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BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. METHODS: This was a collaborative trial-level meta-analysis from the SGLT2i Meta-analysis Cardio-Renal Trialists Consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across 3 patient populations (patients with diabetes at high risk for atherosclerotic cardiovascular disease, heart failure [HF], or chronic kidney disease). The outcomes of interest were MACE (composite of cardiovascular death, myocardial infarction , or stroke), individual components of MACE (inclusive of fatal and nonfatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i versus placebo were meta-analyzed across trials and examined across key subgroups (established atherosclerotic cardiovascular disease, previous myocardial infarction, diabetes, previous HF, albuminuria, chronic kidney disease stages, and risk groups). RESULTS: A total of 78 607 patients across 11 trials were included: 42 568 (54.2%), 20 725 (26.4%), and 15 314 (19.5%) were included from trials of patients with diabetes at high risk for atherosclerotic cardiovascular disease, HF, or chronic kidney disease, respectively. SGLT2i reduced the rate of MACE by 9% (hazard ration [HR], 0.91 [95% CI, 0.87-0.96], P<0.0001) with a consistent effect across all 3 patient populations (I2=0%) and across all key subgroups. This effect was primarily driven by a reduction in cardiovascular death (HR, 0.86 [95% CI, 0.81-0.92], P<0.0001), with no significant effect for myocardial infarction in the overall population (HR, 0.95 [95% CI, 0.87-1.04], P=0.29), and no effect on stroke (HR, 0.99 [95% CI, 0.91-1.07], P=0.77). The benefit for cardiovascular death was driven primarily by reductions in HF death and sudden cardiac death (HR, 0.68 [95% CI, 0.46-1.02] and HR, 0.86 [95% CI, 0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (Pinteraction=0.02). CONCLUSIONS: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of atherosclerotic cardiovascular disease, diabetes, kidney function, or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of cardiovascular death, particularly HF death and sudden cardiac death, without a significant effect on myocardial infarction in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.
Subject(s)
Cardiovascular Diseases , Sodium-Glucose Transporter 2 Inhibitors , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Humans , Cardiovascular Diseases/mortality , Renal Insufficiency, Chronic/mortality , Renal Insufficiency, Chronic/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/mortality , Diabetes Mellitus, Type 2/complications , Female , Male , Treatment Outcome , AgedABSTRACT
Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) were originally developed as antidiabetic agents, with cardiovascular (CV) outcome trials demonstrating improved CV outcomes in patients with type 2 diabetes mellitus (T2D). Secondary analyses of CV outcome trials and later dedicated kidney outcome trials consistently reported improved kidney-related outcomes independent of T2D status and across a range of kidney function and albuminuria. Importantly, SGLT2 inhibitors are generally safe and well tolerated, with clinical trials and real-world analyses demonstrating a decrease in the risk of acute kidney injury. The kidney protective effects of SGLT2 inhibitors generally extend across different members of the class, possibly on the basis of hemodynamic, metabolic, anti-inflammatory, and antifibrotic mechanisms. In this review, we summarize the effects of SGLT2 inhibitors on kidney outcomes in diverse patient populations.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Humans , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Diabetes Mellitus, Type 2/metabolism , Cardiovascular Diseases/metabolism , Kidney/metabolism , Hypoglycemic Agents/therapeutic useABSTRACT
BACKGROUND: Increased vascular endothelial growth factor B (VEGF-B) expression in patients with diabetic kidney disease (DKD) is associated with increased lipid deposition in glomerular podocytes. Reducing VEGF-B activity in animal models of DKD using an anti-VEGF-B antibody improved histological evidence of glomerular injury and reduced albuminuria; effects attributed to prevention of ectopic lipid deposition in the kidney. CSL346 is a novel humanized monoclonal antibody that binds VEGF-B with high affinity. Targeting VEGF-B in patients with type 2 diabetes mellitus may improve DKD progression markers. METHODS: An international, randomized, double-blind, placebo-controlled, phase 2a study (NCT04419467) assessed CSL346 (8 mg/kg or 16 mg/kg subcutaneously every 4 weeks for 12 weeks) in participants with type 2 diabetes mellitus and a urinary albumin-to-creatinine ratio (UACR) ≥150 mg/g (17.0 mg/mmol), and eGFR >20 mL/min/1.73m2. Efficacy, safety/tolerability, pharmacokinetics, and pharmacodynamics of CSL346 were evaluated. The primary analysis compared the change from baseline in log-transformed UACR between the two CSL346 dose groups combined versus placebo at Week 16. RESULTS: In total, 114 participants were randomized. CSL346 did not significantly reduce UACR compared with placebo at Week 16 (combined CSL346 group difference from placebo 95% confidence interval]: 4.0% [-14.7, 26.8]). Furthermore, no effect was seen in participant subgroups (degree of kidney impairment or sodium-glucose cotransporter 2 [SGLT2] inhibitor use) or on urinary biomarkers reflecting proximal tubular injury. CSL346 was generally well tolerated; however, diastolic blood pressure was significantly higher with CSL346 16 mg/kg versus placebo from Week 2 onwards, with differences ranging from +3.8 to +5.3 mmHg (P = 0.002 at Week 16). CONCLUSIONS: CSL346 did not reduce UACR compared with placebo at 16 weeks in participants with type 2 diabetes mellitus and DKD, and was associated with an increase in diastolic blood pressure.
