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IMPORTANCE: Previous studies have reported an association between hypoglycemia and cardiovascular (CV) events in people with type 2 diabetes (T2D), but it is unclear if this association is causal or identifies a high-risk patient phenotype. OBJECTIVE: To evaluate the associations between hypoglycemia and CV outcomes. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis was a post hoc assessment of the multinational, double-blind CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin; 2013-2016) and CAROLINA (Cardiovascular Outcome Trial of Linagliptin vs Glimepiride in Type 2 Diabetes; 2010-2018) randomized clinical trials of the antihyperglycemic drug, linagliptin, a dipeptidyl peptidase 4 inhibitor. Participants were adults with T2D at high CV risk with or without high kidney risk. By design, participants in the CARMELINA trial had longer duration of T2D and had a higher CV risk than participants in the CAROLINA trial. Data analyses were conducted between June 2021 and June 2023. INTERVENTION: Linagliptin or placebo in the CARMELINA trial, and linagliptin or glimepiride in the CAROLINA trial. MAIN OUTCOMES AND MEASURES: The primary outcome for both trials was CV death, myocardial infarction (MI), or stroke (3-point major adverse CV events [3P-MACE]). For the present analyses, hospitalization for heart failure (HF) was added. Hypoglycemia was defined as plasma glucose less than 54 mg/dL or severe hypoglycemia (episodes requiring the assistance of another person). Associations between the first hypoglycemic episode and subsequent CV events and between nonfatal CV events (MI, stroke, hospitalization for HF) and subsequent hypoglycemic episodes were assessed using multivariable Cox proportional hazards regression models. Sensitivity analyses explored the risk of CV events within 60 days after each hypoglycemic episode. RESULTS: In the CARMELINA trial (6979 patients; 4390 males [62.9%]; mean [SD] age, 65.9 [9.1] years), there was an association between hypoglycemia and subsequent 3P-MACE plus hospitalization for HF (hazard ratio [HR], 1.23; 95% CI, 1.04-1.46) as well as between nonfatal CV events and subsequent hypoglycemia (HR, 1.39; 95% CI, 1.06-1.83). In the CAROLINA trial (6033 patients; 3619 males (60.0%); mean [SD] age, 64.0 [9.5] years), there was no association between hypoglycemia and subsequent 3P-MACE plus hospitalization for HF (HR, 1.00; 95% CI, 0.76-1.32) and between nonfatal CV events and subsequent hypoglycemia (HR, 1.44; 95% CI, 0.96-2.16). In analyses of CV events occurring within 60 days after hypoglycemia, there was either no association or too few events to analyze. CONCLUSIONS AND RELEVANCE: This study found bidirectional associations between hypoglycemia and CV outcomes in the CARMELINA trial but no associations in either direction in the CAROLINA trial, challenging the notion that hypoglycemia causes adverse CV events. The findings from the CARMELINA trial suggest that both hypoglycemia and CV events more likely identify patients at high risk for both. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01897532 (CARMELINA) and NCT01243424 (CAROLINA)

Glucagon like peptide-1 (GLP-1) is a hormone produced and released by cells of the gastrointestinal tract following meal ingestion. GLP-1 receptor agonists (GLP-1RA) exhibit kidney-protective actions through poorly understood mechanisms. Here we interrogated whether the receptor for advanced glycation end products (RAGE) plays a role in mediating the actions of GLP-1 on inflammation and diabetic kidney disease. Mice with deletion of the GLP-1 receptor displayed an abnormal kidney phenotype that was accelerated by diabetes and improved with co-deletion of RAGE in vivo. Activation of the GLP-1 receptor pathway with liraglutide, an anti-diabetic treatment, downregulated kidney RAGE, reduced the expansion of bone marrow myeloid progenitors, promoted M2-like macrophage polarization and lessened markers of kidney damage in diabetic mice. Single cell transcriptomics revealed that liraglutide induced distinct transcriptional changes in kidney endothelial, proximal tubular, podocyte and macrophage cells, which were dominated by pathways involved in nutrient transport and utilization, redox sensing and the resolution of inflammation. The kidney-protective action of liraglutide was corroborated in a non-diabetic model of chronic kidney disease, the subtotal nephrectomised rat. Thus, our findings identify a novel glucose-independent kidney-protective action of GLP-1-based therapies in diabetic kidney disease and provide a valuable resource for exploring the cell-specific kidney transcriptional response ensuing from pharmacological GLP-1R agonism.

