Optimization of guideline-directed medical therapies in patients with diabetes and chronic kidney disease.

Diabetes is the leading cause of chronic kidney disease (CKD) and kidney failure worldwide. CKD frequently coexists with heart failure and atherosclerotic cardiovascular disease in the broader context of cardio-kidney-metabolic syndrome. Diabetes and CKD are associated with increased risk of all-cause and cardiovascular death as well as decreased quality of life. The role of metabolic and hemodynamic abnormalities has long been recognized as an important contributor to the pathogenesis and progression of CKD in diabetes, while a more recent and growing body of evidence supports activation of both systemic and local inflammation as important contributors. Current guidelines recommend therapies targeting pathomechanisms of CKD in addition to management of traditional risk factors such as hyperglycemia and hypertension. Sodium-glucose cotransporter-2 inhibitors are recommended for treatment of patients with CKD and type 2 diabetes (T2D) if eGFR is ≥20 ml/min/173 m2 on a background of renin-angiotensin system inhibition. For patients with T2D, CKD, and atherosclerotic cardiovascular disease, a glucagon-like peptide-1 receptor agonist is recommended as additional risk-based therapy. A non-steroidal mineralocorticoid receptor antagonist is also recommended as additional risk-based therapy for persistent albuminuria in patients with T2D already treated with renin-angiotensin system inhibition. Implementation of guideline-directed medical therapies is challenging in the face of rapidly accumulating knowledge, high cost of medications, and lack of infrastructure for optimal healthcare delivery. Furthermore, studies of new therapies have focused on T2D and CKD. Clinical trials are now planned to inform the role of these therapies in people with type 1 diabetes (T1D) and CKD.

Incorporating Evidence and Guidelines for Personalized Care of Diabetes and Chronic Kidney Disease.

Chronic kidney disease (CKD) represents a particularly challenging diabetes complication. Diabetes now is responsible for half of all cases of CKD, thus making diabetes the most common cause of kidney failure worldwide. In patients with diabetes, CKD frequently coexists with heart failure and atherosclerotic cardiovascular disease, which together are associated with marked increases in the risk of cardiovascular and all-cause mortality. Fortunately, new therapeutic agents from several classes now are available with proven benefits for kidney and heart protection when used in patients with type 2 diabetes and CKD. Agents from the sodium-glucose cotransporter-2 inhibitor, glucagon-like peptide-1-receptor agonist, and nonsteroidal mineralocorticoid-receptor antagonist classes now are considered standard of care to improve kidney, heart, and overall survival outcomes in patients with type 2 diabetes. Efforts to educate health care providers on the benefits of these therapies are critically needed to help increase their utilization and improve clinical outcomes. Care decisions should be driven by a holistic view of patient priorities and goals with consideration of a multimodal therapeutic approach to maximize heart and kidney benefits.

Prescription of guideline-directed medical therapies in patients with diabetes and chronic kidney disease from the CURE-CKD Registry, 2019-2020.

AIM: Guideline-directed medical therapy (GDMT) is designed to improve clinical outcomes. The study aim was to assess GDMT prescribing rates and prescribing-persistence predictors in patients with diabetes and chronic kidney disease (CKD) from the Center for Kidney Disease Research, Education, and Hope Registry. MATERIALS AND METHODS: Data were obtained from adults ≥18 years old with diabetes and CKD between 1 January 2019 and 31 December 2020 (N = 39 158). Baseline and persistent (≥90 days) prescriptions for GDMT, including angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide 1 (GLP-1) receptor agonist were assessed. RESULTS: The population age (mean ± SD) was 70 ± 14 years, and 49.6% (n = 19 415) were women. Baseline estimated glomerular filtration rate (2021 CKD-Epidemiology Collaboration creatinine equation) was 57.5 ± 23.0 ml/min/1.73 m2 and urine albumin/creatinine 57.5 mg/g (31.7-158.2; median, interquartile range). Baseline and ≥90-day persistent prescribing rates, respectively, were 70.7% and 40.4% for ACE inhibitor/ARB, 6.0% and 5.0% for SGLT2 inhibitors, and 6.8% and 6.3% for GLP-1 receptor agonist (all p < .001). Patients lacking primary commercial health insurance coverage were less likely to be prescribed an ACE inhibitor/ARB [odds ratio (OR) = 0.89; 95% confidence interval (CI) 0.84-0.95; p < .001], SGLT2 inhibitor (OR 0.72; 95% CI 0.64-0.81; p < .001) or GLP-1 receptor agonist (OR 0.89; 95% CI 0.80-0.98; p = .02). GDMT prescribing rates were lower at Providence than UCLA Health. CONCLUSIONS: Prescribing for GDMT was suboptimal and waned quickly in patients with diabetes and CKD. Type of primary health insurance coverage and health system were associated with GDMT prescribing.

Mechanisms and clinical applications of incretin therapies for diabetes and chronic kidney disease.

PURPOSE OF REVIEW: 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. RECENT FINDING: 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. SUMMARY: 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.

