), 1991: pp 1333-l 336

From the Department of Medicine, The Mirium Hospital and Brown University, Providence, and the &livers& sf Rhode Island. Kingxtown. RI. Supponed by grants from the Nat&al Heart, Lung, and Blood Institute (ROI HL 28467). The Miriam Foundation. Merit Industries, and the McNulty Family. Address reprint requests to Paul D. Thompson. MD, The Miriam Hospital, 164 Summit Ave, Providence, RI 02906. Copyright 0 1991 by W B. Saunders Compatl~~ 0026.0495l91!4012-0019$03.0010 1333

1334

THOMPSON

Table 1. Exercise Results Before and During Lovastatin Therapy

ET AL

500-

MEN Women

Mell

No Drug

Lovastatin

No Drug

Lovastatin

400.

Treadmill time (min) 19.7 2 2.57 19.7 2 2.70 17.0 2 4.33 17.0 t 4.33 MET level Peak HR (bpm)

10.8 + 1.39 10.8 ? 1.39 160 + 19.7

158 + 20.1

8.0 -t 1.82

8.0 2 1.82

165 2 18.0

166 + 21.8

NOTE. All values are mean of.SD. There are no significant differences between conditions using a paired t test. Abbreviations: HR, heart rate; MET, multiple of the resting metabolic rate.

RESULTS

Duration, workload, and peak heart rate were similar during the nodrug and lovastatin exercise tests (Table 1). Total serum CK activity and the isoenzymes before exercise were higher for the men and virtually identical for the women during lovastatin treatment (Table 2; Figs 1 and 2). There was also no significant difference in the increase in CK after exercise between the drug and no conditions. Adjustment for estimated changes in plasma volume did not alter these results. The average increase during drug treatment was primarily due to changes in two men who increased their total CK 183% and 242% and their CK-MM activity 177% and 248% (Fig 1). This observation suggests that exercise during lovastatin therapy can increase CK activity in some susceptible individuals. Average total cholesterol and LDL-cholesterol decreased 23% and 28%, respectively, in the men and 25% and 30% in the women during lovastatin treatment (Table 3). HDL-cholesterol increased 9% in the men and decreased 4% in the women, whereas triglycerides decreased 30% and 19% in both groups, respectively, during drug therapy.

Control pre exercise

) post 0 hr

Lovastatin post 24 hr

post pre exercise 0 hr

Fig 1. Individual CK values for men before, immediately after, and 24 hours after the exercise tests before and during lovastatin treatment.

not clinically or statistically significant. Lovastatin treatment led to an insignificantly greater increase in CK activity after exercise. Despite the absence of change in group CK values, two subjects taking lovastatin had marked increases in CK activity after exercise. Neither subject increased CK activity after exercise before lovastatin treatment (Fig l), but total CK increased 240% and 183% in these two men 24 hours after exercise during lovastatin therapy. Exercise duration for these men was near or below the average for the group as a whole. One of these men had known coronary heart disease and was taking atenolol (100 mg twice daily) and diltiazem (180 mg four times daily) throughout the study. The other subject took tetracycline (250 mg twice daily) for 1 week prior to the second exercise test. None of these drugs has been reported to exacerbate CK changes during lovastatin treatment. It is therefore unlikely that medication use or exercise duration distinguished these men from the other subjects. We have recently noted increases in CK after exercise among 37 subjects treated with fluvastatin, a new HMG-CoA reductase inhibitor, and lovastatin.‘* Four

DISCUSSION

The present study was designed to determine if lovastatin treatment increased the risk of serum CK elevations after exercise. Average preexercise CK values were slightly higher during lovastatin treatment, but these changes were

Table 2. Total CK and lsoenryme Levels Relative to Lovastatin Treatment Ml?ll

and Exercise Women Change

Change h Post

Prs

24

24

Prs CK No drug Lovastatin CK-MM No drug Lovastatin

Post

post 24 hr

146 2 69

6 ? 20

4 + 30

88 +- 22

162 r 68

IO r 12

33 + 115

87 + 22

143 r 66

5 * 20

4 * 29

87 + 21

161 + 68

10 + 12

32 f 114

86 + 22

Post

6*9

-2 t 16

-1 + 11 6&9 -12

h

Post

2 + 31 -12

11

15

2 + 31

CK-MB No drug Lovastatin

3-3 122

l&2 0+1

Ok4 12-4

I?2

o+o

I?1

O&l

-l&2 O&l

NOTE. All values are mean + SD. There are no significant differences using Wilcoxon’s signed rank test for pair-wise comparisons and Bonferroni’s correction.

