OBJECTIVE:The Metformin and Dietary Restriction to Prevent Age-Related Morbid Events in People With Metabolic Syndrome (MeMeMe) trial tested whether 1,700 mg/day metformin (MET) with or without a Mediterranean diet (MedDiet) intervention could reduce the cumulative incidence of major noncommunicable diseases in people with metabolic syndrome. RESEARCH DESIGN AND METHODS:A total of 1,442 participants were randomly assigned to one of four interventions: 1) MET (1,700 mg/day) plus MedDiet intervention (MET+MedDiet); 2) placebo plus MedDiet intervention; 3) MET (1,700 mg/day) alone; and 4) placebo alone. Participants were followed up for 3 years on average. The primary outcome was the cumulative incidence of major noncommunicable diseases (including type 2 diabetes, cardiovascular diseases, and cancer). Secondary outcomes were the incidence of type 2 diabetes and the changing prevalence of metabolic syndrome. RESULTS:The crude incidence of the major noncommunicable diseases was 6.7 cases per 100 person-years in the MET+MedDiet group, 6.9 in the MET alone group, 13.3 in the placebo plus MedDiet group, and 11.3 in the placebo group. The differences were fully explained by the reduction of type 2 diabetes, which was 80% and 92% lower in the MET and MET+MedDiet groups, respectively, compared with placebo. CONCLUSIONS:The use of 1,700 mg/day MET is effective to prevent diabetes in people selected on the basis of metabolic syndrome.

BACKGROUND & AIMS:Breast cancer recurrence risk is strongly influenced by metabolic and hormonal factors linked to adiposity and diet. The DIet ANd Androgens-5 (DIANA-5) randomized controlled trial was primarily designed to test whether adherence to a Mediterranean/macrobiotic diet, combined with moderate physical activity, could reduce the risk of breast cancer recurrence. In the present secondary analysis of the DIANA-5 trial, we investigated associations between dietary intake, anthropometric, metabolic and hormonal profile testing the hypothesis that improvement in metabolic and hormonal parameters after one year of intervention are mediated by increased consumption of recommended foods ("recommended food score") and changes of body composition measures. METHODS:A total of 1542 women with early-stage breast cancer and presence of one or more endocrine/metabolic risk factors were randomized to receive either standard healthy lifestyle recommendations (n = 773) or intensive support including dietary counseling, cooking classes, and moderate physical activity reinforcement (n = 769). Anthropometric (BMI, waist circumference [WC], fat mass/fat-free mass ratio [FM/FFM]), metabolic (glycemia, insulin, HOMA index, total cholesterol, triglycerides, metabolic syndrome), and hormonal (testosterone) endpoints were assessed at baseline and after 12 months. Potential mediation effects of "recommended food score" and WC or FM/FFM on metabolic and hormonal changes were tested by using SPSS version 23 and the PROCESS macro v.4.0 for SPSS. RESULTS:604 and 551 women were available for mediation analyses in intervention and control groups, respectively. The dietary intervention improved all anthropometric, metabolic and hormonal measures. "Recommended food score" together with WC mediated 73 % of the effect of the intervention on glycemia, 67 % on insulin, 70 % on HOMA index, 96 % on total cholesterol, and 86 % on metabolic syndrome. With "recommended food score" and FM/FFM as mediators, proportions mediated were 86 % for glycemia, 73 % for insulin, 78 % for HOMA index, 126 % for total cholesterol, and 66 % for metabolic syndrome. Mediation effects of WC and FM/FFM on triglyceride changes were much weaker (38 % and 37 %, respectively). For all outcomes and all mediators, at least one path had a p-value <0.05. CONCLUSIONS:Most benefits of the DIANA-5 lifestyle intervention were mediated by dietary adherence and reductions in WC and FM/FFM. The proportion of effects mediated on metabolic syndrome, glucose and glycemic tolerance is high enough to suggest that these are the main effectors. The results on triglyceride blood levels suggest that further mechanism, possibly physical activity and energy intake should be investigated. CLINICAL TRIAL REGISTRY NUMBER:NCT05019989. Available at: https://clinicaltrials.gov/search?cond=NCT05019989.

Supplementary Figure 1; Supplementary Figure 2; Supplementary Table 1 ; Supplementary Figure 3; Supplementary Table 2

SUMMARY Breast cancer is the second most common cancer worldwide and the most commonly occurring malignancy in women. In recent decades, the incidence of this cancer has increased rapidly, especially in some regions, such as Europe. As the breast cancer burden is expected to increase in the future, the search for risk factors and primary prevention efforts to decrease their exposure are key aspects to curb this tendency. There is growing evidence that lifestyle factors, including diet, body weight and physical activity, may be associated with higher BC risk. High consumption of plant-based food (vegetables, whole-grain cereals, fruits, legumes and nuts), moderate consumption of fish, and limited or no consumption of sugar-sweetened beverages, processed and red meats, ultra processed food, milk, butter, whole-fat diary and sweets, could reduce the incidence of breast cancer. Autore per corrispondenza: berrinofranco@gmail.com

