Specialty Corner: Physical Activity and Lipid Disorders: Circa 2014

Blood Lipid Response to Physical Activity and Exercise Training
A prevailing myth among patients and many healthcare providers is the notion that physical exercise “burns” or oxidizes cholesterol or cholesterol-rich particles similar to the utilization of fatty acids and glucose. This doesn’t happen. Cholesterol is a sterol, a lipid molecule biosynthesized by all animal cells because, among other purposes, it is an essential structural component of animal cell membranes that is required to maintain both membrane structural integrity and fluidity. In other words, it is not an oxidizable substrate fuel supporting exercise energy. Thus, unlike adipose tissue or even carbohydrate utilization during prolonged exercise, there is at best a minimal relationship between total exercise energy expenditure and diminished total cholesterol or low-density lipoprotein cholesterol (LDL-C). Still, regardless of how you rationalize physical activity, we don’t “burn” off cholesterol. With that said, and for numerous metabolic and genetic reasons, an individual’s lipid and lipoprotein profile is nearly always improved with sufficient weekly physical activity. When all of the many exercise training-lipoprotein trials are taken into consideration, the overall recommendation for the quantity and quality of physical activity necessary for lipid and lipoprotein improvement is provided by the 2014 guidelines on exercise and dyslipidemia by the American College of Sports Medicine:¹ Aerobic exercise, five or more days a week, 30 to 60 minutes per day, at 40 to 75 percent of aerobic capacity.

Although this guideline is somewhat nonspecific, it is helpful to know that this amount of physical activity is consistent with recommendations for long-term weight control, i.e. 200 to 300 minutes/ week of moderate physical activity or ≥ 2,000 kcal/week of activity. This physical activity volume may be accumulated with repeated exercise bouts of ≥ 10 minutes.

LDL-C Response
Although exercise programs have the best chance of reducing LDL-C when there is associated body-weight reduction, they also can favorably alter lipoproteins in the absence of body-weight changes when appropriate exercise training volumes are used. Most studies evaluating the total cholesterol and/or LDL-C response to exercise training have found very little to only moderate decreases in LDL-C. Many studies used inadequate exercise volumes and/or energy expenditure or failed to control for confounding variables such as training-induced changes in plasma volume, dietary habits, or seasonal variation in cholesterol and lipoproteins. On average, sufficient volume exercise training by itself will reduce LDL-C by 4 to 7 percent but the response can be quite variable.^2,3 The percent reduction depends on baseline lipid values, the total energy expenditure of the exercise program plus a host of other variables (Figure).^3,4

Very few controlled exercise trials have been conducted on patients with dyslipidemia, with most evaluating those with normal or modestly elevated triglycerides and/or LDL-C. An often quoted meta-analysis of 13 studies by George Kelley and co-workers found a non-significant decrease of less than 1 percent in LDL-C, independent of changes in body weight.⁵ The problem with this finding, as is often the case in interpreting meta-analysis findings, is that there was a wide range in training modalities (e.g. running, swimming, stationary cycling, dance), often at energy expenditures not reliably reported and an average training stimulus of ~40 minutes per session, 3.9 times a week, at mostly moderate- intensity exercise levels. This weekly volume of exercise, approximately 1,600-1,800 kcal/week, is insufficient by current recommendations (≥ 2,000 kcal/week) to demonstrate meaningful reductions in LDL-C and, of course, at that volume of physical activity most adults are likely to lose some body weight, and experience a reduction in adiposity.

The use of nuclear magnetic resonance imaging technology (NMR) to assess the low-density lipoprotein particle concentration (LDL-P) response to exercise training has demonstrated efficacy.^6-8 Moderate volumes and intensities (e.g., walking ~12 miles per week at 40 to 55 percent of aerobic capacity) significantly reduced LDL-P when total cholesterol and Friedewald-predicted LDL-C remained essentially unchanged.⁸ Such patients on a return clinic visit would be considered unresponsive to exercise therapy when a conventional lipid profile was used to score the patient’s progress. Thus, advanced lipoprotein measures, such as the determination of LDL-P by NMR technology, may improve the ability to track exercise-associated responses.