Y-box–binding protein 1 is a well-described and important regulator of gene transcription, which is linked to various pathologic conditions, including inflammation and fibrosis of the kidney. The identification of a novel and protective crosstalk pathway between podocytes and tubular cells in the kidney with Y-box–binding protein 1 acting as a paracrine messenger sheds new light and provides novel opportunities for renoprotection.

Evidence has demonstrated that albuminuria is a key diagnostic and prognostic marker of diabetic chronic kidney disease, but the impact of its day-to-day variability has not been adequately considered. This study quantified within-individual variability of albuminuria in people with type 2 diabetes to inform clinical albuminuria monitoring.

ABSTRACTIntroductionDiabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD) worldwide. Currently, there is no effective treatment to completely prevent DKD progression to ESRD. Renal fibrosis and inflammation are the major pathological features of DKD, being pursued as potential therapeutic targets for DKD.Areas coveredInflammation and renal fibrosis are involved in the pathogenesis of DKD. Anti-inflammatory drugs have been developed to combat DKD but without efficacy demonstrated. Thus, we have focused on the mechanisms of TGF-β-induced renal fibrosis in DKD, as well as discussing the important molecules influencing the TGF-β signaling pathway and their potential development into new pharmacotherapies, rather than targeting the ligand TGF-β and/or its receptors, such options include Smads, microRNAs, histone deacetylases, connective tissue growth factor, bone morphogenetic protein 7, hepatocyte growth factor, and cell division autoantigen 1.Expert opinionTGF-β is a critical driver of renal fibrosis in DKD. Molecules that modulate TGF-β signaling rather than TGF-β itself are potentially superior targets to safely combat DKD. A comprehensive elucidation of the pathogenesis of DKD is important, which requires a better model system and access to clinical samples via collaboration between basic and clinical researchers.

ABSTRACTIntroductionDiabetic kidney disease (DKD) remains a major cause of morbidity and mortality in diabetes and is a key cause of end-stage kidney disease (ESKD) worldwide. Major clinical advances have been confirmed in large trials demonstrating renoprotection, adding to the benefits of existing intensive glucose and blood pressure control therapies. Furthermore, there are exciting new treatments predominantly at an experimental and early clinical phase which appear promising.Areas coveredThe authors review DKD in the context of existing and emerging therapies affording cardiorenal benefits including SGLT2 inhibitors and GLP-1 receptor agonists. They explore novel therapies demonstrating potential including a newly developed mineralocorticoid receptor antagonist and endothelin receptor blockade, while evaluating the utility of DPP4 inhibitors in current clinical practice. They also consider the recent evidence of emerging therapies targeting metabolic pathways with enzyme inhibitors, anti-fibrotic agents, and agents modulating transcription factors.Expert opinionSignificant improvements have been made in the management of DKD with SGLT2i and GLP-1 agonists providing impressive renoprotection, with novel progress in renin–angiotensin–aldosterone system (RAAS) blockade with finerenone. There is also great potential for several new experimental therapies. These advances provide us with optimism that the outlook of this devastating condition will continue to improve.

To investigate the relationship between serum uric acid (SUA) level and renal outcome in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN).A total of 393 Chinese patients with T2DM and biopsy-proven DN and followed at least 1 year were enrolled in this study. Patients were stratified by the quartiles of baseline level of SUA: Q1 group: 286.02 ± 46.66 μmol/L (n= 98); Q2 group: 358.23 ± 14.03 μmol/L (n= 99); Q3 group: 405.50 ± 14.59 μmol/L (n= 98) and Q4 group: 499.14 ± 56.97μmol/L (n= 98). Renal outcome was defined by progression to end-stage renal disease (ESRD). Kaplan–Meier survival analysis and Cox proportional hazards model were used to analyze the association between SUA quartiles and the renal outcomes.During the median 3-year follow-up period, there were 173 ESRD outcome events (44.02%). No significant difference between SUA level and the risk of progression of DN (P= 0.747) was shown in the Kaplan–Meier survival analysis. In multivariable-adjusted model, hazard ratios for developing ESRD were 1.364 (0.621–2.992; P= 0.439), 1.518 (0.768–3.002; P= 0.230) and 1.411 (0.706–2.821; P= 0.330) for the Q2, Q3 and Q4, respectively, in comparison with the Q1 (P= 0.652).No significant association between SUA level and renal outcome of ESRD in Chinese patients with T2DM and DN was found in our study. Besides, the role of uric acid-lowering therapy in delaying DN progression and improving ESRD outcome had not yet been proven. Further study was needed to clarify the renal benefit of the uric acid-lowering therapy in the treatment of DN.

