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A randomized controlled trial of Mediterranean diet and metformin to prevent age-related diseases in people with metabolic syndrome

Abstract

Purpose

Age-related non-communicable chronic diseases (ArCDs) are the leading cause of mortality. The major metabolic risk factor for their development is the metabolic syndrome (MetS), defined as a clustering of risk factors of metabolic origin such as abdominal obesity, high blood pressure, dyslipidemia and high fasting glycemia. There is increasing observational and experimental evidence that improving diet and the use of metformin (a calorie-restriction mimetic drug) may modify the risk of developing MetS and ArCD. We designed a phase III randomized controlled trial (the Me.Me.Me trial) to evaluate the effect of a comprehensive lifestyle intervention (including moderate physical activity and a Mediterranean-macrobiotic diet) and the effect of treatment with metformin in the prevention of ArCDs in healthy people with MetS. This report describes the scientific protocol of this trial.

Methods

The design of the study is 2 × 2 factorial with 2,000 volunteers to be randomized into 4 equal groups of 500 each, which are allocated to the following treatments: metformin (1,700 mg/day) + active lifestyle intervention, placebo + active lifestyle intervention, metformin (1,700 mg/day) alone, and placebo alone. The metformin/placebo component of the study is double blind. The study is planned for a term of 5 years.

Results

The Me.Me.Me. trial is ongoing and recruitment of participants is underway. No patient has completed the 5 years of follow-up.

Conclusions

We believe that the results of the trial will clarify the importance of lifestyle for primary prevention and the role of metformin as a potential chemopreventive agent. The trial is registred on ClinicalTrials.gov with the identification NCT02960711.

Post author correction

Article Type: CLINICAL TRIAL PROTOCOL

DOI:10.5301/tj.5000599

Authors

Patrizia Pasanisi, Giuliana Gargano, Maria Gaetana Di Mauro, Mauro Cortellini, Alice Casagrande, Anna Villarini, Eleonora Bruno, Eliana Roveda, Gabriella Saibene, Elisabetta Venturelli, Franco Berrino

Article History

Disclosures

Financial support: The Me.Me.Me. study is funded by an advanced grant from the European Research Council (ERC-AdG-2012 n. 322752).
Conflict of interest: The authors declare that they have no conflicts of interest.

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Introduction

Age-related non-communicable chronic diseases (ArCDs) are the leading cause of mortality and are largely due to modifiable lifestyle factors such as smoking, overeating, excess body weight, sedentary lifestyle and industrially processed food (1). A major metabolic risk factor for the development of ArCD is the metabolic syndrome (MetS), an insulin-resistance syndrome whose prevalence in the adult Western population ranges between 20% and 40%. MetS is defined as a clustering of risk factors of metabolic origin such as abdominal obesity, high blood pressure, dyslipidemia and high fasting glycemia (2). MetS is accompanied by a 2-fold increase in the risk of cardiovascular diseases and a 5-fold increase in the risk of type 2 diabetes mellitus (3-4-5). More recently, several studies have shown that MetS is also associated with an increased risk of cancer (including colorectal, liver, pancreas, breast, endometrial, ovarian, kidney and probably prostate cancer), neurodegenerative diseases, non-alcoholic fatty liver disease and cirrhosis, chronic kidney disease, prostate hyperplasia, and other chronic conditions (6).

There is increasing observational and experimental evidence that improving diet and lifestyle may modify the risk of developing MetS and ArCD. The Mediterranean diet (MedDiet), which is largely based on unrefined cereal products (mainly bread and pasta), pulses, vegetables, olive oil, nuts, fruit, moderate wine, occasionally fish and cheese and rarely other animal products, is associated with a lower risk of cardiovascular diseases and diabetes. Subjects with the highest adherence to a traditional MedDiet have a lower cumulative incidence of MetS and several chronic diseases than those with the lowest adherence (7-8-9-10).

