Diabetic kidney disease develops in approximately 40% of patients who are diabetic and is the leading cause of CKD worldwide. Although ESRD may be the most recognizable consequence of diabetic kidney ...disease, the majority of patients actually die from cardiovascular diseases and infections before needing kidney replacement therapy. The natural history of diabetic kidney disease includes glomerular hyperfiltration, progressive albuminuria, declining GFR, and ultimately, ESRD. Metabolic changes associated with diabetes lead to glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Despite current therapies, there is large residual risk of diabetic kidney disease onset and progression. Therefore, widespread innovation is urgently needed to improve health outcomes for patients with diabetic kidney disease. Achieving this goal will require characterization of new biomarkers, designing clinical trials that evaluate clinically pertinent end points, and development of therapeutic agents targeting kidney-specific disease mechanisms (
, glomerular hyperfiltration, inflammation, and fibrosis). Additionally, greater attention to dissemination and implementation of best practices is needed in both clinical and community settings.
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease in the United States and the world alike, and there is a great unmet need for treatments to reduce DKD development and ...progression. Inhibition of sodium/glucose co-transporter 2 (SGLT2) in the proximal tubule of the kidney has emerged as an effective antihyperglycemic treatment, leading to regulatory approval of several first-generation SGLT2 inhibitors for the treatment of type 2 diabetes. In follow-on clinical trials for the cardiovascular safety of the SGLT2 inhibitors, secondary effects to prevent or reduce albuminuria and decline in estimated glomerular filtration rate spurred further investigation into their potential application in DKD. This review summarizes the current understanding of mechanisms by which SGLT2 inhibitors block glucose reabsorption in the proximal tubule and improve systemic glucose homeostasis, the hypothesized mechanisms for kidney-protective effects of SGLT2 inhibition, and current recommendations for use of this class of antihyperglycemic agents in diabetic patients with low estimated glomerular filtration rates. Results of ongoing clinical trials in patients with DKD are eagerly awaited to expand knowledge of how SGLT2 inhibitors might be used for prevention and treatment.
As the prevalence of diabetes continues to climb, the number of individuals living with diabetic complications will reach an unprecedented magnitude. The emergence of new glucose-lowering agents - ...sodium-glucose cotransporter 2 inhibitors and incretin therapies - has markedly changed the treatment landscape of type 2 diabetes mellitus. In addition to effectively lowering glucose, incretin drugs, which include glucagon-like peptide 1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, can also reduce blood pressure, body weight, the risk of developing or worsening chronic kidney disease and/or atherosclerotic cardiovascular events, and the risk of death. Although kidney disease events have thus far been secondary outcomes in clinical trials, an ongoing phase III trial in patients with diabetic kidney disease will test the effect of a GLP1R agonist on a primary kidney disease outcome. Experimental data have identified the modulation of innate immunity and inflammation as plausible biological mechanisms underpinning the kidney-protective effects of incretin-based agents. These drugs block the mechanisms involved in the pathogenesis of kidney damage, including the activation of resident mononuclear phagocytes, tissue infiltration by non-resident inflammatory cells, and the production of pro-inflammatory cytokines and adhesion molecules. GLP1R agonists and DPP4 inhibitors might also attenuate oxidative stress, fibrosis and cellular apoptosis in the kidney.
Diabetic kidney disease (DKD) is now the principal cause of chronic kidney disease leading to end-stage kidney disease worldwide. As a primary contributor to the excess risk of all-cause and ...cardiovascular death in diabetes, DKD is a major contributor to the progressively expanding global burden of diabetes-associated morbidity and mortality. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a newer class of antihyperglycemic agents that exert glucose-lowering effects via glycosuric actions. Preclinical studies and clinical trials of SGLT2 inhibitors have consistently demonstrated reduction of albuminuria and preservation of kidney function. In particular, SGLT2 inhibitors lower risk of congestive heart failure, a major cardiovascular complication in DKD. This Perspective summarizes proposed mechanisms of action for SGLT2 inhibitors, integrates these data with results of recent cardiovascular outcomes trials, and discusses clinical applications for patients with DKD. The American Diabetes Association/European Association for the Study of Diabetes Consensus Report published online in October 2018 recommends SGLT inhibitors as preferred add-on therapy for patients with type 2 diabetes and established cardiovascular disease or chronic kidney disease, if kidney function is adequate. Results of the ongoing and just completed clinical trials conducted in patients with established DKD will facilitate further refinement of current guidelines.