Failure to resolve inflammation underlies many prevalent pathologies. Recent insights have identified lipid mediators, typified by lipoxins (LXs), as drivers of inflammation resolution, suggesting potential therapeutic benefit. We report the asymmetric preparation of novel quinoxaline-containing synthetic-LXA4-mimetics (QNX-sLXms). Eight novel compounds were screened for their impact on inflammatory responses. Structure–activity relationship (SAR) studies showed that (R)-6(also referred to as AT-02-CT) was the most efficacious and potent anti-inflammatory compound of those tested. (R)-6significantly attenuated lipopolysaccharide (LPS)- and tumor-necrosis-factor-α (TNF-α)-induced NF-κB activity in monocytes and vascular smooth muscle cells. The molecular target of (R)-6was investigated. (R)-6activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of (R)-6were further investigated in vivoin murine models of acute inflammation. Consistent with in vitroobservations, (R)-6attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm (R)-6in the context of novel inflammatory regulators.

ABSTRACTIntroduction: Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in diabetes and is the most common cause of proteinuric and non-proteinuric forms of end-stage renal disease (ESRD). Control of risk factors such as blood glucose and blood pressure is not always achievable or effective. Significant research efforts have attempted to understand the pathophysiology of DKD and develop new therapies.Areas covered: We review DKD pathophysiology in the context of existing and emerging therapies that affect hemodynamic and metabolic pathways. Renin-angiotensin system (RAS) inhibition has become standard care. Recent evidence for renoprotective activity of SGLT2 inhibitors and GLP-1 agonists is an exciting step forward while endothelin receptor blockade shows promise. Multiple metabolic pathways of DKD have been evaluated with varying success; including mitochondrial function, reactive oxygen species, NADPH oxidase (NOX), transcription factors (NF-B and Nrf2), advanced glycation, protein kinase C (PKC), aldose reductase, JAK-STAT, autophagy, apoptosis-signaling kinase 1 (ASK1), fibrosis and epigenetics.Expert opinion: There have been major advances in the understanding and treatment of DKD. SGLT2i and GLP-1 agonists have demonstrated renoprotection, with novel therapies under evaluation. Addressing the interaction between hemodynamic and metabolic pathways may help achieve prevention, attenuation or even reversal of DKD.

Evidence from clinical trials to guide patient preparation for maintenance dialysis therapy is limited. Although anemia is associated with mortality and cardiovascular (CV) disease in individuals initiating maintenance dialysis therapy, it is not known if treatment of anemia before dialysis therapy initiation with erythropoiesis-stimulating agents alters outcomes.

Summary:Diabetic kidney disease commonly is associated with an increased risk of cardiovascular disease. There are traditional common risk factors for both conditions including hypertension and poor glycemic control. However, it is likely that there are other pathophysiological mechanisms that explain the clinical phenomenon of increased cardiovascular disease in diabetic patients with chronic kidney and vice versa. Current management of both conditions includes aggressive glucose and blood pressure control. The protective role of treating dyslipidemia has been shown for cardiovascular disease, but the results for renal disease are not as clear. The advent of new classes of glucose-lowering agents such as sodium glucose co-transporter2 inhibitors and glucagon-like peptide-1 agonists has resulted in impressive effects on both cardiovascular and renal disease in diabetes. However, how these drugs act independently of glucose lowering to confer both kidney and cardiovascular protection has not been fully elucidated. Nevertheless, these new treatments provide optimism for reducing both microvascular and macrovascular complications in diabetes, which represent the major causes of morbidity and premature mortality in this condition.

Hypertension is highly prevalent among people with diabetes, and the presence of diabetes among those with hypertension portends an increase in cardiovascular risk. In this review we aim to explore the pathophysiological links between diabetes and hypertension. Renal sodium handling differs in diabetes because there is an upregulation of sodium transporters in the kidneys. The renin-angiotensin-aldosterone system may be upregulated in diabetes, leading to hypertension through a direct effect mediated by angiotensin II, as well as indirectly through upregulation of sympathetic activity. Renin-angiotensin-aldosterone system blockade is a mainstay therapy for hypertension, and evidence suggests that it might also reduce the incidence of diabetes. People with diabetes frequently have autonomic dysfunction, which could contribute to hypertension through increased sympathetic tone and through stimulation of renin production in the juxtaglomerular apparatus. Furthermore, people with diabetes also frequently show an abnormality in their circadian blood pressure pattern. Another important link between hypertension and diabetes is the development as well as progression of diabetic kidney disease, the pathophysiology of which is mediated through several pathways including endothelial dysfunction and advanced glycation end products. Finally, obesity and the metabolic syndrome, through their effects on various hormones and inflammation, might also contribute to the pathogenesis of hypertension and diabetes.

