Pharmacotherapy to delay the progression of diabetic kidney disease in people with type 2 diabetes: past, present and future

Abstract

Diabetic kidney disease (DKD) is a leading cause of morbidity and mortality among people living with diabetes, and is one of the most important causes of end stage renal disease worldwide. In order to reduce progression of DKD, important management goals include treatment of hypertension, glycaemia and control of cardiovascular risk factors such as lipids, diet, smoking and exercise. Use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers has an established role in prevention of progression of DKD. A number of other agents such as endothelin-1 receptor antagonists and bardoxolone have had disappointing results. Recent studies have, however, suggested that newer antidiabetic agents such as sodium-glucose transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 analogues have specific beneficial effects in patients with DKD. Indeed most recent guidance suggest that SGLT-2i drugs should be used early in DKD, irrespective of glucose control. A number of pathways are hypothesised for the development and progression of DKD, and have opened up a number of newer potential therapeutic targets. This article aims to discuss management of DKD with respect to seminal trials from the past, more recent trials informing the present and potential new therapeutic options that may be available in the future.

Keywords: chronic kidney disease; sodium glucose transporter-2 inhibitors; type 2 diabetes.

Figure 1.

Renin angiotensin aldosterone system, its role in diabetic kidney disease and sites of inhibition. ACE Inhibitors, Angiotensin converting enzyme inhibitor; ARB, Angiotensin receptor blocker; AT-1, angiotensin II type 1 receptor; AT 2, angiotensin II type 2 receptor; DRI, direct renin inhibitor; MR, Mineralocorticoid receptor; MRA, Mineralocorticoid receptor antagonist; TGF–β, transforming growth factor-beta.

Figure 2.

Pathogenesis of diabetic kidney disease with potential interventions. ACEI, Angiotensin converting enzyme inhibitor; ARA, Adiponectin receptor agonist; ARB, Angiotensin receptor blocker; DRI, Direct renin inhibitor; GLP1-RA, Glucagon like peptide 1 receptor agonists; JAK/STAT, Janus kinase -signal transducer and activator of transcription; JAK/STAT Inh, Janus kinase -signal transducer and activator of transcription Inhibitor; Keap1/Nrf2, Kelch-like ECH-associated protein 1 -nuclear factor E2-related factor 2; MAPK/ERK, Mitogen-activated protein kinases/extracellular signal-regulated kinase; MiRNA, microRNA; MRA, Mineralocorticoid receptor antagonist; NADPH oxidase, nicotinamide adenine dinucleotide phosphate oxidase; NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; PI3 K/AKT, phosphatidylinositol 3kinase /protein kinase B; SGLT2i, Sodium glucose co-transporter 2 inhibitors; TGFβ1 I, transforming growth factor-beta 1 inhibitor.