Article CommentaryCommentary

Impediments to clinical application of exercise interventions in the treatment of cardiometabolic disease

N. John Bosomworth
Canadian Family Physician March 2019, 65 (3) 164-170;

Before enlightenment, chop wood, carry water. After enlightenment, chop wood, carry water.

Zen proverb

Statins have become a pharmacologic cornerstone for the prevention and treatment of cardiovascular disease (CVD). However, it is clear from the large statin trials that maximal lowering of low-density lipoprotein cholesterol (LDL-C) levels still allows 2 out of 3 cardiovascular events to occur.1 These events represent the so-called residual risk that remains after optimized statin therapy. Attempts to further lower LDL-C levels in patients with established CVD using high-dose statins,2 adding ezetimibe,3 or adding proprotein convertase subtilisin-kexin type 9 inhibitors4,5 have each resulted in a further modest absolute event reduction of 1% to 2% over 2 to 6 years. None of these augmentation trials has shown a reduction in all-cause mortality.

The prevalence of obesity has continued to increase in Canada6 and the United States.7 There is concern that since 1990 the mortality benefits from control of smoking, hypertension, and lipid levels have been offset by the harmful cardiometabolic effects of obesity.7 These effects are associated with hyperinsulinemia, diabetes, and metabolic syndrome. Many people with obesity exhibit the profile of “atherogenic dyslipidemia,” which is characterized by high triglyceride levels, low or dysfunctional high-density lipoprotein (HDL) levels, and a predominance of small dense LDL particles.8 The serum can contain large quantities of intensely atherogenic particles such as very low density lipoprotein, intermediate-density lipoprotein, chylomicron remnants, and remnant lipoproteins.9 Attempts to reduce cardiovascular events by lowering triglyceride levels and raising HDL levels using niacin10 or fenofibrate11 in addition to statins have been ineffective in large randomized trials. Similarly, the addition of cholesterol ester transfer protein inhibitors to statins in high-risk patients has statistically significantly raised HDL levels, but has not resulted in event reduction.12,13

As we seem to have reached maximum therapeutic potential in terms of statin use, and as add-on drug therapy currently affords only modest additional benefit, it seems prudent to refocus our emphasis on lifestyle options that can provide event reduction in conjunction with statin therapy. There has been great success with smoking cessation.14 Dietary and physical activity (PA) interventions can be similarly effective (physical activity is defined in Box 115,16). Suboptimal implementation of effective PA interventions might reflect poor physician uptake as much as patient nonadherence, and the reasons for this will be explored further in this article.

Box 1.

Glossary of terms

  • Cardiovascular fitness: Attributes that enhance ability to perform PA. Measured by maximal oxygen uptake. Might be partially genetic in origin, but can be trainable with exercise15

  • Exercise: A subset of PA that has a conditioning or maintenance objective, and that is planned, structured, and repetitive16

  • MET: 1 MET is defined as 1 kcal/kg per hour and is roughly the energy equivalent expended by an individual at rest

  • PA: Body movement produced by skeletal muscle requiring energy expenditure. Might include occupational, recreational, and conditioning activities, as well as activities of daily living

METs—metabolic equivalents, PA—physical activity.

Evidence for statins and PA

While statin benefits are well established, it might be less appreciated that PA is equally effective in preventing CVD mortality in secondary prevention17 and could actually be superior in CVD and all-cause mortality reduction in primary prevention (Table 1)3,17–57; however, the level of evidence for PA interventions is less robust. Table 13,17–57 summarizes meta-analyses and salient randomized controlled trials (RCTs) evaluating benefits of statins and PA. There is, for example, good evidence that diabetes is increased in statin users,32,33 while PA is a very effective preventive measure.34,35 Similarly, obesity is higher in statin users,36 while PA is an aid in prevention of weight gain.37 Lower incidence of all cancers except melanoma is directly associated with PA,44,45 as is a reduction in falls,48,49 while statins have no such effect.47 Quality of life, a key objective of health interventions, is uniformly improved with PA.55–57 This outcome exists independent of sex and many chronic disease states, including cancer.58 No useful data are available for the influence of statins on quality of life.

View this table:
Table 1.

Meta-analyses and RCTs evaluating effects of statins and PA on health outcomes

Suboptimal implementation

There are several possible reasons for suboptimal implementation of exercise interventions.

Reliance on inappropriate surrogate markers of success

Lipoprotein changes: Triglyceride levels fall reliably with exercise and levels are reduced for up to 15 days following a period of activity.35 High-density lipoprotein cholesterol level is increased, but this occurs primarily in those who exercise the most.59 Total cholesterol and LDL-C levels are generally unchanged with PA in available meta-analyses of RCTs.60–63 Included trials tend to have a duration of 1 to 6 months on average. It has been shown that short-term variability in cholesterol levels might vary by about −0.80 mmol/L to 0.80 mmol/L, and that it might take up to 4 years for long-term variation to exceed short-term variability.64 True benefits of PA are therefore unlikely to be reflected in the standard lipid profile over the short term. Benefits might instead be mediated by a reduction in LDL particle number as reflected by apolipoprotein B values65 or by direct measurement,66 making diffusion of atherogenic particles across the vascular endothelium less likely. Reliance on changes in LDL-C and total cholesterol levels will not reinforce the use of PA as a beneficial intervention.

Weight change: While the recommendation of engaging in moderate exercise for 30 minutes for 5 days a week plus 2 days of resistance training is effective in preserving cardiometabolic health,67 it is insufficient to prevent ongoing weight gain over time. Prevention of transition to overweight or obese status in our current food environment requires exercising for 45 to 60 minutes a day,68 and weight loss would require even more time if exercise alone were the intervention. Improved cardiometabolic health through exercise can be achieved without weight loss.69,70 It seems more reasonable to regularly monitor any changes in activity behaviour patterns as a measure of PA adherence, rather than to have a weight-loss expectation.

