In this randomized trial of four weight reduction diets, we observed the association between weight loss and substantial reductions in hsCRP, an effect that was independent of macronutrient composition. Further, among those randomized to imaging studies, we observed that the percent reduction in hsCRP correlated similarly with changes in all measures of body fat including total fat, abdominal fat, and intrahepatic fat.
Our data confirm prior work from smaller studies demonstrating that diet-induced weight loss substantially reduces hsCRP.3,19,20
In a systematic review of 28 lifestyle weight loss studies ranging from 14 to 90 participants, the weighted correlation between change in hsCRP and change in weight was 0.30,3
similar to our 6 month correlation coefficient of 0.31. The decrease in hsCRP with weight loss in our study is also similar to that observed among participants with impaired glucose tolerance in the Diabetes Prevention Program (DPP), where a 6.7% reduction in body mass was associated with a 30% reduction in hsCRP,21
and among participants with diabetes participating in the Look AHEAD trial, where 8.8% weight loss at one year was associated with a 44% decrease in hsCRP.22
Similarly, studies of bariatric surgery show substantial reductions in hsCRP with weight loss.23,24
Thus, our current data from POUNDS LOST in conjunction with other randomized evidence demonstrate that weight reduction decreases hsCRP by amounts similar to that reported with statin therapy.
Despite evidence for the effect of weight loss on hsCRP, there are scant prior data about the optimal content of weight loss diets that should be prescribed to decrease inflammation, and studies demonstrate conflicting results.5–11
In our large randomized trial, the macronutrient composition of four different weight loss diets did not affect the change in hsCRP at 6 or 24 months. Similarly, there was no difference between high and average protein diets, between high and low fat diets, or when the highest carbohydrate diet was compared to the lowest carbohydrate diet. These findings suggest that macronutrient composition is unlikely to have a differential effect on the reduction of hsCRP with weight loss.
In our trial, there was no difference in the percent change in hsCRP at 6 and 24 months between African-Americans and Caucasians despite significant differences in percent weight loss over time. Similarly, the percent reduction in hsCRP did not differ between overweight and obese individuals or by gender. As anticipated, participants using lipid lowering therapy at baseline had significantly lower baseline hsCRP values. However, as also observed in the LOOK AHEAD trial,22
statin users had similar reductions in hsCRP with weight loss as non-statin users. Taken together, these findings suggest that weight loss will further decrease hsCRP in patients who are already experiencing a reduction in hsCRP from taking statins.
Consistent with other studies examining anthropometric, cardiovascular, and metabolic correlates of hsCRP, we found the largest correlation coefficients for change in weight and waist circumference.21
In addition, several cross-sectional analyses suggest that high hsCRP levels are related to measures of insulin resistance, including fasting insulin and HOMA-IR.25,26
In our study, changes in HOMA and insulin were more correlated with changes in hsCRP than changes in LDL, especially at 24 months. This may be because of the relatively greater impact of weight loss and a healthy diet on hsCRP and insulin levels than upon LDL.
While some cross-sectional studies suggest that visceral fat is more highly correlated with hsCRP than abdominal subcutaneous fat,27,28
other cross-sectional studies suggest that hsCRP is correlated similarly with abdominal subcutaneous fat and visceral fat.29,30
However, few studies have examined how changes in these fat depots with weight loss relate to changes in hsCRP over time.31
In our randomized trial, the percent change in hsCRP correlated similarly with changes in all measures of body fat, including total body fat, and total abdominal, subcutaneous abdominal, and visceral fat. This similar effect is likely because of the similar fat reduction in all compartments in this study.
Hepatic steatosis is associated with both cardiovascular disease risk32
and elevated hsCRP.33
Previous studies demonstrate that hepatic fat infiltration can be reversed with weight loss,34
but few studies have examined how changes in hepatic steatosis with weight loss relate to changes in hsCRP.35
In our study we note a reversal of fat infiltration with weight loss which is significantly correlated with the change in hsCRP over time, a correlation which was magnified in those individuals who had significant hepatic steatosis at baseline.
In this trial, hsCRP levels did not rebound, despite significant weight re-gain by 24 months, an observation seen previously in other studies.21,22
Similarly, in one six month weight maintenance study of 932 adults, hsCRP levels continued to decrease despite slight weight regain, although this effect was more pronounced in the low glycemic index maintenance diets.36
The persistent changes in hsCRP noted in our study may reflect remodeling at the level of adipose tissue, including changes in adipocyte size and/or gene expression,37,38
that could be contributing to a decrease in hsCRP production. Given that all participants were placed on healthy diets that adhere to current recommendations, including fiber intake, carbohydrate quality, and type of fat, it is also possible that participants continued a healthier diet overall despite weight re-gain, regardless of their diet assignment. This is consistent with some studies demonstrating the importance of diet quality, particularly the Mediterranean diet, for reducing inflammation, possibly by modifying inflammatory pathways.19,39
Alternatively, it may be that a particular threshold of weight loss needs to be maintained. Further studies should examine the mechanisms responsible for this effect.
Strengths of our trial include the large diverse population as well as a larger proportion of men (39%), lower drop out rate (20%), and longer follow-up (2 years) than most weight loss studies. The addition of imaging measures of body fat allowed us to examine how changes in body composition relate to changes in hsCRP. Nonetheless, limitations of our analysis merit consideration. Not all of our participants had data at all three timepoints. However, a sensitivity analysis conducted among subjects with complete data demonstrated that the correlations were not substantially different. In addition, since all participants were advised to choose carbohydrate-rich foods with a low glycemic index, the study does not allow for a true comparison between low and high glycemic index diets. However, the fact that there were no significant differences in hsCRP between those assigned to 35% and 65% carbohydrate diets suggests that total carbohydrate content does not significantly affect hsCRP. Finally, as all groups in POUNDS LOST had similar exercise recommendations, we cannot evaluate the effect of physical activity separately from weight loss. However, the recent INFLAME study found that exercise training without weight loss is not associated with a reduction in hsCRP.40
In conclusion, our analysis indicates that diet induced weight loss results in a substantial reduction of hsCRP that is of similar magnitude to statin therapy and is independent of macronutrient composition. As such, physicians concerned about elevated hsCRP levels in their patients should emphasize the importance of weight loss, and suggest that patients choose a weight loss diet that would be most likely to lead to success, regardless of macronutrient composition.