Abstract
For several cardiometabolic risk factors, values considered within normal range are associated with an increased risk of cardiovascular morbidity and mortality. We aimed to investigate the short-term and long-term effects of calorie restriction with adequate nutrition on these risk factors in healthy, lean, or slightly overweight young and middle-aged individuals.
Generated Summary
This is a phase 2, multicenter, randomized controlled trial called CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) conducted in the USA. The study aimed to evaluate the time-course effects of a 25% calorie restriction diet over 2 years in healthy, normal weight, and slightly overweight men (aged 21-50 years) and premenopausal women (aged 21-47 years). Participants were randomly assigned to either a 25% calorie restriction diet or an ad libitum control diet. The primary outcomes were cardiometabolic risk factors, including blood pressure, plasma lipids, high-sensitivity C-reactive protein, metabolic syndrome score, and glucose homeostasis measures. The study was registered with ClinicalTrials.gov (NCT00427193). The intervention involved a 25% reduction in calorie intake based on energy requirements estimated from doubly labeled water measurements. Participants in the calorie restriction group received dietary counseling. Extensive details of the intervention and the study’s design have been published previously. The trial’s main objective was to assess the effects of calorie restriction on cardiometabolic health outcomes over a 2-year period. The outcomes measured in this study were the exploratory cardiometabolic risk factor responses to a prescribed 25% calorie restriction diet for 2 years. Analysis was conducted on an intention-to-treat basis.
Key Findings & Statistics
- The study included 218 participants, with 143 assigned to the calorie restriction group and 75 to the ad libitum control group.
- The calorie restriction group achieved a mean reduction in calorie intake of 11.9% (SE 0.7), from 2467 kcal to 2170 kcal, versus 0.8% (1.0) in the control group.
- The calorie restriction group showed a sustained mean weight reduction of 7.5 kg (SE 0.4) versus an increase of 0.1 kg (0.5) in the control group.
- Of the weight loss, 71% was fat mass loss.
- Change scores for LDL-cholesterol were significantly reduced (p<0.0001).
- Total cholesterol to HDL-cholesterol ratio showed significant improvement (p<0.0001).
- Systolic blood pressure decreased significantly (p<0.0011).
- Diastolic blood pressure decreased significantly (p<0.0001).
- C-reactive protein showed significant improvement (p=0.012).
- Insulin sensitivity index improved significantly (p<0.0001).
- Metabolic syndrome score improved significantly (p<0.0001) relative to control.
- In the calorie restriction group, weight loss was from a baseline mean of 8.4 kg (SE 0.3, 11.5%) at 1 year and 7.5 kg (0.3, 10.4%) at 2 years (p<0.0001); it did not change significantly in the ad libitum group.
- Fat mass decreased from baseline by a mean of 6.1 kg (SE 0.2) at 1 year and 5.3 kg (0.3) at 2 years in the calorie restriction group (p<0.0001); it did not change in the ad libitum group.
- The calorie restriction group significantly restricted their energy intake by a mean of -279 kcal per day (SE 29; p<0.0001) at 1 year and -216 kcal per day (33; p<0.0001) at 2 years; the ad libitum group maintained its intake at 1 year (-83 kcal per day [SE 38]) and reported a reduction of -121 kcal per day (43) at 2 years (p=0.020).
- Total cholesterol and LDL-cholesterol decreased significantly both at 1 and 2 years in the calorie restriction group, but did not decrease significantly in the ad libitum group.
- HDL-cholesterol was increased by calorie restriction at 1 and 2 years, but the change was significantly different from the ad libitum group only at year 2.
- The ratio of total cholesterol to HDL-cholesterol decreased significantly and persistently in the calorie restriction group.
- Calorie restriction caused a drop in serum triglycerides concentrations of 24%.
- Calorie restriction resulted in a significant reduction in systolic, diastolic, and mean blood pressure.
- Fasting glucose was significantly reduced by calorie restriction at year 1, but not at year 2.
- The calorie restriction group had improvements in insulin sensitivity, as reflected in significantly lower homoeostasis model assessment-insulin resistance, insulin response (at 2 years only), and increased insulin sensitivity index.
- Plasma hs-CRP concentrations were significantly reduced in the calorie restriction group, but not in the control group, at 2 years.
- Calorie restriction resulted in a major and persistent reduction in the metabolic syndrome score.
Other Important Findings
- Cardiovascular disease is the leading cause of morbidity, disability, and death worldwide, with approximately 2,200 people dying each day in the USA due to this disease.
- In rhesus monkeys, early-onset calorie restriction reduces the risk of developing and dying of cardiovascular disease by at least 50%.
- Severe calorie restriction provides a powerful protective effect against multiple atherosclerotic risk factors, including less carotid artery intima-media thickening.
- The study’s results suggest a substantial advantage for cardiovascular health by practicing moderate calorie restriction in young and middle-aged healthy individuals.
- The effects of 2 years of 13% calorie restriction on cardiometabolic risk factors—in particular those composing the five components of metabolic syndrome, as well as glucose tolerance using an oral glucose tolerance test and derivatives thereof—raise the possibility of being able to modify the ravages of cardiovascular disease, diabetes, and obesity in high-income countries with relatively modest lifestyle interventions.
- Individuals with optimal cardiometabolic health have a substantially lower lifetime risk of developing cardiovascular disease than those with higher values.
- The 2-year CALERIE trial was designed to evaluate the potential for calorie restriction to promote anti-ageing adaptations in resting metabolic rate and body core temperature; findings for these outcomes have been previously reported.
- Fat loss at 2 years accounted for 71% of the weight loss in the calorie restriction group.
- Oral disposition increased in the calorie restriction group more than in the ad libitum group although the difference between groups was not significant.
- Changes in hs-CRP were only significant after 2 years of calorie restriction even though there was some weight re-gain between 1 and 2 years of calorie restriction.
- The findings of the marginal structural modelling are presented in the appendix.
Limitations Noted in the Document
- The study lacks a clinical measurement of atherosclerotic plaque modifications.
- The study did not include a thorough literature search before commencing.
- The interventions and measures were specific to the study protocol.
- The study may not be generalizable to populations outside the study’s inclusion criteria (healthy, non-obese individuals).
- The effects of the intervention may not be generalizable to those outside of the parameters tested.
Conclusion
The findings from the CALERIE study provide compelling evidence that a moderate calorie restriction regimen can significantly improve multiple cardiometabolic risk factors in healthy, young, and middle-aged adults. The observed benefits, including reductions in LDL-cholesterol, improvements in blood pressure, enhanced insulin sensitivity, and a decrease in the metabolic syndrome score, suggest a substantial advantage for cardiovascular health. These results align with previous research showing that caloric restriction can lead to improvements in multiple cardiometabolic risk factors. The study’s findings support the potential of calorie restriction to optimize cardiometabolic health and reduce the lifetime risk of developing chronic diseases such as cardiovascular disease. The sustained effects observed over a 2-year period suggest that moderate calorie restriction may be a viable strategy for long-term population health benefits, especially given that it is an inexpensive and safe dietary intervention. The study’s strengths include its large sample size, randomized controlled design, and detailed measurement of energy intake and expenditure. The study’s results emphasize that sustained calorie restriction exerts beneficial effects on cardiometabolic health even when baseline risk factors are within normal ranges. The implications of these results are broad, suggesting that dietary interventions like calorie restriction could offer a new tool for clinicians to combat the effects of unhealthy diets and lifestyle choices. Further research should focus on understanding the physiological and molecular mechanisms underlying these beneficial adaptations, which could lead to innovative pharmacological therapies.