The Women’s Health Initiative: Implications for clinicians

INTERPRETING THE RESULTS

It might be tempting to dismiss the results of the WHI dietary intervention trial as not significant and therefore not meaningful. This would be unfortunate. The trial had some remarkable accomplishments and offers important lessons for future investigations.

The initial reductions in total fat intake were impressive, and women who had the highest total fat intake at baseline achieved the greatest reduction of total fat (to less than 22% of total calories).³ Nonetheless, the dietary intervention goal of less than 20% of calories from fat was not achieved despite intensive dietary counseling and a highly motivated study population. Thus, this dietary fat target may not be reasonable in the general population.

Also, despite the absence of targeted intervention on specific fatty acids, the observed blood cholesterol levels were as expected based on the well-known formula of Mensink and Katan,¹⁴ which incorporates information on changes in saturated fat, polyunsaturated fat, and dietary cholesterol intake. The predicted reduction in low-density lipoprotein cholesterol was 2.7 mg/dL; the observed reduction was 2.3 mg/dL.² This illustrates that with greater modifications in specific known dietary risk factors for cardiovascular disease, such as saturated fatty acids, cholesterol, and unsaturated fatty acids, blood cholesterol levels respond in a predictable fashion. This was presumably not observed in WHI precisely because no goals and objectives were provided to participants for intake of saturated or polyunsaturated fatty acids.

Recent findings from the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart)¹⁵ further highlight differences in the total cholesterol response to diets of varying macronutrient (carbohydrate, protein, fat) content compared with the WHI dietary intervention.¹⁵ Participants in OmniHeart had reductions in levels of low-density lipoprotein cholesterol that were predictable from the changes reported in intake of saturated fatty acids. Presumably, the results of the WHI intervention would have been similar if the study had included this level of detail.

QUESTIONS REMAIN

Questions from the WHI that need consideration for future clinical applications include whether the study population may have already been “too old” to achieve a benefit from dietary modification, and whether the best timing for dietary intervention might be earlier adulthood with sustained changes in saturated fat, cholesterol, and unsaturated fat intake throughout life. Future subgroup analyses based on age at baseline will need to address these questions. Likewise, a longer follow-up period may be needed for a definitive evaluation of the impact of a regular low-fat diet on different health outcomes.

As reported by Patterson et al,¹⁶ the major contributors to total dietary fat intake at baseline were “added fats” such as sauces, gravies, butter, and margarines (25.1% of fat intake), followed by meats (20.9% of fat intake), and desserts (12.8% of fat intake). These findings highlight target areas for future interventions in women of this age group.

Another issue is how to standardize the dietary intervention from one clinical center to another—ie, to minimize differences in how each clinical center manages the study patients. Such differences were noted in WHI and other studies.¹⁷ Despite standardized training in delivering the dietary intervention, nutritionists encountered regional and cultural differences that required tailoring the dietary intervention to their patients’ needs. Staff turnover, an unavoidable phenomenon in long-term studies, has previously been reported to negatively influence dietary adherence.¹⁸

LIMITATIONS

A major limitation of diet modification research in general is the self-reporting of dietary intake, primarily by a food-frequency questionnaire. Although the use of a questionnaire is the most practical way to obtain dietary data for large studies, systematic biases may exist that obscure true nutrient-outcome relationships.¹⁹ Biomarker studies of energy balance suggest that people who are overweight or obese may under-report energy intake to a greater degree than people who are not overweight.²⁰ Also, we still do not know how to get people to follow a healthy diet, although theories and models abound, such as social learning and cognitive-behavioral theory, and a lack of data limits our understanding of factors related to dietary adherence.^21,22

FUTURE DIRECTIONS IN WHI

The WHI Extension Study is under way and has been funded through the year 2010. Outcomes ascertainment is the primary focus with no ongoing intervention, although the intervention group participants continue to receive a WHI newsletter that simply reiterates the importance of the study and encourages ongoing participation. As of 2006, an estimated 84% of the cohort, including both observational study and clinical trial participants, are involved. Efforts continue to recruit the remaining 16%, but many of these participants now consider themselves too old or too feeble to respond reliably.

In regard to breast cancer, the results published in 2006 are promising, albeit not statistically significant, and definitive statements cannot yet be made. However, postmenopausal women who are eating the diets highest in fat may have the greatest benefit from reductions in total fat.

Other considerations regarding the lack of statistically significant differences between groups may include the possibility that women in the intervention group may have been at lower risk for breast cancer at baseline. Likewise, although the results of the WHI dietary intervention do not include a statistically significant impact on colorectal cancer outcomes, the significant reduction in polyps and adenomas may later translate into a reduction in invasive cancer risk.

Finally, although no significant reduction was seen in the rate of death due to cardiovascular causes, greater reductions in saturated and trans-fatty acid intake were associated with greater reductions in blood cholesterol and cardiovascular risk.

Numerous subgroup analyses and ongoing assessments of the long-term impact of the diet modification are planned. Further associations are expected to emerge. The current and future results will continue to provide new insights that may lead to new clinical and public health recommendations in the future.

The WHI has raised additional issues that warrant further investigation:

• Will earlier dietary intervention, eg, during premenopausal years or even childhood, alter these results?
• Does the low-fat, high-carbohydrate diet used in WHI facilitate weight maintenance or even weight loss, as proposed by Howard et al²³?
• Do quantitative changes in physical activity and weight control attenuate morbidity and mortality rates beyond changes in diet alone?
• Do vitamin and mineral supplements or hormone therapy alter disease outcomes or quality of life?
• Which behavioral approaches are best suited to the recruitment of patients for dietary intervention trials?