Incretin Therapies for Patients with Type 2 Diabetes and Chronic Kidney Disease.

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.

Use of Glucose-Lowering Agents in Diabetes and CKD.

Diabetes is the most common cause of kidney failure worldwide. Patients with diabetes and chronic kidney disease (CKD) are also at markedly higher risk of cardiovascular disease, particularly heart failure (HF), and death. Through the processes of gluconeogenesis and glucose reabsorption, the kidney plays a central role in glucose homeostasis. Insulin resistance is an early alteration observed in CKD, worsened by the frequent presence of hypertension, obesity, and ongoing chronic inflammation, and oxidative stress. Management of diabetes in moderate to severe CKD warrants special consideration because of changes in glucose and insulin homeostasis and altered metabolism of glucose-lowering therapies. Kidney failure and initiation of kidney replacement therapy by dialysis adds to management complexity by further limiting therapeutic options, and predisposing individuals to hypoglycemia and hyperglycemia. Glycemic goals should be individualized, considering CKD severity, presence of macrovascular and microvascular complications, and life expectancy. A general hemoglobin A1c (HbA1c) goal of approximately 7% may be appropriate in earlier stages of CKD, with more relaxed targets often appropriate in later stages. Use of sodium glucose cotransporter2 (SGLT2) inhibitors and glucagon like peptide-1 receptor agonists (GLP-1RAs) meaningfully improves kidney and heart outcomes for patients with diabetes and CKD, irrespective of HbA1c targets, and are now part of guideline-directed medical therapy in this high-risk population. Delivery of optimal care for patients with diabetes and CKD will require collaboration across health care specialties and disciplines.

Clinical Evidence and Proposed Mechanisms for Cardiovascular and Kidney Benefits from Sodium-Glucose Co-transporter-2 Inhibitors.

The number of people living with type 2 diabetes (T2D) and its complications worldwide is increasing at an alarming rate. Fortunately, our understanding of the benefits of glucose-lowering agents from the sodium-glucose co-transporter-2 (SGLT2) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist classes on cardiovascular and kidney outcomes is advancing; this means we now have new options to mitigate the risks of these complications in patients with T2D. The SGLT2 inhibitors have consistently demonstrated benefits on atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and heart failure (HF) events in dedicated outcome trials. Large guidelines groups now recommend SGLT2 inhibitors as a standard of care in patients with T2D and comorbid ASCVD, CKD and/ or HF. Evolving evidence additionally indicates kidney and HF benefits of SGLT2 inhibitors in populations without diabetes. These agents likely provide heart and kidney benefits through multiple mechanisms, as their impact on heart and kidney outcomes cannot be fully explained by their direct metabolic effects. On-going work to elucidate the beneficial mechanisms at play with SGLT2 inhibitors will help further optimize these life-saving therapies in patients with and without T2D.

Overcoming Barriers to Implementing New Therapies for Diabetic Kidney Disease: Lessons Learned.

As a result of the growing number of patients with type 2 diabetes mellitus, the prevalence of diabetic kidney disease (DKD) has proven to be one of the fastest growing health care challenges globally. Early detection and initiation of appropriate interventions to slow the progression of DKD are impeded by low awareness of the health consequences of DKD, high complexity of care that includes the need for lifestyle modifications, difficulties with adhering to increasingly complicated medication regimens, and low acceptance and application of guideline-directed management. After 2 decades of status quo in the care of patients with DKD, recently approved glucose-lowering agents are promising to transform care by demonstrating slowed DKD disease progression and improved survival. As has been learned over the last 2 decades, multiple barriers exist to the optimal integration and utilization of new therapies to improve kidney outcomes. The health care community, professional societies, and regulatory agencies must join efforts to develop implementation strategies for increasing DKD awareness, detection, and treatment.

Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence.

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.

Medication use, renin-angiotensin system inhibitors, and acute care utilization after hospitalization in patients with chronic kidney disease.

OBJECTIVES: The aims of this secondary analysis were to: (a) characterize medication use following hospital discharge for patients with chronic kidney disease (CKD), and (b) investigate relationships of medication use with the primary composite outcome of acute care utilization 90 days after hospitalization. METHODS: The CKD-Medication Intervention Trial (CKD-MIT) enrolled acutely ill hospitalized patients with CKD stages 3-5 not dialyzed (CKD 3-5 ND). In this post hoc analysis, data for medication use were characterized, and the relationship of medication use with the primary outcome was evaluated using Cox proportional hazards models. RESULTS: Participants were taking a mean of 12.6 (standard deviation=5.1) medications, including medications from a wide variety of medication classes. Nearly half of study participants were taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB). ACE inhibitor/ARB use was associated with decreased risk of the primary outcome (hazard ratio=0.51; 95% confidence interval 0.28-0.95; p=0.03) after adjustment for baseline estimated glomerular filtration rate, age, sex, race, blood pressure, albuminuria, and potential nephrotoxin use. CONCLUSIONS: A large number, variety, and complexity of medications were used by hospitalized patients with CKD 3-5 ND. ACE inhibitor or ARB use at hospital discharge was associated with a decreased risk of 90-day acute care utilization.

