Obesity Treatment to Improve Diabetes

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.