HDL-C Response
The high-density lipoprotein cholesterol (HDL-C) response to exercise training is under considerable genetic influence, with underlying genetic polymorphisms (e.g., lipoprotein and hepatic lipase, apolipoprotein (apo) CII, III) explaining up to 50 percent of the variation in HDL- C.^9,10 For this reason, healthcare providers should be cautious in predicting the HDL-C response in clients, because there is a considerable variation in the magnitude of changes in HDL-C. There also are individuals with genetic variants of very low HDL-C (hypoalphalipoproteinemia: HDL levels <30 mg/dL) and, in general, they will respond minimally to even high volumes of exercise training. On average, exercise training by itself can increase HDL-C by 3 to 25 percent, depending on baseline lipid values, triglyceride response, and total exercise volume (i.e., added weekly energy expenditure) but, as a rule, the HDL-C response to training is quite moderate.³ The increase in HDL is likely linked to triglyceride reduction (via the action of cholesterol ester transfer protein).¹¹ Most exercise trials support between 700 and nearly 2,000 kcal of exercise per week to significantly alter HDL-C.¹² Kodama performed a large meta- analysis of 25 randomized controlled trials of exercise alone, without diet or drug therapy, and found that aerobic exercise at an intensity of ~5.3 MET’s (65 percent of max aerobic capacity) significantly increased HDL-C by 6 percent. Among exercise variables, exercise duration was found to be the most important determinant of increase in HDL-C on multivariate analysis.¹³ There have been mixed findings among studies investigating the relationship between exercise intensity and increases in HDL-C, with some studies reporting the necessity for more vigorous exercise intensities.¹⁴

Resistance training also may generate increases in HDL-C. There are reports that from six to nine weeks of resistance training (eight to 10 exercises) three times a week can significantly increase HDL-C — from 4 to 9 percent — in men and women.^15,16 At least one study demonstrated greater HDL-C increases with higher-intensity resistance training (80 to 90 percent at one-repetition maximum) compared to moderate-intensity training.¹⁶  However, not all studies demonstrate significant increases.¹⁷

Non-HDL Response
As important as non-HDL-C is to managing atherosclerotic risk, there is very little research that has exclusively evaluated the response to exercise training. However, at least one meta-analysis retrospectively looked at non-HDL responsivity and found a decrease of approximately 6 mg/dL in response to aerobic exercise training programs between 10 and 104 weeks.¹⁸ This meta-analysis included male as well as pre- and postmenopausal females. The majority of subjects included in the studies were white, however, blacks, Hispanics, Japanese, and Asians were also represented. The greatest non-HDL response apparently is observed when dietary and exercise interventions are combined.

Triglyceride Response
Compared to other lipids, such as LDL- C, elevated baseline triglycerides (TG) (e.g. >150 mg/dL) are generally more responsive to exercise training of sufficient volume. Triglyceride mobilization and utilization appear to be in direct proportion to exercise energy expenditure. Unlike LDL-C, triglycerides generally decrease immediately after a session of high-volume endurance exercise (e.g., greater than 45 minutes of sustained effort), and remain lower for up to 48 hours after the session. Several facts stand out after reviewing scores of exercise-triglyceride metabolism trials:¹⁹

• Exercise-induced TG-lowering is acute, in that it manifests after just a single bout of exercise and is not the result of repeated exercise sessions (i.e., training), and it is short-lived, in that it is readily reversed when exercise is withdrawn.
• Numerous studies have confirmed the initial hypothesis that the magnitude of the decrease in plasma TG concentration after a single exercise session and after training is the same (i.e., 15 to 50 percent).
• These observations suggest that chronic exercise does not have an equally sustainable effect on plasma triacylglycerol (TAG) concentration, i.e., beyond that attributed to acute exercise; hence, exercise should be performed on a regular and uninterrupted basis to maintain lower TG.