Randomized intervention trials have shown that MetS can be reversed with MedDiet, with an up to 69% reduction of MetS prevalence after 2 years of diet (11). Several other trials supported the favorable effects of MedDiet on body weight, abdominal adiposity, plasma lipid profile and endothelial function (12-13-14-15). High adherence to MedDiet is also associated with lower cognitive impairment and Alzheimer’s disease (16). Several observational studies on dietary patterns found MedDiet to be significantly associated with a lower risk of breast cancer, colon cancer, coronary heart disease, stroke, diabetes and Alzheimer’s disease (7, 16-17-18-19-20).

Several drugs have been proposed in addition to diet and lifestyle interventions to reduce MetS and ArCD. Metformin (MET) is a very safe calorie-restriction mimetic drug that has been used for 50 years to treat diabetes and more recently to prevent diabetes in people with glucose intolerance (21). It has been shown to reduce cardiac risk factors and prevent cardiovascular diseases in diabetics, and to improve clinical outcomes in patients with heart failure. More recently, observational studies showed that diabetic patients treated with MET had a significantly lower risk of developing cancer or a lower cancer mortality (all sites combined) than those untreated or treated with other drugs, with relative risks ranging from 0.28 to 0.90 (21-22-23-24).

MET may lower the cancer risk through 2 main mechanisms (21): 1) reducing insulin resistance and therefore insulin and IGF-I/Akt pathways, and other markers of insulin resistance such as testosterone and IGF-I concentration in blood; 2) activating AMPK, thus mimicking the effect of calorie restriction. AMPK activation results in downregulation of mTORC1 and in p53-mediated cell cycle arrest.

We hypothesized that an intervention that takes into account as many aspects as possible is needed to favorably affect the complex biological system involved in the development of ArCDs. Therefore, we designed a randomized controlled trial to evaluate the effect of a comprehensive lifestyle intervention (including moderate physical activity and a Mediterranean-macrobiotic diet with moderate calorie and protein restriction) and the effect of treatment with MET in the prevention of ArCD in healthy people with MetS (the Me.Me.Me trial). The aim of this report is to describe the scientific protocol of this trial.

Methods

Trial design (Fig. 1)

Me.Me.Me. is the acronym for “metabolic syndrome, Mediterranean diet and metformin”. The Me.Me.Me. trial is a phase III randomized controlled trial on people with MetS to test the hypothesis that comprehensive lifestyle changes and/or MET treatment prevent ArCD. The design of the study is 2 × 2 factorial with 2,000 volunteers to be randomized into 4 equal groups of 500 each, which are allocated to the following treatments:

MET (1,700 mg/day) + active lifestyle intervention

placebo + active lifestyle intervention

MET (1,700 mg/day) alone

placebo alone.

The MET/placebo component of the study is double blind. The study is planned for a term of 5 years. Our hypothesis is that a substantial fraction of the ArCD incidence and mortality, of the order of 25%-33%, could be prevented through a) a sustainable comprehensive change in lifestyle, including moderate calorie and protein restriction, Mediterranean/macrobiotic diet and physical activity, and b) chemopreventive treatment with MET, a drug whose mechanism includes the activation of the same genetic pathways that are activated by calorie restriction and physical activity.

The Me.Me.Me. trial is a single-center trial with a sole center of enrolment at Fondazione IRCCS Istituto Nazionale dei Tumori in Milan. The trial is supported by an ERC grant and was approved by the institutional review board and ethics committee of the Fondazione IRCCS Istituto Nazionale dei Tumori di Milano.

Participants

Potentially eligible people are recruited through cancer screening programs, general practitioners, clinical units dealing with overweight and metabolic diseases, and the media. Interested people are invited to attend information sessions in which we carefully illustrate the study design and aims. The inclusion criteria are age 55-74 years and the presence of MetS.

Different definitions of MetS have been used by different investigators. In the present trial, MetS is defined on the basis of the presence of at least 3 components out of 5 according to the thresholds proposed by the International Diabetic Federation (2) (blood pressure ≥130/85 mmHg, fasting plasma glucose ≥100 mg/dL, triglycerides ≥150 mg/dL, high-density lipoprotein <50 mg/dL for women and <40 mg/dL for men) except for waist circumference, for which we used thresholds of ≥100 cm in men instead of >94 cm and ≥85 cm in women instead of >80 cm (because the constitution of Italian women is not as lean as the constitution of other European women (25).

