DCRM 2.0: Multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.

Mineralocorticoid Receptor-Associated Mechanisms in Diabetic Kidney Disease and Clinical Significance of Mineralocorticoid Receptor Antagonists.

BACKGROUND: Diabetic kidney disease (DKD) is a common disorder with multiple serious clinical implications, including an increased risk of end-stage kidney disease (ESKD), cardiovascular complications, heart failure, onset or worsening of hypertension, and premature death. Patients with DKD frequently require dialysis or kidney transplantation to manage their ESKD. SUMMARY: Upregulation of the renin-angiotensin-aldosterone system is an important contributor to kidney disease progression, as highlighted by the results of trials evaluating angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with albuminuria. Increasing evidence suggests the existence of a multidirectional network that involves aldosterone, the mineralocorticoid receptor (MR), and the Ras-related C3 botulinum toxin substrate 1 (Rac1) as driving forces in the generation of reactive oxygen species and oxidative stress-induced injury in the initiation of interstitial nephritis and eventual fibrosis in chronic kidney disease and DKD. The MR is a key element of this triangle, as highlighted by the beneficial effect of MR antagonists in preventing or reducing aldosterone- or Rac1-related effects in basic science studies, and the improved patient outcomes observed in clinical studies. KEY MESSAGES: Aldosterone can promote kidney disease in diabetes via the MR and via MR-independent actions through Rac1. However, the MR remains a key element of this triangle, with clinical data supporting the use of MR antagonists in delaying the progression of kidney disease in diabetes.

Role of Primary Care Clinicians in the Management of Patients With Type 2 Diabetes and Cardiorenal Diseases.

Individuals with type 2 diabetes are at increased risk of both renal and cardiovascular events. The convergence of type 2 diabetes, chronic kidney disease, and cardiovascular disease, including heart failure, requires management by a multidisciplinary health care team. Primary care clinicians are likely to be the first and most frequent point of contact for individuals with type 2 diabetes who are at high risk of cardiorenal disease and therefore play a pivotal role in early diagnosis, establishment of effective treatment strategies, and coordination of care. This article presents a clinical perspective with multidisciplinary collaboration on a patient case representative of those seen in routine clinical practice. The authors assess reasons why patients may not receive evidence-based care and identify opportunities to initiate therapies that reduce cardiovascular and renal events in the primary care setting.

Chronic Kidney Disease and SGLT2 Inhibitors: A Review of the Evolving Treatment Landscape.

There is currently an unmet need for effective treatment of chronic kidney disease (CKD) that slows disease progression, prevents development of end-stage kidney disease and cardiovascular disease, and prolongs survival of patients with CKD. In the last 20 years, the only agents to show a reduction in the risk of CKD progression in patients with and without type 2 diabetes (T2D) were angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, but neither drug class has provided a decreased risk of all-cause mortality in patients with CKD and evidence for their use in patients with CKD without T2D is relatively limited. This review discusses the mechanisms underlying the progression of CKD, its associated risk factors, and summarizes the potential therapeutic approaches for managing CKD. There is increasing evidence to support the role of sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy in patients with CKD, including data from the designated kidney outcome trials in patients with T2D (CREDENCE) and in patients with or without T2D (DAPA-CKD). These studies showed a significant reduction in the risk of CKD progression with canagliflozin (in patients with T2D) or dapagliflozin (in patients with or without T2D), respectively, with DAPA-CKD being the first trial to show a reduced risk of all-cause mortality. On the basis of these data, individualized treatment with SGLT2 inhibitors represents a promising therapeutic option for patients with diabetic and nondiabetic CKD to slow disease progression.

Chronic kidney disease is a common condition in which the ability of the kidneys to work correctly gradually decreases over time. It is a major risk factor for a number of other serious conditions, including cardiovascular disease and end-stage kidney disease, and for early death. Several treatments have been shown to reduce the risk of chronic kidney disease progressing (particularly in patients with type 2 diabetes), but there have been no treatments that slow chronic kidney disease progression, prevent the development of end-stage kidney disease and cardiovascular disease, and prolong survival. However, evidence is now accumulating to suggest that some drugs initially developed to treat other diseases may be potential treatments for chronic kidney disease. The sodium­glucose cotransporter 2 inhibitors, which are commonly used to lower blood sugar levels in people with type 2 diabetes, are examples of such drugs. Data from two studies of sodium­glucose cotransporter 2 inhibitors­the CREDENCE study of canagliflozin in patients with chronic kidney disease and type 2 diabetes and the DAPA-CKD study of dapagliflozin in patients with chronic kidney disease with or without type 2 diabetes­have shown that these drugs reduce the risk of chronic kidney disease progression in these patients. More importantly, the DAPA-CKD study showed that patients with chronic kidney disease who were taking dapagliflozin had a reduced risk of death compared with placebo. These results show that sodium­glucose cotransporter 2 inhibitors are slowing the progression of chronic kidney disease and improve overall outcomes for properly selected patients.

