Obesity Treatment to Improve Diabetes
- Conditions
- Type 1 Diabetes
- Interventions
- Registration Number
- NCT05390307
- Lead Sponsor
- Dasman Diabetes Institute
- Brief Summary
As 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 chronic kidney disease (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 inhibitors (SGLT2i). If neither achieve metabolic control, then the recommendation is to combine both drugs. The evidence base for combining GLP1RA and SGLT2i are not well developed, and hence the impact of the guidelines are limited. This study will provide evidence of discrete metabolic pathways by the GLP1RA/or SGLT2i alone or in combination contributed to metabolic control. The aim of this randomised control trial (RCT) is to test the impact of the combination of GLP1RA/SGLT2i on body weight and kidney damage, in patients with T1DM and CKD. In addition, we will explore associated changes in metabolic pathways with each of the treatments used in the RCT.
- 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.
Many studies have also shown 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 meta-analysis of 1913 patients in 7 clinical trials with T2D suggests that GLP1RA/SGLT2i combination therapy had greater reduction in weight of 2.6 kg, HbA1c of 0.6%, and systolic blood pressure of 4.1 mmHg compared to GLP1RA alone and a greater reduction of weight by 1.8 kg, HbA1c by 0.9%, and systolic blood pressure by 2.7 mmHg compared to SGLT2i alone. The studies were not adequately powered to examine CKD or mortality.
Additional analysis of Canagliflozin Cardiovascular Assessment Study (CANVAS) in patients with obesity, T2DM, and CKD used randomized treatment by subgroup interaction to compare the effects of Canagliflozin versus placebo across subgroups defined by baseline use of GLP1RA or not. There were 10,142 patients, of whom 407 (4%) used GLP1RA at baseline. The subgroup of patients with GLP1RA/ SGLT2i combinations had the best outcomes as regards to weight loss, glycaemic improvements, and blood pressure changes compared with the other 3 subgroups (i) no GLP1RA or SGLT2i, (ii) only GLP1RA, and (iii) only SGLT2i. This was the first evidence of a potential synergistic effect of combining GLP1RA and SGLT2i, although there are no trial data specifically designed to describe the effects of this combination. This study together with ADA and EASD guidelines advising clinicians to consider combining GLP1RA and SGLT2i, makes an urgent case for better mechanistic understanding. Identification of such discrete pathways will be a breakthrough.
The aim of this RCT is to test the impact of the combination of GLP1RA/SGLT2i on body weight and kidney damage, in patients with T1DM and CKD. In addition, we will explore associated changes in metabolic pathways with each of the treatments used in the RCT. We will also compare patients in the RCT with patients undergoing bariatric surgery as an exploratory study.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 60
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description GLP1RA/SGLT2i combination with intensive lifestyle changes Liraglutide or Semaglutide / Dapagliflozin plus intensive weight loss nutrition 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. GLP1RA alone Liraglutide / Semaglutide 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. Usual Care 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. SGLT2i alone Dapagliflozin Participants in the SGLT2i group will be prescribed dapagliflozin 5-10mg once daily for 6 months. GLP1RA/SGLT2i combination Liraglutide or Semaglutide / Dapagliflozin 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.
- Primary Outcome Measures
Name Time Method Weight 26 weeks Percentage change in total body weight
- Secondary Outcome Measures
Name Time Method Hypertension 26 weeks Change in systolic and diastolic blood pressure
Weight change 26 weeks Proportion of participants reaching total body weight loss of ≥5%, ≥10% and ≥15%
Glycaemia 26 weeks Change in HbA1c
Waist circumference 26 weeks Change in waist circumference
Lipidaemia 26 weeks Change in lipid profile
Albuminuria 26 weeks Change in albumin creatinine ratio
Trial Locations
- Locations (1)
Dasman Diabetes Institute
🇰🇼Kuwait City, Al Asimah, Kuwait