The exclusion criteria are a diagnosis of diabetes or fasting glycemia >126 mg/dL in 2 consecutive blood samples or concomitant treatment with MET; renal, cardiac or hepatic insufficiency; a diagnosis of cancer in the last 5 years (except skin carcinoma); serum creatinine >124 µL/L; proteinuria; concomitant treatment with potassium-sparing diuretics or proton pump inhibitors; excessive alcohol consumption.

In order to exclude potentially intolerant subjects before randomization, all participants receive MET treatment for a trial period of 30 days (1 tablet of 500 mg MET/day) (Fig. 1). Participants with distressing side effects during the trial period are not included in the study.

Trial design.

Participants are requested

to sign the informed consent to participate in the study and to follow the prescribed treatment and lifestyle changes, to provide information on their health status and intervening diseases, and to allow the study officials to contact their treating physicians for the consultation of clinical notes and examination of blood samples for metabolic, genetic and epigenetic studies, even after the end of the active intervention period

to fill in a questionnaire on medical history and risk factors (the EPIC-Italy questionnaire)

to undergo an anthropometric visit (height, weight, waist and hip circumferences, blood pressure, body fat and lean mass measured with a Tanita bioelectric impedance device, at baseline and after each year of the study for 5 years of follow-up)

to donate a 20-mL blood sample for measurement of markers of MetS. Markers are evaluated at baseline and after each year of the study for 5 years of follow-up to check both the efficacy of the intervention and the possible occurrence of diabetes. Fasting blood samples are collected between 8 and 9 am. Glucose, total and HDL cholesterol, and triglycerides are measured immediately. We then prepare 10 aliquots of serum (4 aliquots), plasma (3), red blood celIs (1) and buffy coat (2) to be preserved at -80°C for further analysis of insulin, IGF-I, IGF-BPs, PDGF, sex hormones, hsCRP, and inflammatory cytokines. These analyses will be carried out in appropriate samples of participants from the third year onwards

to fill in a 24-hour dietary and exercise recall form (either directly or by phone) at baseline and after each year of the study for 5 years of follow-up.

Participants are informed that they can retire from the study at any moment but are recommended not to do so because it would damage the interpretation of the results.

Lifestyle intervention

The intervention aims to increase physical activity, control weight, and promote a nutrient-rich (100% recommended dietary allowance for all nutrients), moderately calorie-restricted and protein-restricted, low-glycemic-index diet. As far as physical activity is concerned, the goal of the intervention is to achieve and maintain regular participation in a moderate-intensity physical-activity program (approximately 3 to 5 metabolic equivalents) of 210 minutes over at least 3 days per week (30 minutes on average per day).

To control weight, participants are encouraged to include whole grains and high-fiber vegetables – which add bulk and volume – in every meal, to choose cooked cereals rather than white bread or dry crackers, to eat vegetables or soup before eating higher-energy food, to choose fresh fruit rather than juice, to eat nuts at least every other day, and to avoid potatoes, sugary drinks, commercial sweets, white bread and other products based on refined flours, high-protein meals, and energy-dense industrial food.

In order to reduce glycemic and insulinemic responses, recommendations include

reducing calorie intake through the preferred consumption of highly satiating food such as unrefined cereals, legumes and vegetables

reducing high-glycemic-index foods such as refined flour, potatoes, white rice and corn flakes as well as high-insulin-index foods such as sugar and milk, preferring instead whole-grain rice, barley, millet, oat, spelt, quinoa and buckwheat, legumes (any type including soy products), and seasonal vegetables (any type, except potatoes)

reducing sources of saturated animal fats (red and processed meat, milk and dairy products), preferring instead unrefined vegetable fats such as olive oil, nuts and oleaginous seeds

lowering protein intake, mainly animal protein (except fish), down to 10% of total calorie intake

eating mostly food of plant origin, with a wide variety of seasonal products.

