Mediterranean Diet, Circuit Resistance Training, Empagliflozin in Elderly With Type 2 Diabetes: a Study Protocol

Study Overview
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Brief Summary
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Primary objective: To assess the effects of a modified plant-based Mediterranean diet (vegeterranean diet), circuit resistance training (CRT) and empagliflozin alone or in combination on body composition and physical function in elderly subjects with type 2 diabetes. The rationale for this study is to assess three interventions associated with a negative energy/caloric balance (increased caloric use in exercise, caloric restriction in the vegeterranean diet and caloric wasting by glycosuria with empagliflozin), their interaction and effect on body composition and physical function. Methods and analysis: One hundred and twenty men and women ≥ 65 years of age with type 2 diabetes, and low levels of physical activity will be randomized (1:1:1 manner, gender-stratified) for 10 weeks to one of 3 parallel arms: CRT consisting of 3 home sessions/week; ad-libitum plant-based Mediterranean diet (limited consumption of eggs, dairy and fish, avoidance of red meat and poultry) or empagliflozin 10mg/day. After 10 weeks CRT will be added to the empagliflozin or diet arms for an additional 10 weeks. Allocation concealment and blinding of primary outcome assessors will be implemented. Efficacy will be determined by assessment of lean body mass, body weight, frailty status, sarcopenia, HbA1c and quality of life questionnaires. Safety will be evaluated by routine monitoring of adverse events. This study was approved by the Tel-Aviv Sourasky Medical Center Institutional Review Board

Official Title
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The Effect of a Circuit Resistance Training, Empagliflozin or Vegeterranean Diet on Physical and Metabolic Function in Elderly Subjects With Type 2 Diabetes: a Study Protocol for a Randomized Control Trial (CEV-65 Trial)

Conditions
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Diabetes Mellitus, Type 2, Sarcopenia, Weight Loss, Frailty

Intervention / Treatment
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* Behavioral: Circuit resistance training (CRT)
* Behavioral: Vegeterranean diet (V-Med diet)
* Drug: Empagliflozin 10 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who have type 2 diabetes mellitus in accordance with American Diabetes Association guidelines and: Are ≥65 years of age (inclusive) on the day of signing the informed consent form. Perform <2 days a week of any leisure aerobic physical activity (PA), who are able to walk independently either with or without an assistance device (cane or walker). HbA1C ≥6.5% to ≤8%. Exclusion Criteria: Recent use of steroid agents (<6 months, replacement therapy is allowed) Uncorrected hypothyroidism [thyroid stimulating hormone (TSH) > 6 mlU/L] Diagnosis of malignancy within the past 5 years except for non-melanoma skin cancer. Severe kidney disease (eGFR<45cc/ml) Active depression Recent (≤6 months) or unstable cardiovascular condition; New York Heart Association (NYHA) Class 3 or higher congestive heart failure; Subjects with PA limiting pain due to neuropathy Subjects who are in an active nutritional therapy changed their diet recently (<1 month) and/or in a weight-loss program (actively losing weight). Has other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results.

