Ignite Creation Date:
2024-05-06 @ 5:41 PM
Last Modification Date:
2024-10-26 @ 2:33 PM
Study NCT ID:
NCT05390307
Status:
COMPLETED
Last Update Posted:
2024-02-28
First Post:
2022-05-14
Brief Title:
Obesity Treatment to Improve Diabetes
Sponsor:
Dasman Diabetes Institute
Organization:
Dasman Diabetes Institute
Study Overview
Official Title:
Obesity Treatment to Improve Diabetes
Status:
COMPLETED
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
OTID
Brief Summary:
As the obesity pandemic continues unabated one can expect to see an increase in the prevalence of TIDT2D 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 GLP1RAor 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 GLP1RASGLT2i 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 T1DT2D In a seminal 40-year follow-up study in people with a BMI 30kgm2 the hazard ratio for end-stage kidney disease ESKD due to diabetes was 194 95 CI 141-266 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 T1DT2D 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 T1DT2D 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 GLP1RASGLT2i 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 GLP1RASGLT2i combination therapy had greater reduction in weight of 26 kg HbA1c of 06 and systolic blood pressure of 41 mmHg compared to GLP1RA alone and a greater reduction of weight by 18 kg HbA1c by 09 and systolic blood pressure by 27 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 10142 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 GLP1RASGLT2i 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
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 GLP1RASGLT2i combination therapy had greater reduction in weight of 26 kg HbA1c of 06 and systolic blood pressure of 41 mmHg compared to GLP1RA alone and a greater reduction of weight by 18 kg HbA1c by 09 and systolic blood pressure by 27 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 10142 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 GLP1RASGLT2i 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None