Which Diets Are Effective in Reducing Cardiovascular and Cancer Risk in Women with Obesity? An Integrative Review

Women are more affected by obesity than men which increases their risk of cancer and cardiovascular disease (CVD). Therefore, it is important to understand the effectiveness of different types of diet in the context of women’s health. This review aims to summarize the scientific evidence on the effects of different types of diet for women with obesity and their impact on CVD and cancer risk. This review included epidemiological and clinical studies on adult women and different types of diets, such as the Mediterranean (MED) diet, the Traditional Brazilian Diet, the Dietary Approach to Stop Hypertension (DASH), intermittent fasting (IF), calorie (energy) restriction, food re-education, low-carbohydrate diet (LCD) and a very low-carbohydrate diet (VLCD). Our main findings showed that although LCDs, VLCD and IF are difficult to adhere to over an extended period, they can be good options for achieving improvements in body weight and cardiometabolic parameters. MED, DASH and the Traditional Brazilian Diet are based on natural foods and reduced processed foods. These diets have been associated with better women’s health outcomes, including lower risk of CVD and cancer and the prevention and treatment of obesity.


Introduction
Obesity is a chronic and multifactorial disease which is a risk factor for other conditions such as cardiovascular disease and more than 13 types of cancer. It has also been associated with an increased mortality risk [1]. Obesity and being overweight are more prevalent in women than in men and their occurrence affects two-third of American women. In women, obesity increases the risk of postmenopausal and invasive breast cancers (BC), in addition to the risk of cardiovascular disease [2]. Moreover, in women with a normal body mass index (BMI) but with high body fat, the risk of postmenopausal invasive BC is also elevated [3]. Obesity is also one of the major risk factors for worse COVID-19 outcomes, including a higher risk of mortality [4].
With regard to women's health, obesity specifically increases infertility rates [5], weight gain during pregnancy with potential postpartum complications for women and  Previous meta-analyses of cohort studies have investigated the relationship between carbohydrate intake and all-cause mortality, and also mortality related to other outcomes, such as CVD and cancer, in the general population [42][43][44][45]. Some meta-analyses have found an association of LCD or low-carbohydrate, high-protein diets with increased all-cause mortality [42,43]. A meta-analysis observed that the risk of CVD mortality and incidence were not significantly increased, while another meta-analysis showed that CVD, cerebrovascular and cancer mortality were greater for higher scores of LCD evaluated as quartiles with the highest quartile related to the lowest carbohydrate intake [43]. Two meta-analyses observed that both LCD (HR 1.20; 95% CI 1.09-1.32) and high-carbohydrate diets (HR 1.23; 95% CI 1.11-1.36) were associated with an increased mortality risk [44,45]. In contrast, one of these meta-analyses analysed the source of protein of the diet and it was observed that LCD high in plant-based sources of protein and fat was associated with a lower risk of total (HR 0.89; 95% CI: 0.83-0.94 for highest versus lowest quintile), and CVD mortality (HR 0.82; 95% CI 0.73-0.92 for highest versus lowest quintile) [45]. Thus, the relationship between carbohydrate restriction and all-cause and CVD mortality remains unclear.
In general, the restriction of carbohydrates for women's health seems to promote similar results in weight loss and body composition compared to LFD. For cardiometabolic outcomes, LCDs and VLCDs may promote similar results as control diets. However, for triglycerides and HDL-cholesterol levels, LCD seem to show better improvements than LFD. Thus, LCDs and VLCD can be good options to achieve improvements in weight and cardiometabolic parameters, but they are difficult adhere to over an extended period.
Furthermore, it is reasonable to advise patients regarding the quality of carbohydrate intake, choosing those options associated with reduced cardiometabolic risk, including vegetables, fruits, whole grains, and legumes.

The Mediterranean Diet
Due to synergistic effects between various nutrients, foods, phytonutrients and compounds, focusing on dietary patterns is a better approach to evaluate the relationship between diet and disease [46]. The MED is one of the healthiest dietary pattern in decreasing CVD and cancer risks [47,48] and has been associated with a 12-28% lower risk of CVD, cancer and all-cause mortality [49]. The improvement effect of MED on CVD and cancer may be mediated by reducing oxidative stress, inflammation, obesity indicators, blood pressure, lipid profiles, glucose level and insulin resistance [50].
