This randomized clinical trial examined the short-term benefits of 25% caloric restriction with and without exercise on established and emerging risk factors for CVD. We observed significant reductions in triacylglycerol (TG) in both the CR and CR+EX groups. Additionally, LDL-C, blood pressure and hsCRP were reduced in CR+EX group while factor VIIc level was reduced only with CR. Fibrinogen, homocysteine and endothelial function were not changed by either intervention, despite 10% reductions in body weight in both groups. Estimated 10-year CVD risk was significantly reduced by the interventions, with a tendency towards a greater reduction in the group assigned to caloric restriction and structured exercise.
Weight loss reduces LDL-C and TG whereas active weight loss reduces HDL-C even if HDL-C is increased once weight loss is stabilized. Based on prediction equations 19
and the degree of weight loss achieved in our study at six months, we would expect the CR group to experience a 5.8 mg/dL reduction in LDL-C, a 10.3 mg/dL reduction in TG, and a 2.1 mg/dL reduction in HDL-C if in active weight loss (or a 2.7 mg/dL increase at weight stability). For CR, the change in LDL-C (-4.1 mg/dL) was close to that predicted while HDL-C was increased (+1.2 mg/dL). The decrease in TG (-31 mg/dL) was however substantially greater than predicted. Weight loss and changes in HDL-C and TG were similar in the CR+EX group vs. the CR group. However, the reduction in LDL-C in the CR+EX group (-17 mg/dL vs. Control) was four-times greater than that observed in the CR group and much greater than predicted by weight loss alone. Such a large effect of exercise on LDL-C has not been typically observed 20, 21
and may in part reflect the carefully controlled exercise protocol.
Both atherosclerosis and CVD are recognized as inflammatory diseases 22
and consistently elevated levels of hemostatic factors (factor VIIc, fibrinogen), homocysteine and C-reactive protein (hsCRP) are associated with increased risk for CVD and cardiac events 23-25
. In our study, factor VIIc levels were significantly reduced in the CR group, but not the CR+EX group. This contrasts with an increase in factor VIIc levels in the Control group at M6 providing a significant treatment effect. Changes in factor VIIc levels are known to correlate with changes in TG 26
which may in part explain the observed changes in the Control and CR groups. Homocysteine levels were not affected by the interventions confirming other data 27
. hsCRP and fibrinogen are both acute phase reactants and markers of inflammation 25
. There was a trend for both interventions to lower hsCRP. However, the responses were inconsistent with a large degree of variability and the data suggest that the observed favourable change in inflammatory markers was a function of an improvement in diet quality, rather than an effect of CR or CR+EX.
Endothelial dysfunction, an early event in CVD, can be assessed by measures of flow-mediated endothelium-dependent vasodilation of the brachial artery (BA-FMD). Impaired BA-FMD predicts coronary endothelial dysfunction and is influenced by plasma lipoprotein levels 28
, Type 2 diabetes 29
, insulin resistance 30
and hypertension 31
. Thus, many of the risk factors targeted by caloric restriction could commonly impact endothelial function. However, despite generally favorable changes in many of the CVD risk factors and insulin sensitivity 15
, we did not observe an improvement in BA-FMD in either intervention group. Previous studies of the effects of caloric restriction and weight loss on BA-FMD are controversial with some studies showing improved endothelial function 32
while others have not 27, 33
and may be reflective of health of the studied population. It is conceivable that an effect of the interventios could be identified with a longer intervention period and a larger sample size.
While the changes in individual risk factors were generally modest, when combined in a single prediction equation for CVD risk 18
, the overall effect of caloric restriction was impressive. A 32% reduction in 10-year CVD risk was predicted based upon the combined changes in total cholesterol, HDL-C and systolic blood pressure. All participants in the CR and CR+EX groups experienced some degree of CVD risk reduction relative to baseline, while only 5 of 11 participants in the Control groups experienced such reductions. Furthermore, although not statistically significant, the addition of exercise appeared to be associated with a more favorable CVD risk profile than caloric restriction alone. By study design, we did not examine the effects of energy deficit by exercise alone, but a recent study published by Fontana et al. observed a similar reduction in CVD risk between by exercise alone as compared to CR alone 34
. Several caveats must be considered when interpreting these changes. First, our population was relatively young and included 4 participants under the age of 30 even if the equations were generated for individuals 30-74 years of age. Furthermore, the risk equations take into consideration only changes in serum lipids and blood pressure. Newer equations, currently available for women only 35
, also consider the effects of hsCRP on CVD risks. However, when applied to women only, the equation still predicted a 25-30% reduction in 10-year CVD risk in the CR and CR+EX groups while it was essentially unchanged in the Control group (+2%).
The lack of clear independent effect of training on CVD risk factors was of surprise to us. Yates T et al. 36
systematically reviewed all the controlled trials to determine the independent effect of exercise on glucose levels and risk of type 2 diabetes in people with prediabetes (IGT and/or IFG). They concluded that the contribution of physical activity independent of dietary or weight loss changes to the prevention of type 2 diabetes in people with prediabetes was equivocal. However studies such as the Diabetes Prevention Program clearly identified that intensive lifestyle changes including increased physical activity reduced the incidence of diabetes in persons at high risk 13
. Finally I a prospective epidemiology study, low physical fitness was found to be a strong and independent predictor of CVD and all-cause mortality 37
. However, in a randomized clinical trial of graded dose of exercise training in previously sedentary, overweight or obese postmenopausal women with elevated blood pressure, Church et al did not find exercise training to reduce blood pressure despite observing a graded increase in fitness across doses of exercise 38
. Taken together, while exercise is clearly protective against premature mortality and morbidity the mechanisms responsible for this are unclear with many studies observing common CVD risk factors not improving in response to exercise.
The design of this study was unique from several perspectives. Firstly, care was extended in establishing baseline energy requirements and tailoring the subsequent intervention to achieve a 25% deficit in energy intake in each participant. Second, all estimates of CVD risk factors were obtained while participants were consuming diets of identical macronutrient composition, albeit at different absolute amounts. Importantly this approach allows us to isolate the effects of changes in caloric intake independent of changes in diet composition, a variable known to strongly influence several CVD risk factors. Finally, the interventions were carefully delivered and monitored. As a result, both intervention groups (CR and CR+EX) had gradual and almost identical reductions in body weight throughout the course of the study. However, there are some limitations that should be noted when interpreting these results. First, our study sample size was relatively small limiting our power to detect between group differences. Second, our study was only six months in length. Caloric restriction is viewed as a lifestyle change extending over years. However, the data are generally consistent with the benefits observed with longer caloric restriction in self selected individuals engaging in CR 39