OTID: Obesity Treatment to Improve Diabetes

Sponsor

Dasman Diabetes Institute (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05390307

Collaborator

(none)

Enrollment

Location

Arms

25.3

Anticipated Duration (Months)

2.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The obesity pandemic continues unabated, one can expect to see an increase in the prevalence of TID/T2D and associated CKD. As a result, death will rise, preceded by an increase in kidney failure, requiring dialysis and renal transplantation. Innovative medical treatment may help prevent CKD across our healthcare system. The guideline of the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) suggest that patients with obesity, TID/ T2D, and CKD needed either glucagon-like peptide 1 receptor analogs (GLP1-RA) or sodium-glucose cotransport-2 inhibits (SGLT2i). The clinical trials show the benefits of these medications in TID/T2D. This study will provide evidence of discrete metabolic pathways by the GLP1RA/or SGLT2i alone or in combination contributed to metabolic control.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes	Drug: Liraglutide / Semaglutide Drug: Dapagliflozin Drug: Liraglutide or Semaglutide / Dapagliflozin Drug: Liraglutide or Semaglutide / Dapagliflozin plus intensive weight loss nutrition Other: Usual care Procedure: Bariatric surgery	N/A

Detailed Description

Obesity and CKD are linked by obesity-related insulin resistance, a prodromal state associated with impaired glucose tolerance, dyslipidemia, and hypertension, which frequently progresses to overt T1D/T2D. In a seminal 40-year follow-up study in people with a BMI

30kg/m2, the hazard ratio for end-stage kidney disease (ESKD) due to diabetes was 19.4 (95% CI 14.1-26.6). This further supports the role of diabetes in the pathogenesis of CKD. Several complimentary pathological phenomena are postulated to have a mechanistic role in the causal association between obesity, T1D/T2D, and CKD. Excess adiposity precipitate multiple stimuli, including metabolic, hypertensive, and local mechanical stress, which combine to elicit pathogenic responses causing CKD. Changes in volume, structure, and function of adipose tissue contribute to kidney injury through multiple mechanisms. Attendant glucotoxicity can provoke mesangial and tubular cell stress in the kidney through excess glycolysis-driven oxidative stress and the accumulation of advanced glycation end-products. Hyperglycaemia is implicated in the development of glomerular hypertension and hyperfiltration by enhancing proximal tubular sodium reabsorption through sodium-glucose cotransporter-2. This reduces sodium delivery to the macula densa thereby reducing vasoconstrictory tubuloglomerular feedback to the afferent arteriole. Ectopic lipid accumulation in the kidney and the presence of toxic levels of intracellular lipid metabolites (such as ceramide), drive oxidative stress, induce insulin resistance in podocytes, and lead to associated glomerular filtration barrier dysfunction. Adipose tissue stress also causes kidney injury through alterations in the profile of secreted adipokines such as Adiponectin. In humans and rodents, Adiponectin directly supports podocyte health and maintenance of glomerular permselectivity by inducing the expression of the tight junction protein 1 (TJP1) gene (also known as ZO1) and by stimulating fatty acid oxidation and ceramidase activity, which prevents lipotoxicity and oxidative stress. A mechanical role for excess adipose tissue deposition can be posited as a driver of hypertension and kidney injury in obesity. Compression of the kidney parenchyma by expanded perirenal and renal sinus fat lying deep to the renal fascia might promote sodium reclamation by slowing peritubular capillary flow and enhancing tubular solute reabsorption by the counter-current multiplier. This intricate network of metabolic pathways all conspires together to leave many patients with a combination of obesity, T1D/T2D, and CKD. The multitude of these pathways suggests that interventions should simultaneously address as many of these as possible and to date, it is unclear whether GLP1RA/SGLT2i combinations have synergistic benefits pertaining to these pathways.

This study also showed sustained weight loss for decades following bariatric surgery and profound improvements in metabolic control. Weight loss is a dominant mechanism for improving peripheral insulin resistance and glycaemic control after bariatric surgery, but several additional weight-loss-independent mechanisms also contribute. A randomized controlled trial in humans established that obesity, T1D/T2D, and early CKD can be placed into remission by bariatric surgery. The study confirmed that remission of hypertension is another putative renoprotective effect of bariatric surgery. Also demonstrated by transcriptomic analysis of the kidney that bariatric surgery profoundly impacts multiple fibrosis, inflammation, and metabolic pathways implicated in the progression of obesity, T1D/T2D, and CKD. This will allow the investigators to use bariatric surgery as a gold standard and control group in this project.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