A recent meta-analysis of 57 RCTs illustrated that MED has reduced the risk of CVD, stroke, angina, pre-diabetes, breast cancer, but not metabolic syndrome (MetS) [51]. A large cross-sectional study conducted with 497,308 European adults (71% women) from ten countries suggested that a higher adherence to MED was associated with a lower WC [52]. In addition, intensive lifestyle modification including MED and exercise in one RCT reduced BMI and altered lipid profiles [53].
Low adherence to MED was more frequent in women with obesity and was associated with an increased asymptomatic atherosclerosis occurrence [54]. Abdominal obesity is a common component of menopausal MetS [55]. The valuable effects of MED in reducing overweight/obesity and abdominal obesity indicators in perimenopausal and postmenopausal women [56,57] was associated with lower estrogen levels [58]. Adiposity, obesity-related breast cancer as well as menopausal status have been associated with the methylation levels of the ZNF577 gene [59][60][61][62]. Furthermore, the MED can moderate the various genes' methylation like ZNF577 related to noncommunicable diseases such as CVD [63], stroke [64], and cancer [65]. Lorenzo et al. showed that a greater adherence to MED was associated with higher methylation levels of ZNF577 [66]. MED diet also had beneficial changes on weight loss and maintenance, WC, WHR, body fat and some inflammatory markers such as IL-6 and TNF-a after a 4-month period, compared to the United States Department of Agriculture (USDA)'s MyPyramid diet in breastfeeding women [67].
A meta-analysis of six trials reported that compared to low fat diet, MED diet had greater long-term favorable effects on CVD risk factors like BMI, blood pressure, fasting blood glucose, total cholesterol and inflammatory markers such as hs-CRP in individuals with obesity [68]. Another RCT found that the Central European Diet (CED) and MED with calorie restriction (CR) had significantly reduced the effect on body weight, blood pressure and metabolic biomarkers including insulin, HOMA2-IR, total cholesterol, triglyceride, with no difference between diets on postmenopausal women with abdominal obesity and at least one other MetS component [69]. Thus, it was concluded that CR, irrespective of their macronutrient compositions, could improve obesity and other CVD risk factors [69]. Moreover, a recent meta-analysis of thirty RCTs with moderate quality evidence in primary prevention of CVD risk factors and low-quality evidence of little or no effect in secondary prevention indicated a significant blood pressure reduction in MED compared to no diet as well as reductions in triglycerides and LDL-cholesterol levels compared to another diet in primary prevention. However, there were no changes in secondary prevention. Thus, it was concluded that there was uncertainty related to the effect of MED on preventing CVD [70] ( Table 2).
The favorable effects of MED are likely due to synergistic interactions among diverse elements of this diet rather than specific food groups [71]. Some potential mechanisms which explain the cardio-protective role and obesity prevention of MED are its beneficial effects on insulin resistance, endothelium-dependent vasoreactivity, oxidation and inflammation biomarkers [72,73].
Current evidence has shown a protective effect of MED in the risk of cardiovascular disease and cancer in women with obesity in different life cycles. This could be attributed to the various genes' methylation related to NCDs such as CVD [63] and cancer [65]. The MED also had beneficial changes in weight loss and maintenance, reduction of body fat and inflammatory factors [67]. However, there is some controversy about the effect of MED on the secondary prevention of CVD [70].

The Traditional Brazilian Diet
A diet pattern named the Traditional Brazilian Diet [74][75][76][77] was tested in a randomized clinical trial as a treatment in individuals with class II/III obesity (BMI = 35 kg/m 2 ), in which more than 85% of the sample where women. We have decided to include this diet in this review due to its features, such as being a kind of plant-based and reduced ultra-processed foods. It is a healthy diet pattern which can be easily incorporated in eating habits due to its common food components such as rice, beans, fruits, and vegetables largely consumed in many cultures. This diet pattern does not include food such as nuts, olive oil, seafood and wine, which can be difficult to find in most countries or are expensive for people who live in low-or middle-income countries. A comparative analysis of the MED and Traditional Brazilian diets can be found in a previous publication [77].
