Aims and Objectives

 

Aim:

“To Compare Remission Approaches for Type 2 Diabetes - Intensive Lifestyle Modification vs. Combination Therapy with Oral Semaglutide and Dapagliflozin as an addon to Metformin vs. a control arm receiving glimepride and vildagliptin in combination with Metformin”

Primary Objective:

1)    To determine the remission rates of Type 2 Diabetes in participants undergoing intensive lifestyle modification compared to those receiving combination therapy of oral Semaglutide and Dapagliflozin as an add-on to Metformin monotherapy, in comparison to control arm receiving glimepride and vildagliptin in combination with Metformin.

2)    Exploration of transcriptome and epigenome landscape and determine its correlation with the remission of diabetes.

3)    Determine the key pathways and proteins associated with diabetes.

Secondary Objectives:

1) To assess and compare the impact of intensive lifestyle modification, combination therapy of oral Semaglutide and Dapagliflozin, and standard medical management on the following parameters:

·                                  Glycemic control, as measured by HbA1c levels.

·                                  Weight loss and changes in body composition.

·                                  Blood pressure and lipid profile.

·                                  Quality of life and overall well-being.

2) To analyze the safety and tolerability profiles of intensive lifestyle modification, combination therapy of oral Semaglutide and Dapagliflozin, and standard medical management in participants with Type 2 Diabetes.

3) To assess the adherence and sustainability of the intensive lifestyle modification intervention and the pharmacotherapy regimens over the study duration.

4) To identify predictors of successful remission in participants undergoing each treatment approach.

5) To evaluate participant-reported outcomes, including satisfaction with treatment, treatment preferences, and perceived health improvements.

6) To assess the change in pancreatic fat pre and post intervention with MRI and MRS of Pancreas in all the groups.

7) To assess the change in level of gastrointestinal tract and Adipose tissue derived peptide levels viz. GLP1, Adiponectin, Leptin pre and post intervention among the study groups.

 

To assess the change in quality of life by pre-validated SF-36 questionnaire pre and post intervention, in both the group

 

 To assess glycemic variability and risk hypoglycemia with the help of  CGMS in both intervention and control groups prior to intervention, during intervention phase and after intervention follow up period.

To study the body composition and metabolic vascular age prior to and after intervention.

Material and Methods

 

This randomized control trial will be performed in PGIMER, a tertiary care health institute in Chandigarh UT, India. The study will be conducted in the department of Endocrinology. Ethical approval will be obtained from the ethics review committee of the institute. A written informed consent will be obtained from every participant.

 

Duration of Study: 3 years

 

Sample Size:  This is is a pilot study using this pharmacotherapy to target remission of diabetes. therefore a sample size of convenience has been choosen and a  sample size 15 in each group will be enrolled.

 

Study Subjects: This study will be conducted among type 2 diabetes mellitus patients visiting the Endocrinology and Medicine OPD of PGIMER, Chandigarh who will full fill the Inclusion and Exclusion criteria.

 

Inclusion Criteria:

 

Type 2 Diabetes Mellitus diagnosed within 2 years with

 

HbA1c <9 %.

 

Exclusion Criteria:

 

Age <18 years or > 65 years.

 

BMI<23kg/m2

 

Current Insulin/ GLP1 analogue or SGLT-2 inhibitor therapy.

 

Acute or Chronic Pancreatitis

 

History of Ketoacidosis.

Objective evidence of Diabetic Neuropathy.

 

Renal Failure defined as eGFR<60 ml/min/1.73m2.

 

24hr Urinary protein >500 mg or Albumin to Creatinine ratio >300mg/g.

 

Moderate to severe non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, diabetic maculopathy.

Liver disease defined as ALT> 3 times ULN, Bilirubin > 2 mg/dl, USG evidence of Cirrhosis.

Any major chronic illness.

 

Symptomatic Coronary artery disease/ Peripheral arterial disease/ cardiac failure/ diabetic foot/ Acute coronary syndrome <3 months duration

On steroid treatment.

 

Pregnancy / Lactation

 

Drug specific CI like MCT, MEN2.

 

Positive GAD

 

Fasting C -peptide < 0.6 ng/ml

 

Post COVID-Diabetes (onset of diabetes within 3 months of COVID)

 

Methodology:

 

All consecutive patients with type 2 DM will be recruited following fulfillment of Inclusion and exclusion criteria.

All patients will undergo baseline clinical and biochemical assessment as per proforma.

All patients will be advised lifestyle modification and dietary advice, statin therapy, blood pressure control.

All patients will be assessed for chronic diabetes related complications.

Baseline body fat composition, GLP-1 level, adiponectin, leptin level will be done for all patients.

Baseline Mixed meal tolerance test will be done for all patients.

All antidiabetic drug other than metformin will be stopped.

Metformin will be added or continued in all patients.

A run-in phase of two weeks will be given for drug washout.

Patient will be randomized in two groups by the help of random number generating software.