DCRM Multispecialty Practice Recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

Type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF)-along with their associated risk factors-have overlapping etiologies, and two or more of these conditions frequently occur in the same patient. Many recent cardiovascular outcome trials (CVOTs) have demonstrated the benefits of agents originally developed to control T2D, ASCVD, or CKD risk factors, and these agents have transcended their primary indications to confer benefits across a range of conditions. This evolution in CVOT evidence calls for practice recommendations that are not constrained by a single discipline to help clinicians manage patients with complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. The ultimate goal for these recommendations is to be comprehensive yet succinct and easy to follow by the nonexpert-whether a specialist or a primary care clinician. To meet this need, we formed a volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM Practice Recommendations, a multispecialty consensus on the comprehensive management of the patient with complicated metabolic disease. The task force recommendations are based on strong evidence and incorporate practical guidance that is clinically relevant and simple to implement, with the aim of improving outcomes in patients with DCRM. The recommendations are presented as 18 separate graphics covering lifestyle therapy, patient self-management education, technology for DCRM management, prediabetes, cognitive dysfunction, vaccinations, clinical tests, lipids, hypertension, anticoagulation and antiplatelet therapy, antihyperglycemic therapy, hypoglycemia, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), ASCVD, HF, CKD, and comorbid HF and CKD, as well as a graphical summary of medications used for DCRM.

FATTY KIDNEY DISEASE: A NEW RENAL AND ENDOCRINE CLINICAL ENTITY? DESCRIBING THE ROLE OF THE KIDNEY IN OBESITY, METABOLIC SYNDROME, AND TYPE 2 DIABETES.

Objective: To determine whether fatty kidney disease deserves be designated as a distinct clinical entity similar to fatty liver disease. Methods: Analysis and interpretation of the literature in a novel conceptual framework. Results: The kidney contributes to hyperglycemia, hypertension, inflammatory cytokines, and thus to diabetes and metabolic syndrome. Fat accumulation in and around the kidney drives this process and contributes to progression of chronic kidney disease itself. Weight loss improves these complications of fatty kidney. Diagnosis currently must be inferred from comorbidities but ultimately should be made by imaging once the importance of fatty kidney disease is established, much like fatty liver disease. Conclusion: Fatty kidney disease merits designation as a specific clinical entity similar to fatty liver disease. Greater attention to this may help encourage research into ameliorating the negative consequences of fatty kidney disease and developing new therapies. Abbreviations: BP = blood pressure; CKD = chronic kidney disease; CT = computed tomography; ESRD = end-stage renal disease; FFA = free fatty acid; FKD = fatty kidney disease; GFR = glomerular filtration rate; MetS = metabolic syndrome; MRI = magnetic resonance imaging; NAFLD = nonalcoholic fatty liver disease; RAAS = renin-angiotensin system; SGLT2 = sodium-glucose cotransporter 2; SNS = sympathetic nervous system; T2D = type 2 diabetes; TG = triglyceride.

Efficacy of nebivolol-valsartan single-pill combination in obese and nonobese patients with hypertension.

Antihypertensive efficacy of single-pill combinations (SPCs) consisting of a ß1 -selective adrenergic blocker with vasodilatory properties via ß3 -agonism (nebivolol) and an angiotensin II receptor blocker (valsartan) was demonstrated in an 8-week phase 3 trial (NCT01508026). In this post hoc analysis, seated blood pressure, heart rate, 24-hour ambulatory blood pressure monitoring, plasma aldosterone, estimated glomerular filtration rate, and safety measures were assessed in obese (body mass index >32 kg/m2 ; n=1823) and nonobese (body mass index <27 kg/m2 ; n=847) adults with hypertension (stage I or II) treated with nebivolol-valsartan SPCs, nebivolol or valsartan monotherapy, or placebo. At week 8, reductions from baseline in blood pressure and ambulatory blood pressure monitoring were greater with SPCs and most nebivolol and valsartan monotherapy doses vs placebo regardless of obesity status. Aldosterone declined with all active treatments and estimated glomerular filtration rate remained steady. The nebivolol-valsartan 5/80 mg/d SPC was efficacious regardless of degree of obesity.