The prevalence of diabetes mellitus is increasing and is associated with a range of complications including nephropathy. New antidiabetic agents are sought which also have positive effects to diminish diabetic complications. Examples of promising new classes of such agents are glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter 2 inhibitors. In addition to cardiovascular protective effects such as weight loss and decreased blood pressure of some of these agents, there is evidence for renoprotective effects with these agents. This review elaborates on the main results of renoprotective effects of these 3 treatment classes. In conclusion, currently available trials have demonstrated renoprotective effects for certain glucagon-like peptide-1 receptor agonists, liraglutide and semaglutide, and the sodium-glucose cotransporter 2 inhibitors, empagliflozin and canagliflozin. Dipeptidyl peptidase-4 inhibitors did not show a significant renoprotective effect. Nevertheless, larger studies with respect to renoprotective effects of these 3 drug classes are currently being performed, and thus, no conclusions for all of these agents can yet be made.

Sodium glucose cotransporter 2 (SGLT2) inhibitors reduce HbA1c, blood pressure, and weight in patients with type 2 diabetes. To investigate the effect of renal function on reductions in these parameters with the SGLT2 inhibitor empagliflozin, we assessed subgroups by baseline estimated glomerular filtration rate (eGFR; Modification of Diet in Renal Disease) in pooled data from five 24-week trials of 2286 patients with type 2 diabetes randomized to empagliflozin or placebo. Reductions in HbA1c with empagliflozin versus placebo significantly diminished with decreasing baseline eGFR. Reductions in systolic blood pressure (SBP) with empagliflozin were maintained in patients with lower eGFR. The mean placebo-corrected changes from baseline in systolic blood pressure at week 24 with empagliflozin were -3.2 (95% confidence interval -4.9,-1.5) mmHg, -4.0 (-5.4, -2.6) mmHg, -5.5 (-7.6, -3.4) mmHg, and -6.6 (-11.4, -1.8) mmHg in patients with an eGFR of 90 or more, 60 to 89, 30 to 59, and under 30 ml/min/1.73m2, respectively. Similar trends were observed for diastolic blood pressure. Weight loss with empagliflozin versus placebo tended to be attenuated in patients with a lower eGFR. Results were consistent in a 12-week ambulatory blood pressure monitoring trial in 823 patients with type 2 diabetes and hypertension. Thus, unlike HbA1c reductions, systolic blood pressure and weight reductions with empagliflozin are generally preserved in patients with chronic kidney disease.

Supplemental Digital Content is available in the text.

How cardiovascular (CV) events affect progression to end-stage renal disease (ESRD), particularly in the setting of type 2 diabetes, remains uncertain.

Major clinical advances over the last 20 years in the area of diabetic kidney disease (DKD) have been confirmed in large seminal clinical trials. These findings add to the previously identified benefits resulting from intensive glucose and blood pressure control therapies. Furthermore, newer glucose lowering treatments such as SGLT2 inhibitors and GLP-1 agonists appear very promising and are likely to transform the management and outlook of DKD over the next decade. In addition, novel mineralocorticoid receptor antagonists and a recently reported trial with an endothelin receptor blocker also have the potential to change clinical practice.

The prevalence of diabetes around the world has reached epidemic proportions and is projected to increase to 642 million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The presence of kidney disease is associated with a markedly elevated risk of cardiovascular disease and death in people with diabetes. Several new therapies and novel investigational agents targeting chronic kidney disease patients with diabetes are now under development. This conference was convened to assess our current state of knowledge regarding optimal glycemic control, current antidiabetic agents and their safety, and new therapies being developed to improve kidney function and cardiovascular outcomes for this vulnerable population.