Diabetic kidney disease is among the most frequent complications of diabetes, with approximately 50% of patients with ESRD attributed to diabetes in developed countries. Although intensive glycemic ...management has been shown to delay the onset and progression of increased urinary albumin excretion and reduced GFR in patients with diabetes, conservative dose selection and adjustment of antihyperglycemic medications are necessary to balance glycemic control with safety. A growing body of literature is providing valuable insight into the cardiovascular and renal safety and efficacy of newer antihyperglycemic medications in the dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, and sodium-glucose cotransporter 2 inhibitor classes of medications. Ongoing studies will continue to inform future use of these agents in patients with diabetic kidney disease.
Diabetic kidney disease (DKD), one of the most common and severe microvascular complications of diabetes, is the leading cause of chronic kidney disease and end-stage kidney disease worldwide. Since ...the development of renin-angiotensin system inhibition nearly three decades ago, no new therapeutic agents have received regulatory approval for treatment of DKD. Glucagon-like peptide-1 (GLP-1) receptor agonists, a class of newer antihyperglycemic agents, have shown promise for prevention of DKD onset and progression. This perspective summarizes clinical and experimental observations to give insight into biological mechanisms beyond glycemic control, such as natriuresis and anti-inflammatory actions, for preservation of kidney function in patients with diabetes.
Since the early 2000s, an influx of novel glucose-lowering agents has changed the therapeutic landscape for treatment of diabetes and diabetes-related complications. Glucagon-like peptide-1 (GLP-1) ...receptor agonists represent an important therapeutic class for the management of type 2 diabetes (T2D), demonstrating benefits beyond glycemic control, including lowering of blood pressure and body weight, and importantly, decreased risk of development of new or worsening chronic kidney disease (CKD) and reduced rates of atherosclerotic cardiovascular events. Plausible non-glycemic mechanisms that benefit the heart and kidneys with GLP-1 receptor agonists include anti-inflammatory and antioxidant effects. Further supporting their use in CKD, the glycemic benefits of GLP-1 receptor agonists are preserved in moderate-to-severe CKD. Considering current evidence, major guideline-forming organizations recommend the use of GLP-1 receptor agonists in cases of T2D and CKD, especially in those with obesity and/or in those with high cardiovascular risk or established heart disease. Evidence continues to build that supports benefits to the heart and kidneys of the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide. Ongoing outcome and mechanistic studies will continue to inform our understanding of the role of GLP-1 and dual GLP-1/GIP receptor agonists in diverse patient populations with kidney disease.
Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Development of DKD increases risks for cardiovascular events and death. Glucagon-like peptide-1 (GLP-1) receptor ...agonist have demonstrated improved cardiovascular and kidney outcomes in large-scale clinical trials.
GLP-1 and dual GLP-1/glucose-depending insulinotropic polypeptide (GIP) receptor agonists have robust glucose-lowering efficacy with low risk of hypoglycemia even in advanced stages of DKD. Initially approved as antihyperglycemic therapies, these agents also reduce blood pressure and body weight. Cardiovascular outcome and glycemic lowering trials have reported decreased risks of development and progression of DKD and atherosclerotic cardiovascular events for GLP-1 receptor agonists. Kidney and cardiovascular protection is mediated partly, but not entirely, by lowering of glycemia, body weight, and blood pressure. Experimental data have identified modulation of the innate immune response as a biologically plausible mechanism underpinning kidney and cardiovascular effects.
An influx of incretin-based therapies has changed the landscape of DKD treatment. GLP-1 receptor agonist use is endorsed by all major guideline forming organizations. Ongoing clinical trials and mechanistic studies with GLP-1 and dual GLP-1/GIP receptor agonists will further define the roles and pathways for these agents in the treatment of DKD.
This study showed that despite a recent decline, a high incidence of CKD in the United States persists. The incidence was lower among White adults with diabetes than among most other adults with ...diabetes.
PDF
