A recent paper published in the American Journal of Clinical Nutrition provides updated results from the Women’s Health Initiative (WHI) Dietary Modification Trial (1). One of the questions raised is whether there is still hope for a low-fat dietary approach for the prevention of heart disease.
The primary aim of the WHI Dietary Modification Trial was to test whether behavioral intervention intended to produce a dietary pattern low in total fat, along with increased intakes of vegetables, fruits, and grains, would decrease the incidence of breast and colorectal cancer in postmenopausal women. A secondary aim was to test whether such a dietary intervention, which did not focus on the intake of specific fats, would also reduce the risk of cardiovascular disease (CVD) (2).
The study hypothesis was that a diet capable of effectively lowering LDL-cholesterol would reduce the risk of CVD.
A total of 48 835 postmenopausal women aged 50 to 79 years, of diverse backgrounds and ethnicities, were randomly assigned to an intervention (19 541 [40%]) or comparison group (29 294 [60%]) in a free-living setting. Study enrollment occurred between 1993 and 1998 in 40 US clinical centers; mean follow-up in this analysis was 8.1 years.
The intervention group received intensive behavior modification in group and individual sessions designed to reduce total fat intake to 20% of calories and increase intakes of vegetables/fruits to 5 servings/d and grains to at least six servings/d. The comparison group received diet-related education materials.
The study results, published in 2006, showed that this particular intervention did not significantly reduce the risk of coronary heart disease (CHD), stroke, or CVD in this particular population.
Today, eleven years after the original publication, the results of this large trial are still highly debated. Some believe the study proved that the diet-heart hypothesis was wrong while others pointed out that the lowering of LDL-cholesterol in the intervention group was too small to be able to make a difference.
In their recently published paper, Prentice and coworkers point out that CHD incidence may not have been reduced because of a risk elevation among the 3.4% of participants reporting CVD before trial involvement. It was also observed that the risk of CHD was higher for women with hypertension (43.2% of the trial population) than for women without hypertension.
Interestingly, updated CVD and all-cause mortality results for both the intervention and post-intervention periods, including mortality data through 2013 are provided in the paper.
The Updated WHI Dietary Modification Trial Results
The updated data on all-cause mortality during the trial intervention period did still not reveal any significant differences between the intervention and control groups. In other words, the low-fat intervention did not lower all-cause mortality.
However, interestingly, the effects of the low-fat dietary pattern intervention varied strongly based on whether hypertension or cardiovascular disease was present at baseline or not.
The CHD hazard ratio (HR) was significantly lower for participants with normal blood pressure than for hypertensive participants. That is, the low-fat intervention appeared more effective among those who had normal blood pressure. However, this benefit was partially offset by an increase in stroke incidence in the intervention group.
Interestingly, in women with prior CVD, the risk of CHD was increased in the low-fat interevntion group, yielding a marginal increase in total CVD risk.
The low-fat intervention reduced HDL-cholesterol and increased the triglyceride/HDL-cholesterol ratio, both of which may be considered negative. However, there were also positive effects including reductions in insulin levels and glucose along with favorable changes in weight, waist circumference, and blood pressure.
LDL-cholesterol at one year was lower in the intervention group by an estimated 2 mg/dL in women who were healthy but was larger by an estimated 15.9 mg/dL in women with prior CVD. The lowering of LDL-cholesterol in the intervention group appeared consistent throughout the intervention period after exclusion of women who were taking cholesterol-lowering medication at baseline.
Statin use rates during follow-up did not differ significantly between randomization groups.
Will the Updated Results Change Our View of the WHI Dietary Modification Trial
The updated results confirm the conclusion of the original trial; replacing dietary fat with carbohydrates does not lower CVD risk.
The authors of the paper, however, believe that their subset analyses may be of importance although they acknowledge the challenges associated with multiple testing. However, post-randomization confounding by statin use may offer a potential explanation for some of the differences.
As mentioned above, women with prior CVD seemed to do worse on a low-fat diet compared with the control group. However, the authors believe the results are uninterpretable (due to confounding by post-randomization statin use) although they underscore that they were not able to rule out the possibility that dietary changes in the low-fat intervention group may have contributed to the worse outcome.
On the other hand, the authors believe that the beneficial effect of the low-fat intervention among women with normal blood pressure and no CVD is unlikely to have been affected bay post-randomization statin-use. Hence, they conclude that total fat reduction is an important driver of the observed CHD reduction in these women. This could be mediated by the favorable effects on LDL-cholesterol, insulin, and glucose.
However, they also point out that this positive effect of the low-fat intervention may be tempered by a corresponding increase in stroke risk.
The paper’s final words are:
“These analyses, in which there is little potential for post-randomization confounding by cholesterol-lowering medications, suggest that CVD incidence rates in healthy postmenopausal women in the United States are quite sensitive to moderate dietary change. Intervention participants chose varying approaches toward achieving dietary goals, with a corresponding range of potential cardiovascular benefits and risks. Trial data are currently undergoing further analyses in an attempt to identify dietary pattern changes by women in the intervention group that retain CHD benefit while avoiding any adverse effects.”
Well, an interesting paper that raises several questions. But still, the conclusion from the original study remains intact.
It is well known that multiple comparisons may reveal an apparently statistically significant observation that may have arisen by chance. This statistical phenomenon has sometimes been called the look-elsewhere effect (3). If a certain diet is beneficial, why should it only work for women without hypertension? For me that’s a bit difficult to comprehend.
Hence, it is hardly justified to promote a low-fat high-carb diet of the type tested in the WHI trial for the purpose of preventing heart disease.
However, the authors appear to believe there remains a glimmer of hope that a truce of some kind can still be salvaged.