Participants will learn to prepare traditional Mediterranean and macrobiotic gastronomic dishes based on whole-grain cereals, durum wheat pasta and legumes seasoned with vegetable sauces and little fat, and competitive cakes and cookies without sugar, milk, butter and refined flour, using instead dried fruit such as raisins and apricots, oleaginous seeds, soy milk, cereal flakes and unrefined flour.

Dietary sources of antiinflammatory food are used such as unrefined cereals, small-size oily fish, seaweeds, turmeric, green tea, olive oil, wild berries and other quercetin-rich vegetables such as capers, apples, onions, horseradish, broccoli and other green vegetables, as well as other vegetables rich in phytochemicals that have been shown in vitro to inhibit Akt (which is critical to both cancer and atherothrombotic diseases) and other relevant genetic pathways, such as genistein, morin, apigenin and luteolin.

Metformin intervention

Treatment with 850 mg of MET or placebo twice a day (1,700 mg total/day) is only given to participants who have already been randomized (Fig. 1). As stated earlier, prior to randomization there is a trial period with 500 mg MET/day for 30 days, at the end of which participants showing no side effects are randomized to the MET or placebo arms.

After randomization participants receive a supply of 62 tablets of MET or placebo, which covers 2 months of treatment according to the Me.Me.Me. protocol (one 850-mg tablet/day of MET/placebo) (Fig. 1). The next step is to provide the supply of full treatment (62 tablets of MET/placebo), which covers 1 month (2 tablets, 1,700 mg/day of MET/placebo in total) (Fig. 1). Then all participants are given a 6-month supply.

In case of gastrointestinal discomfort occurring after randomization, participants are asked to continue with a single tablet (half dose, one 850-mg tablet/day of MET/placebo). Throughout the trial all adverse events are monitored, collected and recorded in the electronic case report form (eCRF).

Outcomes

The main outcome is the total incidence of ArCDs including cancer, coronary heart disease, stroke and diabetes. Secondary outcomes are total mortality, total cancer incidence, and incidence of diabetes, cardiovascular diseases, myocardial infarction and stroke. These outcomes have been selected as major objectives because they are fairly easily identifiable in clinical charts according to standardized criteria. Other ArCDs associated with MetS, however, are registered in the follow-up records and may eventually contribute to the overall disease burden. Secondary outcomes are also the changing prevalence of MetS and its metabolic and anthropometric components. Markers of MetS are evaluated at baseline and after each year of the study for 5 years of follow-up through blood exams and clinical visits.

Statistical analysis

The primary outcome of interest is the total incidence of ArCDs. For this outcome, differences in event incidence or times to event will be used. The main analytic approaches will include standard methods for analyzing clinical trial or follow-up data: Poisson regression (for outcomes with count data), Cox proportional hazards regression (for outcomes measured as time to event) and generalized estimating equations (GEE) (for correlated outcomes).

The intention-to treat principle will be adopted. Because our randomization is stratified by sex, all the performed analyses will take into consideration this variable. Although randomization would minimize differential distribution of other potential confounders for the treatment effects (e.g., age), we will examine differential distributions across study arms and make statistical adjustments accordingly.

Sample size

Power computations have been based a) on expected mortality and ArCD incidence in the study area in men and women aged 55 or more (assuming the same age distribution as the general population); b) on the assumption that MetS is associated with a 1.5-fold higher incidence of ArCD (and a 3-fold higher incidence of diabetes); c) on the hypothesis that the planned interventions may reduce the ArCD incidence by 25% or 33%; d) on a 3.5-year average follow-up (within the 5-year study period); and e) on an alpha error of 0.05.

Hypothesizing to recruit 1,000 people with MetS per year in the first 2 years, excluding the person years accumulated in the recruitment year, plus 200 people to compensate for the power loss due to expected attrition (for mortality and decisions to stop participation), we would expect about 174 deaths, 175 cancers, 119 major cardiovascular events (myocardial infarction and stroke), and 219 cases of diabetes, i.e., a total of over 500 incident cases of major ArCDs.