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a single center, open-label (primary outcome assessors blinded), parallel group, clinical trial of circuit resistance training for 10 weeks; V-Med diet for 10 weeks and then circuit resistance training on top of diet for 10 weeks; empagliflozin 10mg/day for 10 weeks and then circuit resistance training on top of drug therapy for 10 weeks in subjects with type 2 diabetes mellitus
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Circuit resistance training (CRT)<br>2-3 circuits * 10 exercises * 3 times per week | Behavioral: Circuit resistance training (CRT)<br>* Subjects will be allocated to CRT which consists of 10 resistance exercises for different body parts (=1 circuit) repeated 12-15 times, using modest weights (approximately 40-60% of one repetition maximum, RM). Each exercise is expected to be completed within 30-40 sec. The participant will move quickly (within 15-30 seconds) from one exercise to the next. The circuit will be repeated up to three times depending on the week of intervention. Thus, it will take about 30 min to complete an exercise session. For a summary of articles on CRT in older adults based on a meta-analysis, we performed please see: Circuit resistance training is an effective means to enhance muscle strength in older and middle-aged adults: A systematic review and meta-analysis. Ageing Res Rev. 2017 Aug;37:16-27<br>|
| Experimental: Empagliflozin 10 MG<br>10 mg once daily | Drug: Empagliflozin 10 MG<br>* Subjects allocated to empagliflozin will be asked to add empagliflozin 10mg, preferably in the morning, to their medication regimen. Subjects will be monitored for adverse events including hypoglycemic events during all study visits.<br>|
| Experimental: Vegeterranean diet (V-Med diet)<br>The modified V-Med diet will be considered as ad-libitum (using fat sources), aimed for sufficient protein from animal and mainly plant-based sources with carbohydrates limitation. | Behavioral: Vegeterranean diet (V-Med diet)<br>* The modified V-Med diet will be considered as ad-libitum (using fat sources) aimed for a minimum of 1 gr/kg/day of protein, limiting carbohydrates: 3 servings for men and 2 servings for women per main meal and 1 serving per intermediate meal for both genders. Subjects will be asked to avoid red meat and poultry completely and the consumption of dairy and eggs products will be limited to 2 servings per day. 2-3 servings of fish should be consumed during the week. The rest of protein consumption will be recommended from legumes sources. The target legume consumption will be 1.5 cup per day (2 servings per day) of cooked beans, chickpeas, lentils and/or using pulses-based flour or pulses-based bread. Consumption of whole grain carbohydrate foods will be recommended.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in body weight | Using the In-Body (720) body composition analyzer. Change in body weight (%) will be calculated as body weight at the end of 10 weeks (and 20 weeks) minus baseline body weight divided by body weight at baseline and multiplied by 100. | After 10 weeks (for all 3 arms) and after 20 weeks (for diet and drug arms only) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in fasting plasma glucose | Change in fasting plasma glucose (%) will be calculated as fasting plasma glucose (mg/dl) at the end of 10 weeks (and 20 weeks) minus baseline fasting plasma glucose divided by fasting plasma glucose at baseline and multiplied by 100. | After 10 weeks (for all 3 arms) and after 20 weeks (for diet and drug arms only) | 
| Change in sarcopenia | Sarcopenia will be assessed by results obtained in the In-Body (720) body composition analyzer, following the consensus definitions offered elsewhere (Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, et al. Sarcopenia: European consensus on definition and diagnosis. Age Ageing. 2010 Jul;39(4):412-23.). Shortly, the skeletal muscle index (SMI = skeletal muscle mass/body mass x 100) will be compared to gender-specific reference norms of young adults (aged 18-39 years). Sarcopenia will be defined as any value < 10.76 kg/m2 for men and < 6.76 kg/m2 for women. Sarcopenia change will be considered as improved vs. not improved; change from one level to the other | After 10 weeks (for all 3 arms) and after 20 weeks (for diet and drug arms only) | 
| Change in strength | Grip strength, assessed as the average of 3 readings of the dominant hand by a handheld dynamometer [Jamar® Plus+ Digital Hand Dynamometer (Jamar® Smart) 200-lb.]. Change in grip strength (%) will be calculated as grip strength at the end of 10 weeks (and 20 weeks) minus baseline grip strength divided by grip strength at baseline and multiplied by 100. | After 10 weeks (for all 3 arms) and after 20 weeks (for diet and drug arms only) | 
| Relative lean mass change | Relative lean mass change will be calculated as % lean mass (the proportion of lean mass out of weight) at the end of study minus % lean mass at baseline divided by lean mass % at baseline and multiplied by 100 | after 10 weeks (for all 3 arms) and after 20 weeks (for diet and drug arms only) | 
| Change in frailty syndrome | Will be assessed using a modification of the Fried assessment (Fried LP et al. J Gerontol A Biol Sci Med Sci. 2001 Mar 1;56(3):M146-57) based on low hand grip strength, low four meters average walking speed, low caloric expenditure on physical activity, self-reporting of extreme fatigue or low functionality and a spontaneous reduction of at least 4.5 kg in the past year. In this method, the low hand grip criterion is met when grip strength, assessed as the average of 3 readings of the dominant hand by a handheld dynamometer is less than or equal to the sex- and body mass index-specific cutoff points provided by Fried et al. The slow gait speed criterion is met if the participant scored more than 4 seconds. Frailty scores range from 0 to 5 (ie, 1 point for each component; 0 = best score, 5 = worst score) and are further categorized into: frail (3-5), pre-frail (1-2), and robust (0). Frailty change will be considered as improved vs. not improved; change from one level to the other. | After 10 weeks (for all 3 arms) and after 20 weeks (for diet and drug arms only) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Weight loss; Diabetes; Frailty; Sarcopenia