To better characterize the Traditional Brazilian Diet, consider a dinner plate and divide its half into three parts that will be one part rice, one part beans and one part lean red or white meat. The other half of the plate will be filled with boiled or raw vegetables in the form of salad, grilled or baked culinary preparations [74][75][76][77].
Cardiovascular risk is a public health issue worldwide, which increases the risk of mortality mainly in postmenopausal women. Therefore, it is important to reduce this risk factor. The Traditional Brazilian Diet intervention was effective in decreasing some cardiometabolic risk parameters in individuals with severe obesity, mainly LDL-cholesterol, HbA1c, triglycerides and triglycerides/HDL ratio [77]. This diet pattern had not been analyzed in terms of its impact on cancer. Overall, women have a higher prevalence of anxiety and depression [74]. In the abovementioned RCT, in which 85% of the sample were women, the Traditional Brazilian Diet showed a significant reduction of 46% of anxiety symptoms, 50% of depression and 67% of both anxiety and depression [74]. After a 12-week follow-up, those participants with severe obesity had a mean weight reduction of −2.83 ± 5.79 kg [74]. Even a modest weight loss can lead to health benefits. This diet pattern has been shown to be more effective in reducing other risk factors that affect women with severe obesity than weight loss itself. The Traditional Brazilian Diet can potentially be a good option to treat women with obesity when the objectives are to reduce cardiometabolic risk, depression, and anxiety symptoms.

DASH
The DASH is a dietary pattern originally developed to treat hypertension without medication by the United States National Institutes of Health (NIH). It is characterized for eating a high number of vegetables which will result in high levels of potassium, magnesium, and calcium, and limits the consumption of macro-and micronutrients that have been pointed out as a risk factor for hypertension, as total and saturated fat, cholesterol, and sodium. The DASH diet has mainly fruit and vegetables, low-fat dairy foods, whole grains, nuts, and legumes and low consume of red and processed meats, sweets, and sugar-sweetened beverages [78,79].
There is relevant evidence of DASH on prevention and treatment of hypertension and cardiovascular risk, such as reducing body weight, LDL-C and insulin. DASH is recommended by the international diabetes and cardiovascular clinical association guidelines [80][81][82][83].
Some studies that have evaluated DASH diet in overweight and individuals with obesity do not present data stratified by sex [84][85][86]. In a meta-analysis of 13 randomized controlled clinical trials, which included 2292 overweight and adults with obesity [87], only three studies presented women's data separately (n = 213) [88][89][90]. The main findings showed a significant association between DASH diet and BMI reduction, compared to the control diet [87]. Some studies have been conducted only with women [91][92][93][94], as shown in Table 3. Four randomized clinical trials have assessed the consumption of calorie-restricted DASH diet compared to a calorie-restricted control diet in overweight and women with obesity with polycystic ovary syndrome for 8-12 weeks [91][92][93][94]. The calorie-restricted DASH diet resulted in greater body weight, BMI [91][92][93][94], fat mass, WC [91] and hip [94] circumferences reduction. These clinical trials also evaluated cardiometabolic outcomes and found a greater reduction in insulin levels, HOMA-IR score, triglycerides, VLDLcholesterol, total antioxidant capacity, total glutathione, and nitric oxide in overweight and women with obesity with polycystic ovary syndrome after a calorie-restricted DASH diet [91][92][93][94] (Table 3).   A cohort study with 1760 pregnant women found no association between adherence to the DASH diet during early pregnancy, compared to a control diet, and pregnancy outcomes or complications. However, adherence to the DASH diet was unexpectedly associated with greater gestational weight gain in women with obesity before pregnancy [95]. The Women's Health Initiative, a cohort study with 93,122 postmenopausal women, found no association between a higher DASH diet score and cardiovascular mortality. They found an association between higher DASH diet quintiles and lower BMI and lower waist-to-hip ratio [96].
The DASH diet seems to be effective to reduce and control cardiovascular diseases, as well as reducing weight in women with obesity [87,[91][92][93][94]96], except for pregnant women with obesity [95]. The DASH diet may be relevant to treat obesity, mainly when the focus is to reduce cardiometabolic risk; however, the impact of this eating pattern on cancer has not been analysed.