 

In Study group A, patients will receive Dapagliflozin 5 mg and that will be escalated to 10 mg after one week,

Semaglutide will be titrated as 3 mg for 2 weeks then 7 mg for 2 weeks and then 14 mg. If anybody developed mild gastro-intestinal complications, same titration schedule will be followed. If severe gastro-intestinal intolerance occurs following dose escalation, a more gradual escalation over 4 weeks will be tried. The maximum tolerated dose will be continued.

Metformin will be titrated to 2 gm prior to intervention with other medication.

 

Insulin will be added if glycemic target is not achieved and those patients will be included in final analysis in Intervention arm only.

Monitoring will be done every week.

 

In Study Group B, will continue to receive metformin and intensive lifestyle modification will be advised as follows,

 

Plan is to introduce raw food in their diet to achieve a ratio raw Diet (80) : Cooked Diet (20).

Fruits and salads are rich sources of raw food.

We will give the patients a diet having more of uncooked food like fruits and salads and less quantities of cooked food like chapati, dal tadka and cooked sabzi for 3 months and then we will follow the same diet with some variation for next 3 months. The dietary modifications will be such thatthese can be sustained for entire life.

The diet schedule will be as follows:

Juice Time

Sprout Time

Dryfruit Time

Coconut Water Time

Citrus Fruit Time

Lunch Time

Juice Time

Flax Seed Time

Dinner Time

 

Diet Chart is prepared in such a way that the ratio of carbohydrates, proteins and fats is maintained. All vitamins and minerals are there in the diet. Fiber content is kept high in the diet.

As this diet is followed with a discipline, following time schedule is being given with the diet:

Time	Schedule
05:30 AM	3 Glasses luke warm water
06:00 AM to 07:00 AM	Bath and Exercise
07:00 AM	Juice Time
08:30 AM	Sprout Time
10:00 AM	Dry Fruit Time
11:00 AM	Coconut Water Time
12:00 Noon	Citrus Fruit Time
01:30 PM	Lunch Time
04:00 PM	Juice Time
05:30 PM	Flaxseed Time
07:00 PM	Dinner Time

 

 

 

	Quantity	Calories ( In Kcal)
Juice Time – Bottle Gourd or Safed Petha, Juice of Karela Juice	300 ml	22
Sprout time – Moong Sabut Sprouts  Salad	100 gm 300gm	30 61
Dry Fruit Time Almonds Moong Phali Walnut Resins Apricot Fig   Pumpkin Seeds Sunflower Seeds Melon Water melon Seeds   + Cinnamon Tea ( w/o milk or sugar) + 10 Leaves each of Basil, Mint, Neem and Curry Patta	6 6 1 5 1 1   5g 5g 5g 5g	42   26          120 15 17 20   27 28 27          112 30     20
Coconut Water Time	250 ml	44
Citrus Fruit Time Amla and Mausambi	2   1	5   43
Lunch Time Salad (cucumber, carrot, reddish, beetroot etc.) Chapati Boiled Daal	700 gm   ½ 1 Cup	119   53 147
Juice Time Bottle Gourd Juice	300 ml	22
Makhane Time Fox Nut Seeds Flax Seeds Apple + 1 Cup cinnamon tea w/o milk or sugar	20 10 gm 1	18 53 90
Dinner Time Salad (cucumber, carrot, reddish, beetroot etc.) Chapati (Small) Boiled vegetable	700 gm   ½ 1 cup	119   53 45

 

 

Total Calorie Intake

Item Name	Calorie Intake
Morning Juice Time	22 Kcal
Sprout Time	91 Kcal
Dry fruit Time	252 Kcal
Coconut Water	44 Kcal
Citrus Fruit	48 Kcal
Lunch Time	319 Kcal
Evening Juice Time	22 Kcal
Makhana Time	151 Kcal
Dinner Time	217 Kcal
2 Lemons (at any time as per choice)	34 Kcal
Total	1200 Kcal

It is necessary for the patient to adopt active life style. Patients will be adviced to do atleast one hour of physical activity which will include eith brisk walk, dance , yoga or anyother work out. We will give Yoga module to the patients consisting of Asanas, Pranayam and meditation.  We have adopted Intensive Indianized Life Style (IILS) using Yog as a tool for balancing the mind. ‘Yog’ is derived from Sanskrit word ‘YUJ’ which means ‘to connect’. So in every asna being performed by the practioner, his consciousness should remain aware of the body movements. While performing any asana, we have to visualize that body part which is being used in that asana. Gradually this will lead to perfection of the asana. As BMI of these patients is >25, participants are advised to do loosening exercises so as to make the body flexible.

After taking 3 glasses luke warm water, participants are advised to do

Tadasana = 10 Times

Tiryak Tadsasana = 10 Times left side

                     10 Times right side            

Katichakrasana =  10 Times each side

                  10 times right side

If motion (potty) does not happen, then again the participant should take one more glass of luke warm water and practice.