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SIGNIFICANCE STATEMENT: SGLT2 inhibitors reduce risk of kidney progression, AKI, and cardiovascular disease, but the mechanisms of benefit are incompletely understood. Bioimpedance spectroscopy can estimate body water and fat mass. One quarter of the EMPA-KIDNEY bioimpedance substudy CKD population had clinically significant levels of bioimpedance-derived "Fluid Overload" at recruitment. Empagliflozin induced a prompt and sustained reduction in "Fluid Overload," irrespective of sex, diabetes, and baseline N-terminal pro B-type natriuretic peptide or eGFR. No significant effect on bioimpedance-derived fat mass was observed. The effects of SGLT2 inhibitors on body water may be one of the contributing mechanisms by which they mediate effects on cardiovascular risk. BACKGROUND: CKD is associated with fluid excess that can be estimated by bioimpedance spectroscopy. We aimed to assess effects of sodium glucose co-transporter 2 inhibition on bioimpedance-derived "Fluid Overload" and adiposity in a CKD population. METHODS: EMPA-KIDNEY was a double-blind placebo-controlled trial of empagliflozin 10 mg once daily in patients with CKD at risk of progression. In a substudy, bioimpedance measurements were added to the main trial procedures at randomization and at 2- and 18-month follow-up visits. The substudy's primary outcome was the study-average difference in absolute "Fluid Overload" (an estimate of excess extracellular water) analyzed using a mixed model repeated measures approach. RESULTS: The 660 substudy participants were broadly representative of the 6609-participant trial population. Substudy mean baseline absolute "Fluid Overload" was 0.4±1.7 L. Compared with placebo, the overall mean absolute "Fluid Overload" difference among those allocated empagliflozin was -0.24 L (95% confidence interval [CI], -0.38 to -0.11), with similar sized differences at 2 and 18 months, and in prespecified subgroups. Total body water differences comprised between-group differences in extracellular water of -0.49 L (95% CI, -0.69 to -0.30, including the -0.24 L "Fluid Overload" difference) and a -0.30 L (95% CI, -0.57 to -0.03) difference in intracellular water. There was no significant effect of empagliflozin on bioimpedance-derived adipose tissue mass (-0.28 kg [95% CI, -1.41 to 0.85]). The between-group difference in weight was -0.7 kg (95% CI, -1.3 to -0.1). CONCLUSIONS: In a broad range of patients with CKD, empagliflozin resulted in a sustained reduction in a bioimpedance-derived estimate of fluid overload, with no statistically significant effect on fat mass. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03594110 ; EuDRACT: 2017-002971-24 ( https://eudract.ema.europa.eu/ ).
Subject(s)
Diabetes Mellitus, Type 2 , Glucosides , Renal Insufficiency, Chronic , Sodium-Glucose Transporter 2 Inhibitors , Water-Electrolyte Imbalance , Humans , Diabetes Mellitus, Type 2/complications , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Blood Pressure , Benzhydryl Compounds/adverse effects , Renal Insufficiency, Chronic/drug therapy , Water , Double-Blind MethodABSTRACT
Current management of chronic kidney disease (CKD) in type 1 diabetes centres on glycaemic control, renin-angiotensin system inhibition and optimisation of risk factors including blood pressure, lipids and body weight. While these therapeutic approaches have significantly improved outcomes among people with type 1 diabetes and CKD, this population remains at substantial elevated risk for adverse kidney and cardiovascular events, with limited improvements over the last few decades. The significant burden of CKD and CVD in type 1 diabetes populations highlights the need to identify novel therapies with the potential for heart and kidney protection. Over the last decade, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide 1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists have emerged as potent kidney-protective and/or cardioprotective agents in type 2 diabetes. The consistent, substantial kidney and cardiovascular benefits of these agents has led to their incorporation into professional guidelines as foundational care for type 2 diabetes. Furthermore, introduction of these agents into clinical practice has been accompanied by a shift in the focus of diabetes care from a 'glucose-centric' to a 'cardiorenal risk-centric' approach. In this review, we evaluate the potential translation of novel type 2 diabetes therapeutics to individuals with type 1 diabetes with the lens of preventing the development and progression of CKD.