A RCT indicated similar effects of ADF and CR diets on reducing CVD risk factors, weight loss and weight maintenance after one year [98]. Another RCT showed circulating leptin reduction and increased free fat mass (FFM) to total mass ratio without affecting the visceral adipose tissue to subcutaneous adipose tissue (VAT: SAT) ratio and other adipokines during a 24-week intervention. However, HOMA-IR had a greater reduction in ADF compared to the CR group [99]. Contrary to the assumption of easier compliance in ADF, this study showed less sustainability of ADF due to dissatisfaction of subjects with long-term ADF compared with CR [98]. A RCT in overweight and women with obesity also revealed similar improvements in body composition through these two interventions [100].
Time restricted eating (TRE) has been shown to result in good weight management and cardiometabolic beneficial effects including reduction in body weight, VAT, total fat mass, fasting blood glucose (FBG), impaired glucose tolerance, insulin resistance, dyslipidaemia, hypertension, appetite and inflammatory markers [101][102][103]. Especially, increasing the time of fasting from 12 to 14 h per day could produce more improvements in weight loss and FBG [102].
An RCT among overweight and with obesity East Asians in Hawaii showed a significant reduction in obesity indicators, including body weight, BMI, WC, VAT, SAT, body fat percent and total fat mass. However, there was no reduction of the VAT: SAT after IF: MED (2 consecutive days with 70% energy restriction: 5 days euenergetic MED) compared to euenergetic DASH diet after 12 weeks. There was also a decrease in the total lean body mass and muscle [104]. A recent review by Dong et al. showed that both IF and CR diets could reduce CVD risk factors including hypertension, insulin resistance and dyslipidaemia. In addition, IF was linked with CVD events in cardiac patients and weight reduction in individuals with obesity. The potential mechanisms for CVD prevention of IF consist of improving oxidative stress, promoting ketogenesis and a close relationship with the circadian rhythm hypothesis. Due to the time restricted nature of fasting, IF has better adherence and hence increased chance of more weight reduction in individuals with obesity than CR diet [105]. A meta-analysis of seven RCTs among 269 subjects demonstrated that ADF for at least one month could reduce body weight, BMI, fat mass, lean mass, blood pressure, and improve cardiometabolic risk factors including total cholesterol, LDL-cholesterol and triglycerides levels compared with the control group in normal weight and participants with obesity. For the first time, this meta-analysis illustrated that ADF could have greater beneficial effects than CR diet in normal and overweight individuals. ADF plus physical activity produced superior cardiometabolic improvements and weight related indicators such as the least decrease in lean mass compared with ADF alone [106]. Some studies on women showed the improvement effects of IF on obesity and CVD risk factors. A 24-week RCT with women with obesity showed body weight, LDL-cholesterol and triglycerides reductions of 7%, 10% and 17%, respectively [107].
A combination of IF with CR diet (IFCR) showed a stronger effect in reducing weight and CVD risk factors compared to each intervention alone [108]. In addition, a RCT in women with obesity showed that IFCR in its liquid (IFCR-L) had a stronger effect in reducing body weight, BMI, fat mass VAT, glucose, insulin, heart rate, total cholesterol, triglyceride and LDL-cholesterol as well as LDL-cholesterol particle size, but no changes on fat-free mass, SAT, blood pressure and CRP compared to with normal food (IFCR-F) in weight loss period. The greater weight loss and hence other better cardioprotective effect of the IFCR-L intervention is likely to be attributed to its better dietary adherence [108]. Different types of IF diet can have a reduction effect on obesity and body composition. However, it can be complicated to sustain the use of IF for a prolonged period. In addition, IF may reduce various CVD risk factors in cardiac patients. We summarized the main evidence for IF in studies conducted in women in Table 4. Table 4. Summary of studies with intermittent fasting diet for weight loss, obesity and cardiometabolic outcomes.

General Healthy Diet and/or Food Re-Education
Healthy eating is defined as a diet capable of promoting health and preventing diseases, reducing the risk of being overweight/with obesity and to develop CVD and cancer [109]. General public health recommendations on healthy eating to prevent NCDs include frequent consumption of fruits, vegetables and legumes, oilseeds and whole grains and limited intake of saturated fat, trans fat, sugar and salt [109][110][111][112]. As a general recommendation for the entire population, the combination of foods and meals should also consider the traditional/cultural dietary patterns of each population and sustainable food systems. In other words, involving a diversified diet, considering cultural traditions, geographical and environmental aspects [112]. A systematic review showed an association between diet quality indices and lower percentage of body fat, lower BMI and abdominal obesity, and lower weight gain in adults of both sexes [113].