Metformin is a commonly prescribed type II diabetes medication that exhibits promising anticancer effects. Recently, these effects were found to be associated, at least in part, with a modulation of microRNA expression. However, the mechanisms by which single modulated microRNAs mediate the anticancer effects of metformin are not entirely clear and knowledge of such a process could be vital to maximize the potential therapeutic benefits of this safe and well-tolerated therapy. Our analysis here revealed that the expression of miR-21-5p was downregulated in multiple breast cancer cell lines treated with pharmacologically relevant doses of metformin. Interestingly, the inhibition of miR-21-5p following metformin treatment was also observed in mouse breast cancer xenografts and in sera from 96 breast cancer patients. This modulation occurred at the levels of both pri-miR-21 and pre-miR-21, suggesting transcriptional modulation. Antagomir-mediated ablation of miR-21-5p phenocopied the effects of metformin on both the clonogenicity and migration of the treated cells, while ectopic expression of miR-21-5p had the opposite effect. Mechanistically, this reduction in miR-21-5p enhanced the expression of critical upstream activators of the AMP-activated protein kinase, calcium-binding protein 39-like and Sestrin-1, leading to AMP-activated protein kinase activation and inhibition of mammalian target of rapamycin signaling. Importantly, these effects of metformin were synergistic with those of everolimus, a clinically relevant mammalian target of rapamycin inhibitor, and were independent of the phosphatase and tensin homolog status. This highlights the potential relevance of metformin in combinatorial settings for the treatment of breast cancer.

Abstract Purpose: The DIANA-5 randomized controlled trial assessed the effectiveness of a diet based on Mediterranean and macrobiotic traditions (macro-Mediterranean diet) in reducing breast cancer recurrence. Patients and Methods: The DIANA-5 study involved 1,542 patients with breast cancer at high risk of recurrence because of estrogen receptor–negative cancer, or metabolic syndrome, or high plasma levels of insulin or testosterone. Women were randomly assigned to an active dietary intervention (IG) or a control group (CG). Both groups received the 2007 American Institute for Cancer Research/World Cancer Research Fund recommendations for cancer prevention. The intervention consisted of meetings with kitchen classes, community meals, and dietary recommendations. Recommended foods included whole grain cereals, legumes, soy products, vegetables, fruit, nuts, olive oil, and fish. Foods to be avoided were refined products, potatoes, sugar and desserts, red and processed meat, dairy products, and alcoholic drinks. A compliance Dietary Index was defined by the difference between recommended and discouraged foods. Results: Over the 5 years of follow-up, 95 patients of the IG and 98 of the CG developed breast cancer recurrence [HR = 0.99; 95% confidence interval (CI): 0.69–1.40]. The analysis by compliance to the dietary recommendations (IG and CG together) showed that the women in the upper tertile of Dietary Index change had an HR of recurrence of 0.59 (95% CI: 0.36–0.92) compared with women in the lower tertile. Conclusions: The DIANA-5 dietary intervention trial failed to show a reduction in breast cancer recurrence, although self-reported diet at year 1 in IG and CG combined showed a protective association with the higher Dietary Index change. See related commentary by McTiernan, p. 931

Representativeness of Study Participants

Immortal time bias (ITB) is common in cohort studies and distorts the association estimates between the treated and untreated. We used data from an Italian study on COVID-19 vaccine effectiveness, with a large cohort, long follow-up, and adjustment for confounding factors, affected by ITB, with the aim to verify the real impact of the vaccination campaign by comparing the risk of all-cause death between the vaccinated population and the unvaccinated population. We aligned all subjects on a single index date and considered the “all-cause deaths” outcome to compare the survival distributions of the unvaccinated group versus various vaccination statuses. The all-cause-death hazard ratios in univariate analysis for vaccinated people with 1, 2, and 3/4 doses versus unvaccinated people were 0.88, 1.23, and 1.21, respectively. The multivariate values were 2.40, 1.98, and 0.99. Possible explanations of this trend of the hazard ratios as vaccinations increase could be a harvesting effect; a calendar-time bias, accounting for seasonality and pandemic waves; a case-counting window bias; a healthy-vaccinee bias; or some combination of these factors. With 2 and even with 3/4 doses, the calculated Restricted Mean Survival Time and Restricted Mean Time Lost have shown a small but significant downside for the vaccinated populations.

Figure Legend Supplementary Material

Figure Legend Supplementary Material

Supplementary Table 1 - miR-125a-5p expression across different databases; Supplementary Table 2 - miR-99b expression across different databases; Supplementary Table 3 - miR-199a-5p expression across different databases; Supplementary Table 4 - miR-199b-5p expression across different databases; Supplementary Table 5 - miR-892b expression across different databases; Supplementary Table 6 - miR-141 expression across different databases; Supplementary Table 7 - miR-582-5p expression across different databases; Supplementary Table 8 - miR-138 expression across different databases; Supplementary Table 9 - miR-181c* expression across different databases; Supplementary Table 10 - miR-28-3p expression across different databases; Supplementary Table 11 - miR-1288 expression across different databases; Supplementary Table 12 - miR-224 expression across different databases; Supplementary Table 13 - miR-520a-3p expression across different databases; Supplementary Table 14 - miR-223 expression across different databases; Supplementary Table 15 - miR-539 expression across different databases; Supplementary Table 16 - miR-542-5p expression across different databases; Supplementary Table 17 - miR-122* expression across different databases; Supplementary Table 18 - miR-920 expression across different databases.