EFFECT OF EXERCISE AND LOVASTATIN

ON CK

1335

Table 3. Serum Lipid Concentrations

500

WOMEN

(mg/dL)

Before and After 4

Weeks of Lovastatin Treatment ____TOT CHOL

COO

LDL-C

HDL-C

TRIG

Men

:oo

No Drug

310 * 32.6

225 + 39.9

44 f- 10.8

Lovastatin

239 -+ 38.2$

161 ? 34.7t

48 ? 9.5*

209 t 91.3 146 _+59.0*

No drug

348 i 77.2

253 i 88.7

52 + 6.5

214 i 83.4

Lovastatin

262 t 58.0*

178 i- 70.0*

50 t 5.5

173 2 92.8*

Women

“00

NOTE. All values are mean + SD. Abbreviations: ‘00

TOT CHOL, total cholesterol:

lipoprotein cholesterol;

LDL-C, low-density

HDL-C, high-density lipoprotein cholesterol;

TRIG, triglycerides. *P < .05; tP < .Ol;*P < ,001compared wtth before treatment. (

pie exercw

post 0 hr

p&t 24 hr

pre

exercise

post

post

0 hr

24 hr

Fig 2. individual CK values for women before, immediately after, and 24 hours after the exercise tests before and during lovastatin treatment. men experienced marked increases in CK to levels of 500 to 31,000 IU (500% to 40,000% above their baseline values.) In each instance, these marked CK increases followed unusually vigorous exertion, but no other exacerbating factor could be identified. Consequently, the present study and these case reports suggest that unknown factors may produce considerable individual variation in CK response to 8:xertion. ‘The mechanism for possible muscle injury from HMGCoA reductase inhibitors is not known. Another lipidlowering agent, clofibrate, also has well-documented myopai hit effects.“’ Clofibrate appears to reduce mitochondrial paimitoyl transferase activity while impairing both fatty acid and glucose oxidation.‘” HMG-CoA reductase inhibitors potentially reduce production of ubiquinone,21 which is required for mitochondrial electron transport and could thereby disrupt muscle energy production. Another HMGCoA reductase inhibitor, compactin or mevastatin, does not lower serum ubiquinone-10 levels in humans.” No other relevant data are available, and we are unaware that intramuscular concentrations of ubiquinone have been de‘ermined during therapy with HMG-CoA reductase inhibitors. Several studies have assessed CK activity after treadmill cxcrcise. Chahine and Kazantzis’ as well as Steele et al” tound significant increases of 13% to 15% in total CK activity immediately after treadmill exercise. These changes were largely due to a 14% increase in the CK-MM isoenzyme.” We observed no increase in average total CK or C&.-MM isoenzyme activity after treadmill exercise despite the fact that exercise workloads were similar and exercise duration was more prolonged in the present than in prt.vious studies.‘.” McAllister and Weidne? also reported

no increase in CK activity after an exercise duration (8 minutes and 24 seconds) similar to that performed in the present study. None of these earlier reports noted individual increases in CK of the magnitude seen in two of our subjects during lovastatin therapy. A limitation of the present study is that all nondrug exercise tests preceded lovastatin treatment. It is unlikely that an order effect alone increased CK levels in the two men experiencing the largest increases because prior exercise reduces the CK increase from subsequent exertion for up to 6 weeks.” On the other hand. higher doses of lovastatin might have produced larger increases in postexercise CK levels. Lovastatin, 40 mg, increased resting CK activity 15% in 89 hypercholesterolemic subjects.’ whereas 20 mg/d increased resting CK only 11% in the men and 2%’ in the women in the present study. The present results indicate that lovastatin, 20 mg daily, does not significantly alter the average increase in CK/d activity following treadmill exercise. The substantial CK increase in two subjects suggests that some individuals may be vulnerable to muscle injury from vigorous exercise during treatment with this drug. In neither subject, however, was the increase in CK clinically important or associated with symptoms, making it unlikely that the brief exercise of a maximal exercise test would provoke clinically important muscle injury. Also asymptomatic individuals on lovastatin who experience small increases in CK after exercise do not necessarily require alternate therapy. On the other hand, until more definitive studies arc performed, physically active individuals requiring treatment with HMGCoA reductase inhibitors should consider temporarily discontinuing these medications before any extreme physical exertion. ACKNOWLEDGMENT The authors would like to thank Stanley Sady. PhD. and David Morris, PhD, for their help in statistical analysis and CK measurement. and Kim Bradford and Teresa Silva for preparing the manuscript.

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ET AL

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