Regarding meals, a 12-week randomized clinical trial with 93 overweight and women with obesity with metabolic syndrome compared the weight loss in two isocaloric diets (1400 kcal): one diet with high caloric intake during breakfast (700 kcal) (BF) and the other diet with high caloric intake at dinner (700 kcal) (D). The BF group showed greater weight loss, waist circumference, serum ghrelin and lipids, and insulin resistance indices reduction than the D group [114]. Two other randomized controlled trials evaluated the association between snack and weight loss in women and their results indicated that a reduced-calorie diet containing snacks may contribute to weight loss, depending on whether snacks consist of healthy foods, such as fruits, vegetables, and dark chocolate or reflect unhealthy eating habits and may in fact contribute to weight gain [115,116] (Table 5). Most studies have assessed women with obesity during their reproductive period, including pregnancy. During this period, a healthy and balanced diet, associated with nutritional education provided by a nutritionist/dietitian, has been shown to be crucial to prevent excessive weight gain and postpartum weight retention in women [117][118][119][120][121][122]. It also is a protective factor for the occurrence of gestational diabetes and hypertension, and pre-eclampsia [119,123].
A randomized clinical trial [121] and a systematic review [119] demonstrated that sugary food consumption was a risk factor for greater gestational weight gain in a cohort study of 46,262 pregnant women [122]. Women eating healthier diets, assessed by the Healthy Eating Index, have a lower risk of cancer mortality, according to a meta-analysis of cohort studies that evaluated 638,770 adult women [124].
We have used the NOVA classification to define healthy eating. That is, the major consumption of fresh and minimally processed foods, with the contribution of culinary ingredients and processed foods, characterizing culinary preparations [125][126][127][128][129]. Regarding NOVA, we did not find randomized controlled trials evaluating the impact of food consumption on women with obesity. A recent meta-analysis presented data from two studies showing a significant association between the consumption of ultra-processed foods and greater gestational weight gain in pregnant women [130].
Public health policies and programs to support population to promote a healthy food environment are important instruments for the prevention of obesity and other NCDs and require the involvement of government, the public and private sectors [131]. Food guides with graphic representations of the diet [132] and healthy eating recommendations are part of these initiatives and are relevant guidelines for the general population to adopt new healthy eating habits [132][133][134][135][136][137][138][139][140][141]. Another example is the program 5-a-day, which is a campaign to help people ensure that they eat five portions of fruit and vegetables a day [142][143][144][145]. In view of the prominence of this theme for health promotion and disease prevention, as well as the lack of specific recommendations targeted at women, it is relevant to have programs that focus their approach on specific recommendations for them.

Conclusions
The Med [146], DASH [80,87,147] and the Traditional Brazilian Diet [74][75][76][77]148] have in common the feature of being varieties of "plant-based diet" with the incorporation of natural foods and a reduction of ultra-processed foods. These diets have shown good results for women's health through the prevention and treatment of obesity in their different life cycles [149], and there is also evidence of a reduction in the risk of cardiovascular disease and cancer in individuals with obesity. In addition, these diets promote a reduction in lowgrade inflammation that affects individuals with obesity. Therefore, it is worth following the campaigns of "unpack less and peel more" as ways to reduce the consumption of industrialized products, especially those with high concentrations of sugar, sodium and sugary drinks, and to increase the consumption of natural foods such as fruits, vegetables, and whole grains.
LCDs, VLCD diets [31,[33][34][35][36][37] and IF [107,108] seem to promote interesting results with regards to weight control and reduced CVD and cancer risk in women with obesity. However, such diets may be difficult to adhere to over an extended period. From a dietary point of view, we must consider that a healthy diet should be learned and incorporated into the daily routine and not only for some periods with a focus only on weight loss. This type of nutritional treatment, which relies mostly on the adoption of a healthier dietary pattern and food education, is the best approach to prevent and treat overweight and obesity in women and to reduce CVD and cancer risk.