Diabetes and kidney disease: the role of sodium-glucose cotransporter-2 (SGLT-2) and SGLT-2 inhibitors in modifying disease outcomes.

Patients with type 2 diabetes (T2D) often have coexisting chronic kidney disease (CKD). However, healthy renal function is crucial in maintaining glucose homeostasis, assuring that almost all of the filtered glucose is reabsorbed by the sodium glucose cotransporters (SGLTs) SGLT-1 and SGLT-2. In diabetes, an increased amount of glucose is filtered by the kidneys and SGLT-2 is upregulated, leading to increased glucose absorption and worsening hyperglycemia. Prolonged hyperglycemia contributes to the development of CKD by inducing metabolic and hemodynamic changes in the kidneys. Due to the importance of SGLT-2 in regulating glucose levels, investigation into SGLT-2 inhibitors was initiated as a glucose-dependent mechanism to control hyperglycemia, and there are three agents currently approved for use in the United States: dapagliflozin, canagliflozin, and empagliflozin. SGLT-2 inhibitors have been shown to reduce glycated hemoglobin (A1C), weight, and blood pressure, which not only affects glycemic control, but may also help slow the progression of renal disease by impacting the underlying mechanisms of kidney injury. In addition, SGLT-2 inhibitors have shown reductions in albuminuria, uric acid, and an increase in magnesium. Caution is advised when prescribing SGLT-2 inhibitors to patients with moderately impaired renal function and those at risk for volume depletion and hypotension. Published data on slowing of the development, as well as progression of CKD, is a hopeful indicator for the possible renal protection potential of this drug class. This narrative review provides an in-depth discussion of the interplay between diabetes, SGLT-2 inhibitors, and factors that affect kidney function.

Application of direct renin inhibition to chronic kidney disease.

PURPOSE: Chronic kidney disease has serious implications with a high risk for progressive loss of renal function, increased cardiovascular events as well as a substantial financial burden. The renin-angiotensin-aldosterone system (RAAS) is activated in chronic kidney disease, especially in diabetes and hypertension, which are the leading causes of chronic kidney disease. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) decrease the rate of progression of diabetic and non-diabetic nephropathy and are recommended therapy for chronic kidney disease. METHODS: Key clinical trials supporting the use of ACE inhibitors and ARBs in chronic kidney disease are discussed. Recent developments in our understanding of RAAS biology and the use of direct renin inhibition are reviewed in the context of their potential impact on the prevention and management of chronic kidney disease. RESULTS: Despite the clinical success of ACE inhibitors and ARBs the rates of mortality and progression to renal failure remain high in these patient populations. ACE inhibitor or ARB monotherapy, in doses commonly used in clinical practice does not result in complete suppression of the RAAS. Aliskiren, a direct renin inhibitor, offers a novel approach to inhibit the RAAS in chronic kidney disease. CONCLUSIONS: High dose ARB therapy or combination therapies with ACE inhibitors and ARBs have shown beneficial effects on surrogate markers of chronic kidney disease. Early data based on urinary protein excretion rates as a surrogate marker for renal function suggest a possibly novel role for aliskiren alone or in combination with ARBs in chronic kidney disease.

Improving antihypertensive therapy in patients with diabetic nephropathy.

Nearly all patients with diabetic nephropathy have comorbid hypertension, which greatly elevates the risk for cardiovascular events. As patients are surviving longer, their risk of progressing to end-stage renal disease is increasing, particularly in patients with type 2 diabetes. Prevention of cardiovascular and renal events in this population requires diligent efforts to control blood pressure, serum glucose, and serum lipids. Improving antihypertensive therapy in patients with diabetic nephropathy relies on the following unified strategies: reducing blood pressure to <130/80 mm Hg, prescribing an agent that blocks the renin-angiotensin system, and designing an antihypertensive regimen that both reduces albuminuria and provides cardiovascular protection. A majority of patients will require three or more antihypertensive agents to achieve these objectives. Appropriate antihypertensive therapy in patients with diabetic nephropathy delays progression of renal disease and leads to substantial cost savings.