Subject(s)
Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Renal Insufficiency, Chronic , Sodium-Glucose Transporter 2 Inhibitors , Humans , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Renal Insufficiency, Chronic/drug therapy , GlucoseABSTRACT
The mechanisms responsible for glomerular hemodynamic regulation with sodium-glucose co-transporter 2 (SGLT2) inhibitors in kidney disease due to type 2 diabetes remain unclear. Therefore, we investigated changes in glomerular hemodynamic function using an animal model of type 2 diabetes, treated with an SGLT2 inhibitor alone or in combination with a renin-angiotensin-aldosterone system inhibitor using male Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats. Afferent and efferent arteriolar diameter and single-nephron glomerular filtration rate (SNGFR) were evaluated in ZDF rats measured at 0, 30, 60, 90, and 120 minutes after the administration of a SGLT2 inhibitor (luseogliflozin). Additionally, we assessed these changes under the administration of the adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine), along with coadministration of luseogliflozin and an angiotensin II receptor blocker (ARB), telmisartan. ZDF rats had significantly increased SNGFR, and afferent and efferent arteriolar diameters compared to ZL rats, indicating glomerular hyperfiltration. Administration of luseogliflozin significantly reduced afferent vasodilatation and glomerular hyperfiltration, with no impact on efferent arteriolar diameter. Urinary adenosine levels were increased significantly in the SGLT2 inhibitor group compared to the vehicle group. A1aR antagonism blocked the effect of luseogliflozin on kidney function. Co-administration of the SGLT2 inhibitor and ARB decreased the abnormal expansion of glomerular afferent arterioles, whereas the efferent arteriolar diameter was not affected. Thus, regulation of afferent arteriolar vascular tone via the A1aR pathway is associated with glomerular hyperfiltration in type 2 diabetic kidney disease.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Glomerular Filtration Rate , Kidney Glomerulus , Rats, Zucker , Sodium-Glucose Transporter 2 Inhibitors , Animals , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Male , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/drug therapy , Kidney Glomerulus/drug effects , Kidney Glomerulus/physiopathology , Kidney Glomerulus/pathology , Kidney Glomerulus/blood supply , Glomerular Filtration Rate/drug effects , Rats , Diabetic Nephropathies/etiology , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/physiopathology , Hemodynamics/drug effects , Xanthines/pharmacology , Arterioles/drug effects , Arterioles/physiopathology , Adenosine A1 Receptor Antagonists/pharmacology , Renin-Angiotensin System/drug effects , Sodium-Glucose Transporter 2/metabolism , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Sorbitol/analogs & derivativesABSTRACT
BACKGROUND: The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied. METHODS: We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m2 of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding. RESULTS: Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo. CONCLUSIONS: In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.).
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glycosides/therapeutic use , Renal Insufficiency, Chronic/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Aged , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/mortality , Diabetes Mellitus, Type 2/complications , Diabetic Ketoacidosis/chemically induced , Diarrhea/chemically induced , Double-Blind Method , Female , Glycosides/adverse effects , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Mycoses/etiology , Renal Insufficiency, Chronic/complications , Sodium-Glucose Transporter 1/antagonists & inhibitors , Sodium-Glucose Transporter 2 Inhibitors/adverse effectsABSTRACT
INTRODUCTION: Collaborative management of kidney disease relies on coordinated and effective partnerships between multiple providers. Siloed traditional health systems often result in delays, barriers to treatment access, and inefficient monitoring. METHODS: We conducted a 1-year observational mixed-methods study. We included all consecutive referrals except for patients without telephone access. We assessed 4 domains of outcomes: (1) patient and caregiver experience, (2) provider experience (e.g., physicians and pharmacists), (3) clinical outcomes specific to medication-related outcomes (e.g., adherence, adverse drug events [ADEs]), and (4) value and efficiency (i.e., medication access, defined as time to treatment and resolution of medication reimbursement issues). RESULTS: Sixty-five patients were referred to the integrated virtual pharmacy (iVRx) model. Most (72%) patients were male. Patients had a median (min, max) age of 60 (27, 85) years and were taking 8 (4, 13) medications. Compared with traditional care delivery models, medication access improved for 56% of participants. Direct home delivery of medication resulted in 91% of patients receiving prescriptions within 2 days of a nephrologist visit. During more than 2,000 pharmacist-patient encounters, 208 ADEs were identified that required clinician intervention to prevent