Introduction:Bidirectional associations between hypoglycemia and cardiovascular (CV) outcomes were evaluated in 2 CV outcome trials of the DPP-4 inhibitor, linagliptin.Methods:CARMELINA and CAROLINA trials evaluated CV outcomes with linagliptin vs placebo or glimepiride, respectively, in adults with type 2 DM at high CV ± kidney risk; of the 2, CARMELINA was longer duration/higher risk cohort. The primary outcome for both trials was CV death, myocardial infarction (MI), or stroke (3P-MACE), with heart failure (HHF) added to the primary outcome for the present analyses. Hypoglycemia was defined as plasma glucose <54 mg/dL; severe hypoglycemia defined as needing external help. Associations between the first hypoglycemic episode and subsequent CV events, and conversely, between non-fatal CV events (MI, stroke, HHF) and subsequent hypoglycemic episodes, were assessed using multivariable Cox proportional hazards models. Sensitivity analyses explored the risk of CV events within 60 days after each hypoglycemic episode.Results:In CARMELINA, there was an association between hypoglycemia and subsequent 3P-MACE + HHF (adjusted HR: 1.23; 95% CI 1.04-1.46), and between non-fatal CV events and subsequent hypoglycemia (adjusted HR: 1.39; 95% CI 1.06-1.83). In CAROLINA, there was no significant association between hypoglycemia and subsequent 3P-MACE + HHF (adjusted HR: 1.00; 95% CI 0.76-1.32), nor between non-fatal CV events and subsequent hypoglycemia (adjusted HR: 1.44; 95% CI 0.96-2.16) (Fig). In analyses of CV events occurring within 60 days after hypoglycemia, in both trials, there was either no association observed or too few events to analyze.Conclusion:The observed bidirectional associations between hypoglycemia and CV outcomes in CARMELINA and no significant associations in CAROLINA challenge the notion that hypoglycemia causes adverse CV events, but rather suggest that both hypoglycemia and CV events identify vulnerable patients at risk for both.

Supplemental Digital Content is available in the text.

Chronic kidney disease (CKD) is a common comorbidity in patients with type 2 diabetes mellitus (T2DM) and both conditions are increasing in prevalence. CKD is estimated to affect ~50% patients with T2DM globally, and its presence and severity markedly influences disease prognosis. CKD is more common in certain patient populations, including the elderly, those with youth-onset diabetes mellitus, those who are obese, certain ethnic groups, and disadvantaged populations. These same settings have also seen the greatest increase in the prevalence of T2DM, as exemplified by the increasing prevalence of T2DM in low-to- middle income countries. Patients from low-to-middle income countries are often the least able to deal with the burden of T2DM and CKD and the health-care facilities of these countries least able to deal with the demand for equitable access to renal replacement therapies. The increasing prevalence of younger individuals with T2DM, in whom an accelerated course of complications can be observed, further adds to the global burden of CKD. Paradoxically, improvements in cardiovascular survival in patients with T2DM have contributed to patients surviving longer, allowing sufficient time to develop renal impairment. This Review explores how the changing epidemiology of T2DM has influenced the prevalence and incidence of associated CKD across different populations and clinical settings.

Although assessment of cardiovascular safety is mandated by regulatory agencies for the development of new drugs to treat type 2 diabetes, evaluation of their renal safety has been relatively neglected.

Introduction: The epidemic of diabetes has now taken on epic proportions and therefore reducing the impact of diabetic complications represents one of the major global challenges in improving health and well-being worldwide. Preventing the development of diabetic kidney disease (DKD) is particularly important, as diabetes is one of the main risk factors for the development of chronic kidney disease, which in turn is strongly linked to development of cardiovascular disease, end-stage renal failure, hospitalization and premature death. Intensive glucose-lowering treatment has been shown to prevent and slow progression of DKD, yet to date, only certain populations have benefited from this intervention.Areas covered:We review the evidence for existing glucose-lowering treatments in the prevention of DKD, and research into techniques to better target individuals who will benefit from these therapies.Expert opinion:Diabetic patients with established kidney disease may benefit from glucose-lowering treatment, particularly if a safer side-effect profile of these treatments is achieved. Better understanding of glucose homeostasis and evaluation of compounds inhibiting its downstream effects are required in order to improve the outlook for individuals with DKD. An additional approach to improve the success rate of glucose-lowering treatment is to improve the selection of individuals who may benefit from treatment. A potential means to identify such subjects could involve the use of biomarkers.

Nox-4 is a member of the NADPH oxidase (Nox) family of enzymes implicated in reactive oxygen species generation. Nox-4 is distributed in many tissues; however, its physiological functions remain poorly understood. In contrast to other Nox isoforms, it is unique in that it produces large amounts of hydrogen peroxide constitutively and does not require other cytosolic oxidase components for its activation. This review highlights the recent developments in Nox-4 research and progressive kidney disease as well as the potential of new Nox-4 inhibitors to reduce renal damage.