Efficacy and safety of sodium glucose cotransporter 2 inhibitors plus standard care in diabetic kidney disease: A systematic review and meta-analysis

Approximately 1 in 3 people living with type 2 diabetes develops diabetic kidney disease (DKD), formally known as diabetic nephropathy (DN), which is the most common cause of chronic and end-stage kidney disease (ESKD) 1. DKD is associated with a 3-fold increase in risk of cardiovascular disease and related mortality 2. The complex interaction between hemodynamic and metabolic pathways promotes the pathogenesis of DKD, leading to the focus on strict blood pressure and glucose control as the cornerstones of DKD prevention and treatment 3.

The benefits of blockade of the renin-angiotensin system (RAS) using angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) in delaying the development and progression of DKD have been demonstrated in 4 major randomized controlled trials (RCTs) involving ACE inhibitors and ARBs 4., 5., 6., 7.. High blood pressure and constriction of the efferent arterioles are mainly responsible for increasing intraglomerular pressure and causing structural and functional glomerular damage, ultimately resulting in proteinuria 3. Angiotensin II (Ang II) is a key mediator of the detrimental effects involved in the pathogenesis of DKD via increased oxidative stress through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and promotion of inflammation and fibrosis3. These Ang II-induced effects are ameliorated through treatment with ACE inhibitors and ARBs4., 5., 6., 7., with proteinuria reduced by 35 % in some cohorts4. ACE inhibitors reduces circulating Ang II and ARBs block the binding of Ang II to angiotensin II type 2 receptor, causing vasodilation in the efferent glomerular arterioles and therefore reducing intraglomerular pressure and hyperfiltration6. Fig. 1 summarized the underlying mechanisms and the role of ACE inhibitors and ARBs in management of DKD. Prescribing of ACE inhibitors/ ARBs is now widely recommended as ‘gold standard’ therapy in guidelines for type 2 diabetes and associated microvascular complication management 8.

Despite the use of RAS inhibition, many people with type 2 diabetes still progress to the advanced stages of kidney disease 9, highlighting the importance of new and innovative treatments to improve its management. There is now convincing evidence that sodium glucose co-transporter 2 (SGLT2) inhibitors represent a novel drug class to slow progression of kidney disease associated with type 2 diabetes. The SGLT2 co-transporter proteins in the proximal tubule are responsible for removing glucose and sodium ions from the filtrate. The macula densa detects sodium ion concentration in the tubule and signals the glomerulus to regulate the filtration rate via the tubuloglomerular feedback loop10. During hyperfiltration, SGLT2 co-transporters are upregulated, and the reabsorption of glucose and sodium ions increases. Consequently, the macula densa detects lower levels of sodium ions, and instructs the glomerulus to increase the filtration rate to increase the delivery of sodium ions to the distal tubule10. Aside from treating hyperglycemia, SGLT2 inhibitors re-establish sodium ion delivery to the macula densa10. The renoprotective effects of SGLT2 inhibitors have been reported to result from a combination of several factors including reduced glomerular hyperfiltration, constriction of the afferent arterioles in the nephron and tubular hypertrophy 11. Vasoconstriction of the afferent arteriole reduces intraglomerular pressure and reduces the amount of protein filtered through the glomerulus; otherwise known as albuminuria 12. Reducing albuminuria by 30 % has been associated with a 20 % lower risk of ESKD 13. SGLT2 inhibitors also exert favorable effects on blood pressure, body weight and cardiovascular morbidity, which may prevent complications such as DKD 14.

Currently, there is only 1 meta-analysis investigating the effects of SGLT2 inhibitors on urine albumin-to-creatinine ratio (UACR) when added to standard care with ACE inhibitors or ARBs; however this study only included 3 studies in the meta-analysis and only investigated the effects of dapagliflozin and empagliflozin 9. In light of the rapidly developing literature in this area, we performed an updated systematic review and meta-analysis of 8 RCTs, including those involving canagliflozin, to evaluate the additional benefits of SGLT2 inhibitors over and above contemporary guideline recommended therapies in DKD.

留言 (0)

沒有登入
gif