Clinical Characteristics of and Risk Factors for Chronic Kidney Disease Among Adults and Children: An Analysis of the CURE-CKD Registry.

Importance: Chronic kidney disease (CKD) is serious and common, yet recognition and public health responses are limited. Objective: To describe clinical features of, prevalence of, major risk factors for, and care for CKD among patients treated in 2 large US health care systems. Design, Setting, and Participants: This cohort study collected data from the Center for Kidney Disease Research, Education, and Hope (CURE-CKD) registry, an electronic health record-based registry jointly curated and sponsored by Providence St Joseph Health and the University of California, Los Angeles. Patients were adults and children with CKD (excluding end-stage kidney disease) and adults at risk of CKD (ie, with diabetes, hypertension, or prediabetes) identified by laboratory values, vital signs, prescriptions, and administrative codes. Data were collected from January 2006 through December 2017, with analyses performed from March 2019 through November 2019. Exposures: Diabetes, hypertension, and prediabetes. Main Outcomes and Measures: Clinical and demographic characteristics, prevalence, and prescribed medications. Results: Of 2 625 963 adults and children in the sample, 606 064 adults (23.1%) with CKD had a median (interquartile range [IQR]) age of 70 (59-81) years, with 338 785 women (55.9%) and 434 474 non-Latino white individuals (71.7%). A total of 12 591 children (0.4%) with CKD had a median (IQR) age of 6 (1-13) years, with 7079 girls (56.2%) and 6653 non-Latino white children (52.8%). Median (IQR) estimated glomerular filtration rate was 53 (41-61) mL/min/1.73 m2 among adults and 70 (50-95) mL/min/1.73 m2 in children. Prevalence rates for CKD in adults were 4.8% overall (606 064 of 12 669 700) with 1.6% (93 644 of 6 011 129) during 2006 to 2009, 5.7% (393 455 of 6 903 084) during 2010 to 2013, and 8.4% (683 574 of 8 179 860) during 2014 to 2017 (P < .001). A total of 226 693 patients (37.4%) had category 3a CKD; 100 239 (16.5%), category 3b CKD; 39 125 (6.5%), category 4 CKD; and 20 328 (3.4%), category 5 CKD. Among adults with CKD, albuminuria and proteinuria assessments were available in 52 551 (8.7%) and 25 035 (4.1%) patients, respectively. A renin-angiotensin system inhibitor was prescribed to 124 575 patients (20.6%), and 204 307 (33.7%) received nonsteroidal anti-inflammatory drugs or proton pump inhibitors. Of 1 973 258 adults (75.1%) at risk, one-quarter had diabetes or prediabetes (512 299 [26.0%]), nearly half had hypertension (955 812 [48.4%]), and one-quarter had both hypertension and diabetes or prediabetes (505 147 [25.6%]). Conclusions and Relevance: This registry-based cohort study revealed a burgeoning number of patients with CKD and its major risk factors. Rates of identification and use of kidney protective agents were low, while potential nephrotoxin use was widespread, underscoring the pressing need for practice-based improvements in CKD prevention, recognition, and treatment.

Rationale and design of a multicenter Chronic Kidney Disease (CKD) and at-risk for CKD electronic health records-based registry: CURE-CKD.

BACKGROUND: Chronic kidney disease (CKD) is a global public health problem, exhibiting sharp increases in incidence, prevalence, and attributable morbidity and mortality. There is a critical need to better understand the demographics, clinical characteristics, and key risk factors for CKD; and to develop platforms for testing novel interventions to improve modifiable risk factors, particularly for the CKD patients with a rapid decline in kidney function. METHODS: We describe a novel collaboration between two large healthcare systems (Providence St. Joseph Health and University of California, Los Angeles Health) supported by leadership from both institutions, which was created to develop harmonized cohorts of patients with CKD or those at increased risk for CKD (hypertension/HTN, diabetes/DM, pre-diabetes) from electronic health record data. RESULTS: The combined repository of candidate records included more than 3.3 million patients with at least a single qualifying measure for CKD and/or at-risk for CKD. The CURE-CKD registry includes over 2.6 million patients with and/or at-risk for CKD identified by stricter guide-line based criteria using a combination of administrative encounter codes, physical examinations, laboratory values and medication use. Notably, data based on race/ethnicity and geography in part, will enable robust analyses to study traditionally disadvantaged or marginalized patients not typically included in clinical trials. DISCUSSION: CURE-CKD project is a unique multidisciplinary collaboration between nephrologists, endocrinologists, primary care physicians with health services research skills, health economists, and those with expertise in statistics, bio-informatics and machine learning. The CURE-CKD registry uses curated observations from real-world settings across two large healthcare systems and has great potential to provide important contributions for healthcare and for improving clinical outcomes in patients with and at-risk for CKD.