For a 33% (and 25%, respectively) reduction in the cumulative incidence of major ArCDs (cardiovascular + diabetes + cancer) we will have:

99% (92%) power to compare 1,000 people treated with MET with 1,000 people receiving a placebo (or 1,000 people with or without active lifestyle intervention)

97% (84%) power to compare 500 people treated with both MET and lifestyle intervention with respect to the other 1,500

89% (65%) power to compare 500 people receiving both interventions with the group of 500 receiving no intervention.

Comparing 1,000 treated and 1,000 untreated people, we will have 69% power to detect a significant 33% difference in total mortality or in the cumulative incidence of cancer, and 98% power to detect a 33% difference in the cumulative incidence of diabetes (85% for 25% reduction).

Randomization

The Me.Me.Me. trial requires 2 consecutive randomizations: diet randomization (based on registration data) and treatment randomization (based on anthropometric and hematological eligibility) (Fig. 1). These distinct randomizations are due to the fact that several weeks may elapse between the date of recruitment and the date of the anthropometric visit and blood sampling.

The software created ad hoc for the management of the trial is able to balance the randomized groups (26), so that groups will be comparable at any time. The software balancing mechanisms are automatic, not modifiable by the operators, and accessible to operators at any time by summarizing statistics.

As far as diet randomization is concerned, 2 features of the population are considered to get the balance: sex: male/female, and family relationship: members belonging to the same family are included in the same randomization group.

The participant is assigned to the active lifestyle intervention/no intervention arms by the software when the data manager saves the registration data (27). The color blue marks the active lifestyle intervention; green marks the control group.

As far as treatment randomization is concerned, 2 features of the population are considered to get the balance: sex: male/female, and age: up to 67/over 67 years.

The treatment randomization process starts only if the participant fulfills all the following entry criteria:

completed registration data on lifestyle, 24-hour diet diary, physical activity diary, concomitant medications in the eCRF

presence of MetS and absence of exclusion criteria (based on anthropometric measures, blood and urine)

no adverse events in the first 30 days of MET treatment (trial period with administration of 1 tablet of 500 mg MET/day) (Fig. 1).

The data entry procedure unlocks the randomization for MET versus placebo.

Results

The Me.Me.Me. trial is ongoing and participant recruitment is underway. Among the approximately 600 volunteers who signed the informed consent, 379 are currently receiving MET/placebo treatment. No patient has completed 5 years of follow-up.

Conclusions

Obesity, inactivity and poor diet contribute to around 20% of annual mortality worldwide (28). The aim of this innovative trial is to prevent the occurrence of virtually all ArCDs through a comprehensive change of several aspects of Western lifestyle, supported by a chemopreventive agent that acts on the same genetic pathways affected by lifestyle factors. We believe that the results of the Me.Me.Me. trial will enrich efforts already implemented by the scientific community to clarify the importance of lifestyle for primary prevention and the role of MET as a potential chemopreventive agent.

Acknowledgment

We thank all the volunteers who took part in the trial. We acknowledge the help of Mrs. Daniela Del Sette in managing the participants’ data and Mrs. Patrizia Curtosi in recruitment. Thanks to Dr. Giuseppe Fornaciari for information system support and Dr. Daniele Morelli and Mr. Adalberto Cavalleri for laboratory support. We are grateful to Dr. Elena Togliardi for her support in drug storage in the institutional pharmacy and to Mrs. Maria Grazia Guerrini for editorial support.

Disclosures

Financial support: The Me.Me.Me. study is funded by an advanced grant from the European Research Council (ERC-AdG-2012 n. 322752).
Conflict of interest: The authors declare that they have no conflicts of interest.
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Authors

Affiliations

  • Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy
  • Department of Biomedical Sciences for Health, Università di Milano, Milan - Italy
  • Pharmacy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy

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