Tadasana = 5 Times

Tiryak Tadsasana = 5 Times each side

Katichakrasana = 5 Times each side

 

After this we start with following loosening practices :

Pivot Joint Movement:

Neck Up Down = 10

Neck Left Right = 10

Neck Rotation :

Clockwise = 10

Anticlockwise = 10

Ball and Socket Joint Movement (Shoulder)

Shoulder Up and Down = 10

Shoulder Rotation = 10

Hip Joint Movement

Hip Rotation Clockwise = 10

Hip Rotation Anticlockwise = 10

Knee Movement

Knee Bending Up and Down = 10

Ankle Movement

Malasana = 3 times with 10 second rest

 

TRIKONASANA = 5 times from left side, 5 times from right side

Jumping on Toes (Feet Forward) = 30 Times | Pause | 30 Times | Pause | 30 Times

Jumping on Toes (Feet Backward) = 30 Times | Pause | 30 Times | Pause | 30 Times

Jumping on Toes (Feet Sidewise) =30 Times | Pause | 30 Times | Pause | 30 Times

Skipping = 30 Times | Pause | 30 Times | Pause | 30 Times

 

 

Sr. No	Yoga Practice		Duration
1	Prayer and Affirmation		1 Minute
2	Loosening Practices Neck bending Shoulder Movement Hip Movement Knee Movement		5 minutes
3	Yogasana		30 minutes
	Standing Postures Tadasana Tiryak Tadasana Kati Chakrasana Hastttotaanasana Pad Hastasana Trikonasana Agnisaar	Sitting Postures Bhadrasana Vajrasana Ushtrasana Shashank Asana Bhu Naman Asana Vakrasana Ardha Matsyendra Asana Janu Shirasana Paschimottansana
	Prone Postures Makrasana Bhujangasana Shalabhasana Naukasana Dhanurasana Balasana	Supine Postures Uttan Padasana Paad Chakrasana Kandharasana Halasana Chakrasana Pawan muktasana
4	Shatkriya Kapaalbhati		3 minutes
5	Pranayama Nadi Shodhan Seetkari or Sheetli Bhramari		10 minutes
6	Meditation or Yog Nidra		10 Minute
7	Thanks to the Mother Nature		1 Minute

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      

 

 

 

 

 

 

 

 

Level of Glycemic off target	Drug and Dose
0-30 mg/dl	Vildagliptin 100 mg/day
20-50 mg/dl	Vildagliptin 100 mg/day + Glimepiride 1mg
50-75 mg/dl	Vildagliptin 100 mg/day + Glimepiride 2 mg
75-100 mg/dl	Vildagliptin 100 mg/day + Glimepiride 3 mg
>100 mg/dl	Vildagliptin 100 mg/day + Glimepiride 4mg

For control arm a prespecified formulation with Glimepiride and Vildagliptin will be added as per target and actual plasma glucose level.

Group C- Vildagliptin and glimepiride will be added according to the following titrate. Patients will be advised

 

 

 

 

 

 

 

 

standard lifestyle modification i.e., 150 min of brisk walk or any other activity and 1200 Kcal diet as stated above.

Vildagliptin and Glimepiride will be started based upon the difference between the patient’s glucose values and the target values. If glucose levels are off target levels, dose titration will be done approximately as following,

Dose titration will then be done on each follow up based on glucose level. Further glycemic control if required will be done by alpha-glucosidase inhibitor. They will not be started on SGLT2 inhibitor and GLP-1 analogue. Monitoring and titration will be done each week.

Once glycemic targets i.e., FBS<100 and PPBS< 140 are achieved in both the groups, patients will be treated for a total of 24 weeks with the drugs and dose required to maintain glycemic targets.

After 24 weeks following achieving glycemic goal, therapy will be stopped in patients who have achieved HbA1c of <6.5%. All patients will undergo mixed meal challenge test, body fat composition, GLP-1 level, adiponectin, leptin level assessment.

MRI and MRS will be done in those patients who have undergone tests at baseline.

 

Quality of life will be assessed pre and post intervention in both the group by SF-36 pre-validated questionnaire.

Symptomatic and biochemical hypoglycemia and glycemic variability will be assessed in both the groups by CGMS at base line during intervention at 3 months and during post intervention follow up period.

 

Following discontinuation of drugs, patients who achieve glycemic target in both the arm will be followed monthly for 3 months and 3 monthly till the completion of this study or till FBS > 126 mg/dl or HbA1c> 6.5%, whichever come earlier.

Remission

 Patients will be deemed to be in remission who will have HbA1C of <6.5% after 3 months of stopping all the medications.

 

Patients will be called to out-patient department monthly in all the groups for dose titration and councelling.

Monthly Gpaq will be to assess adherence to lifestyle intervention.
Global physical activity questionnaire scoring will be done at baseline.

In all the groups once glycemic targets are achieved, the patients will be treated for total of 24 weeks, including dose titration time, with the same drugs and dose required to achieve glycemic target.

At the end of the 24 weeks, all drugs will be stopped for those patients achieved HbA1c of < 6.5%. All patient will undergo Mixed meal test, GLP1, Adiponectin, Leptin level assessment and Pancreatic MRI and MRS at the base line, the same will be repeated in them.