Overall, exercise training programs also have been shown to decrease fasting triglycerides by 4 to 37 percent (approximate mean change of 24 percent).²⁰  Overall, exercise is most effective in lowering triglycerides when baseline levels are elevated (i.e., >150 mg/ dL), activity is moderate to intensive, and total caloric intake is reduced.²¹  The same exercise-generated response holds true for exercise training and very low density lipoprotein (VLDL) because VLDL’s carry most of the triglyceride in plasma — the VLDL triglyceride and plasma triglyceride levels are almost the same.¹⁹

Inactivity and Lipids
Being sedentary, particularly daily sitting time, has been associated with elevated triglycerides and decreased HDL-C, as well as other cardiometabolic risk factors.²² A modest amount of exercise training can prevent the deteriorating lipid profile that is seen with inactivity.²³ This is particularly true for LDL and HDL size, LDL-P, and total HDL cholesterol. In fact, it appears that only seven to 10 miles of walking a week will prevent inactivity-associated deterioration in these lipid parameters.²³

Exercise and Postprandial Lipemia
Postprandial lipemia is essentially the blood lipid, particularly triglyceride (and associated triglyceride-rich particles), response to a meal, particularly a fatty meal. Depending on how much fat or sugar is consumed in a meal, a person with normal fasting triglycerides will increase their triglycerides by 100 to 200+ mg/dL for two to six hours after a high fat meal.²⁴ Those with visceral obesity, the metabolic syndrome or type 2 diabetes can have much larger increases in post-meal triglycerides. The problem of prolonged, elevated postprandial triglyceride states is that, for the amount of time triglycerides are elevated much above 250-300 mg/dL, there is diminished arterial function, lower HDL-C and exposure of the arterial wall to atherogenic lipoprotein particles (e.g., intermediate-density lipoprotein (IDL) and VLDL remnant particles). Over the past 15 years, there has been abundant research supporting the finding that sufficient exercise timed anywhere from several hours to 12 hours before a fat-rich meal will reduce postprandial lipemia by 20 to 40 percent.²⁵ This also was observed in men with baseline hypertriglyceridemia, who experienced a 30 to 39 percent reduction in postprandial triglycerides with prior moderate and vigorous exercise, respectively.²⁶ The relative suppression of triglycerides can last up to 36 hours after a significant bout of exercise, e.g., >400 kcal. Some investigators report that women may be more responsive than men to reducing postprandial TG with exercise.²⁷ This somewhat blunted triglyceride response to high-fat or high- glycemic meals is one of the benefits of engaging in aerobic physical activity every day. There also are reports that higher-intensity exercise may be more effective than moderate intensity exercise at reducing postprandial TG, even when both are matched for the same total energy expenditure.²⁸ Having patients exercise at least every other day is an excellent way to keep triglycerides and associated triglyceride-rich atherogenic particles reasonably suppressed.

Resistance Training and Lipid Disorders
Resistance training (RT) has shown some promise as a means to improve the blood lipid profile, but the effect is modest at best. It is not recommended as the primary form of exercise therapy for people with dyslipidemia but RT certainly can play a supportive role. The lipid and lipoprotein response to RT largely depends on the energy expenditure of the resistance training session, which essentially means that each session (e.g., 30+ minutes) includes an abundance of contraction repetitions versus, for example, just three sets of 10 to 12 repetitions of four or five exercises. A recent review of 13 published RT and lipid response trials reinforced the requirement of higher repetition RT doses for a sufficient stimulus lipid and lipoprotein response.²⁹ The review concluded that it consistently has been shown that the increased volume of movement via increased numbers of sets and/or repetitions has a greater impact on the lipid and lipoprotein parameters than increased RT intensity (e.g. high-weight, low-repetition training) a view also supported by other recent studies.³⁰

Final Word
Although there is wide individual variation in the lipid and lipoprotein response to a given amount of exercise training, nearly all studies have demonstrated some improvement in the lipid profile. The greatest exercise-induced changes in lipoproteins occur when there are significant reductions in adiposity. Lastly, it is important to note that there are numerous variables that control the lipid response to exercise training, not the least of which are baseline lipid values, net energy cost (in kcal) of the exercise program, gender, and a host of genetic influences (e.g., Apo CII and III genotypes, to name but a few). The precise mechanisms responsible for these changes remain to be elucidated but very likely include those denoted in Figure 1.

Disclosure Statement: Mr. LaForge received speaker honorarium from AstraZeneca.

References are listed on page 35 of the PDF.