72 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

A randomised controlled trial in people aged between 21-65 years, have a BMI above 27kg/m2, and have Type 1 Diabetes with Chronic Kidney Disease. Sixty participantswill be randomised to receive one of 5 possible treatments i) usual care, ii) GLP1RA alone, iii) SGLT2i alone, iv) the combination of GLP1RA and SGLT2i, v) the combination of GLP1RA, SGLT2i and intensive weight loss. Twelve matched patients undergoing bariatric surgery will also be selected for this study.A randomised controlled trial in people aged between 21-65 years, have a BMI above 27kg/m2, and have Type 1 Diabetes with Chronic Kidney Disease. Sixty participantswill be randomised to receive one of 5 possible treatments i) usual care, ii) GLP1RA alone, iii) SGLT2i alone, iv) the combination of GLP1RA and SGLT2i, v) the combination of GLP1RA, SGLT2i and intensive weight loss. Twelve matched patients undergoing bariatric surgery will also be selected for this study.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Obesity Treatment to Improve Diabetes

Anticipated Study Start Date :

May 22, 2022

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Jul 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GLP1RA alone Participants in the GLP1RA will be prescribed either Liraglutide 3.0mg or Semaglutide 1.0mg, whichever is licensed and available locally. The dose and titration will follow the usual clinical practice. The treatment will continue for 6 months.	Drug: Liraglutide / Semaglutide Liraglutide 3mg once daily or semaglutide 1mg once weekly subcutaneous injection for 6 months. Other Names: GLP1RA
Experimental: SGLT2i alone Participants in the SGLT2i group will be prescribed dapagliflozin 5-10mg once daily for 6 months.	Drug: Dapagliflozin Dapagliflozin 5-10 mg once daily for 6 months. Other Names: SGLT2i
Experimental: GLP1RA/SGLT2i combination Participants in the combination GLP1RA and SGLT2i group will be prescribed liraglutide 3mg once daily or semaglutide1mg once weekly subcutaneous injection plus dapagliflozin 5-10mg for 6 months.	Drug: Liraglutide or Semaglutide / Dapagliflozin Combined treatment with Liraglutide 3mg once daily or semaglutide 1mg once weekly subcutaneous injection plus Dapagliflozin 5-10 mg once daily for 6 months. Other Names: Combination of GLP1RA and SGLT2i
Experimental: GLP1RA/SGLT2i combination with intensive nutrition program Participants in the combination GLP1RA and SGLT2i and intensive weight loss groupwill be prescribed liraglutide 3mg once daily or semaglutide 1mg once weekly subcutaneous injection plus dapagliflozin 5-10mg together with an intensive dietary and lifestyle approach for 6 months. This typically involves dietary advice to reduce energy intake (and may includea period of partial or total meal replacement), accompanied -if available -by a physical activity programme, both supported by behavioural change techniqueswith regular professional contacts.	Drug: Liraglutide or Semaglutide / Dapagliflozin plus intensive weight loss nutrition Liraglutide 3mg once daily or semaglutide 1mg once weekly subcutaneous injection plus Dapagliflozin 5-10 mg once daily for 6 months combined with intensive nutrition for weight loss. Other Names: Combination of GLP1RA, SGLT2i and intensive weight loss nutrition
Experimental: Usual Care Participants in the usual care arm will follow the best medical care by following the international guidelines for 6 months. This usually involves diet and exercise advice.	Other: Usual care Follow up guideline with usual care
Experimental: Bariatric surgery Matched patients undergoing bariatric surgery.	Procedure: Bariatric surgery Participants in the bariatric surgery group are those who are undergoing bariatric surgery as per their usual medical care.

Outcome Measures

Primary Outcome Measures

Weight [6 months]
Absolute change in weight (kg) from baseline

Secondary Outcome Measures

Glycaemia [6 months]
Change in HbA1c
Hypertension [6 months]
Change in systolic and diastolic blood pressure
Lipidaemia [6 months]
Change in lipid profile
Albuminuria [6 months]
Change in ACR
eGFR [6 months]
Change in iohexol clearance

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

inclusion criteria:

To be considered eligible to participate in this study, a patient must:

Be aged between 21-65 years,
Have a BMI ≥ 25 kg/m2,
Have established diagnosis of Type 1 Diabetes
Have established diagnosis of Chronic Kidney Disease(not applicable to patients undergoing bariatric surgery)
Able to give informed consent