Reliance on short-term RCTs for information on long-term outcomes

There are no long-term RCTs that establish the causal effect of PA on CVD incidence.60 Ethical and feasibility issues make group assignment and adherence impossible to initiate and maintain. In fact, different studies are necessary to differentiate the efficacy and effectiveness of an intervention.71 Randomized controlled trials address efficacy and establish what we might expect. Effectiveness under real-world conditions requires an observational study, preferably a pragmatic controlled trial, with follow-up of study cohorts over time.72 It is difficult to enforce randomization in a preference-dominated world for sufficiently long periods of time.71 The most informative PA studies are prospective cohorts that are followed long enough to detect potential adverse effects and that stratify participants to be compared according to baseline risk, controlling as best as possible for confounding. Strength of association is also enhanced if a number of the Bradford Hill criteria73,74 for establishment of causality are met (Table 2).15,19,23,31,73–79 Randomized controlled trials cannot properly evaluate benefits and adverse effects over time while addressing patient preference and ensuring adherence under real-world conditions.

View this table:
Table 2.

Bradford Hill criteria for assessing the causal nature of an observed association

Concern over nonadherence

No studies were found on documenting adherence to an exercise prescription over time. A 2-year prospective study found that 18% to 24% of adults maintained recommended PA levels over the entire period.80 These subjects were self-motivated and received no prescription. On the other hand, 2-year adherence to statin medication was 40% following acute coronary syndrome, but only 25% for primary prevention.81 It seems likely that if activity interventions were reinforced as often and as enthusiastically as drug interventions, uptake and adherence might be similar to statin therapy. Small changes in activity produce large gains. Going from a sedentary state to a low level of any activity is associated with the highest incremental cardiometabolic benefit.82 Interventions far short of current recommendations can still have a considerable effect on cardiovascular outcomes.83

Failure to address diet

Excessive caloric and simple carbohydrate intake will completely overwhelm the weight-moderating effects of PA.84 Physical activity can aid weight control, and beneficial cardiometabolic effects will occur without weight loss, but there must be control of excess caloric and simple carbohydrate intake in our obesogenic environment if the usual default weight gain is to be avoided over time.85,86 The Mediterranean eating pattern is the best alternative for avoidance of weight gain,87 with no weight increase shown over 5 years despite unrestricted caloric intake in a large RCT.88

Insufficient knowledge to provide an appropriate prescription

Physicians’ lack of knowledge or confidence in generating an exercise prescription (Box 2) is a reflection of the fact that our teaching lacks the conviction that PA can be an effective health intervention. We therefore rely upon drugs, which are inferior to PA in many ways, including in mortality reduction and improvement in quality of life. The exercise prescription should be tailored for the individual patient considering baseline status, available time, and desired outcome. Brief interventions regularly reinforced have been shown by some to be effective.89,90 A sample prescription form can be found at www.exerciseismedicine.org/canada/assets/page_documents/EIMC_Pad_ENnewlogo_v3.0_1_copy.pdf. Table 356,67,68,83,89,91–100 presents illustrative exercise intervention scenarios for different patient needs.

Box 2.

Strategies that might help reinforce an increase in PA

When trying to increase a patient’s PA levels ...

  • Be an enthusiastic and committed prescriber with confidence in the evidence

  • Pay attention to objective measures of behaviour change rather than to unhelpful surrogates as measures of success

  • Consider suggesting dietary modification and simple carbohydrate reduction to avoid hyperinsulinemia and avoid default weight gain

  • Have confidence in generating an appropriate exercise prescription for every sedentary patient

  • Be willing to reinforce an exercise prescription with a program referral or a brief intervention at every visit

  • Recognize that we must not rely only upon pharmacotherapy to improve QOL and longevity

PA—physical activity, QOL—quality of life.

View this table:
Table 3.

Illustrative exercise interventions for varying patient needs

Cardiorespiratory fitness, a measurable outcome of increased PA, is one of the strongest prognostic indicators for long-term survival, surpassed only by patient age.75 The combination of increased fitness and statin therapy is additive when examined in long-term retrospective75 and prospective23 cohorts. Most older adults can achieve an exercise capacity of 5 to 7 metabolic equivalents (METs), which confers the same protection as a statin given to unfit subjects with an exercise capacity of less than 5 METs (Box 1)15,16; however, adding a statin at this level of fitness produces a further 35% relative risk reduction.23 Generally, an improvement in exercise capacity of 1 MET confers a mortality risk reduction of 12% to 15% according to meta-analysis.101

Statins added to PA might expose the patient to increased myopathy risk, especially at the extremes of drug and activity dosing, and in the elderly.102 The exercise prescription should precede the statin prescription, and an optimized PA program should be in place before adding drug therapy.103,104

Conclusion

Atherosclerosis is a lifestyle problem and deserves a lifestyle solution, especially in primary prevention.105 Strategies outlined in Box 2 might help reinforce an increase in PA.

Footnotes

  • Competing interests

    None declared

  • The opinions expressed in commentaries are those of the authors. Publication does not imply endorsement by the College of Family Physicians of Canada.

  • This article has been peer reviewed.

  • La traduction en français de cet article se trouve à www.cfp.ca dans la table des matières du numéro de mars 2019 à la page e79.

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Impediments to clinical application of exercise interventions in the treatment of cardiometabolic disease
N. John Bosomworth
Canadian Family Physician Mar 2019, 65 (3) 164-170;
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