The COVID-19 vaccination prevents COVID-19 specific mortality. Well planned population-based studies, however, are necessary to evaluate the overall effectiveness of vaccination programmes. A study carried out in the province of Pescara is used to illustrate the potential biases that may affect such studies. The Pescara study analysed total and non-COVID-19 mortality and the occurrence of Potentially Vaccine-Related Serious Adverse Events (PVR-SAEs) in vaccinated and unvaccinated people, from January 2021, when vaccines became available, to July 2022. The study reported a lower probability of both total and non-COVID-19 death in vaccinated people. However, the authors did not include in the denominator of the unvaccinated cohort the population experience of the vaccinated cohort before vaccination (immortal time bias). Correcting the denominator of the unvaccinated cohort, the crude death rate of vaccinated and unvaccinated persons becomes the same. For the same reason, the unvaccinated non-COVID-19 mortality was overestimated, as was the mortality of people receiving only one or two vaccine doses. Confounding by indication and the healthy vaccinee bias will also be discussed, as well as the bias deriving by not considering the evolution of risk over time.

Impaired sleep and low daily activity levels increase the risk of developing metabolic syndrome (MS). Metformin (MET), an insulin sensitizer drug, is effective in regressing MS and has been recently studied as an adjuvant agent for managing sleep disorders. The present study aimed to assess whether 1,700 mg/day of MET treatment modifies sleep and daily activity levels in people with MS evaluated by Rest-Activity circadian Rhythm (RAR), which is the expression of 24 h of spontaneous activity parameters. A total of 133 subjects with MS, randomized into the MET (n = 65) or placebo (PLA, n = 68) group, underwent a clinical/anthropometric examination and carried out a continuous 7-day actigraphic monitoring to investigate sleep and RAR parameters at baseline and after 1 year of intervention. After 1 year of intervention, 105 subjects were analyzed. The MET group showed greater anthropometric and metabolic improvements compared with placebo, with a significant reduction in weight (p = 0.01), body mass index (p = 0.01), waist circumference (p = 0.03), and glucose (p < 0.001). With regard to sleep parameters, the MET group showed a significant increase in actual sleep time (p = 0.01) and sleep efficiency (p = 0.04) compared with placebo. There were no significant changes reported in the RAR parameters. Our study suggests that MET might be used as an adjuvant treatment for sleep disorders in people with MS.

Supplementary Tables 1S-7S, Figure 1S from Haplotype Analysis of the HSD17B1 Gene and Risk of Breast Cancer: A Comprehensive Approach to Multicenter Analyses of Prospective Cohort Studies

INTRODUCTION:Recruitment is essential for the success of clinical trials. We are conducting a randomized clinical trial to test the effect of a Mediterranean dietary intervention with or without 1700 mg/day of metformin for the prevention of age-related chronic diseases, the MeMeMe trial (Trial registration number: EudraCT number: 2012-005427-32 ClinicalTrials.gov ID: NCT02960711). MeMeMe recruiting experience, highlighting strengths, limitations encountered and results is reported.PATIENTS AND METHODS:Statistical analysis focused on the reasons for withdrawal according to the recruitment method ("active" versus "passive" criterion) and the time of withdrawal. Logistic regression models were used to explore the associations between the risk of withdrawal and sex, recruitment method, randomization arm, and with markers of compliance to the intervention, such as one-year change in body weight.RESULTS:Out of 2035 volunteers, 660 (32.4%) were recruited "actively" and 1375 (67.6%) "passively". Among people who dropped out of the trial after randomization, there were 19.5% for the "active" and 22.0% for the "passive" method (p = 0.28). The risk of withdrawal was significantly higher in women (OR:1.91; 95% CI:1.17-3.12; p = 0.01), in volunteers older at recruitment (OR:1.25; 95% CI:1.07-1.45; p = 0.004), and in those with a higher BMI at baseline (OR:1.23; 95% CI:1.07-1.43; p = 0.004). Volunteers who lost at least 2 kg (the median weight change) in the first year of intervention were significantly less (53%) likely to withdraw from the trial (OR:0.48; 95% CI:0.30-0.75; p = 0.001).CONCLUSION:Our findings suggest that the "passive" recruitment method was more effective than the "active" one to advance recruitment. The benefits of "passive" recruitment hardly outweighed the drawbacks.TRIAL REGISTRATION:Trial registration number: EudraCT number: 2012-005427-32. ClinicalTrials.gov ID: NCT02960711.