patient harm. When these ADEs were classified by severity, 53% were mild, 45% were moderate (e.g., delaying dose titration in patients initiated on glucagon-like peptide 1 (GLP-1) agonists due to intolerable gastrointestinal side effects), and the remaining 2% of ADEs were severe, meaning clinical intervention was required to prevent a serious outcome (e.g., uncontrolled blood pressure, prevention of acute kidney injury). Nephrologists reported high satisfaction with iVRx, citing efficiency, timely response, and collaboration with pharmacists as key facilitators. Of the 65 patient participants, 98% reported being extremely satisfied. CONCLUSIONS: The iVRx is an acceptable and feasible clinical strategy. Our pilot program was associated with improved kidney care by increasing medication access for patients and avoiding potential harms associated with ADEs.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Pharmacy , Renal Insufficiency, Chronic , Humans , Male , Female , Drug-Related Side Effects and Adverse Reactions/prevention & control , Pharmacists , Referral and Consultation , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapyABSTRACT
Volume overload represents a hallmark clinical feature linked to the development and progression of heart failure (HF). Alleviating signs and symptoms of volume overload represents a foundational HF treatment target that is achieved using loop diuretics in the acute and chronic setting. Recent work has provided evidence to support guideline-directed medical therapies, such as sodium glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor (MR) antagonists, as important adjunct diuretics that may act synergistically when used with background loop diuretics in people with chronic HF. Furthermore, there is growing interest in understanding the role of SGLT2 inhibitors, carbonic anhydrase inhibitors, thiazide diuretics, and MR antagonists in treating volume overload in patients hospitalized for acute HF, particularly in the setting of loop diuretic resistance. Thus, the current review demonstrates that: 1) SGLT2 inhibitors and MR antagonists confer long-term cardioprotection in chronic HF patients but it is unclear if natriuresis or diuresis represents the primary mechanisms for this benefit, 2) SGLT2 inhibitors, carbonic anhydrase inhibitors, and thiazide diuretics increase natriuresis in the acute HF setting, but implications on long-term outcomes remain unclear and warrants further investigation, and 3) a multi-nephron segment approach, using agents that act on distinct segments of the nephron, potentiate diuresis to alleviate signs and symptoms of volume overload in acute HF.
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BACKGROUND AND HYPOTHESIS: This post-hoc analysis explored the semaglutide effects on eGFR slope by baseline glycemic control, blood pressure (BP), body mass index (BMI), and albuminuria status in people with type 2 diabetes and high cardiovascular risk. METHODS: Pooled SUSTAIN 6 and PIONEER 6 data were analyzed for change in estimated glomerular filtration (eGFR) slope by baseline HbA1c (<8%/≥8%; <64 mmol/mol/≥64 mmol/mol), systolic BP (<140/90 mmHg/≥140/90 mmHg), and BMI (<30 kg/m2/≥30 kg/m2). SUSTAIN 6 data were analyzed by baseline urinary albumin: creatinine ratio (UACR; <30/30 - 300/>300 mg/g). RESULTS: The estimated absolute treatment differences (ETD) overall in eGFR slope [95% confidence intervals] favored semaglutide versus placebo in the pooled analysis (0.59 [0.29;0.89] mL/min/1.73m2/year) and in SUSTAIN 6 (0.60 [0.24;0.96] mL/min/1.73m2/year); the absolute benefit was consistent across all HbA1c, BP, BMI, and UACR subgroups (all p-interaction > 0.5). CONCLUSION: A clinically meaningful reduction in risk of chronic kidney disease progression was observed with semaglutide versus placebo regardless of HbA1c, BP, BMI, and UACR levels.
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BACKGROUND AND HYPOTHESIS: Volenrelaxin, is a half-life-extended recombinant human relaxin protein developed for improving kidney perfusion and cardiorenal function. This study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of volenrelaxin following single- and multiple-ascending doses (SAD and MAD) administration. METHODS: In this Phase 1, 4-part, randomized, double-blinded, placebo-controlled SAD and MAD study in healthy participants, SAD participants (n = 56) received an intravenous (IV) or subcutaneous (SC) dose of volenrelaxin or placebo in a dose-ascending manner. MAD participants (n = 77) received volenrelaxin or placebo SC once weekly for 5 weeks. Effective renal plasma flow (ERPF) and measured glomerular filtration rate (mGFR) were determined by para-aminohippurate and iohexol clearance, respectively. RESULTS: Volenrelaxin demonstrated an extended half-life and increased acute and chronic placebo-adjusted ERPF change from baseline by 50% and 44%, respectively (p < 0.0001). Measured GFR was unchanged, while filtration fraction and afferent/efferent renal arteriolar resistances were reduced. Systolic and diastolic blood pressures decreased, and pulse rate increased with increasing volenrelaxin exposures, demonstrating maximal model-derived placebo-adjusted changes (90% confidence interval) of -6.16 (-8.04, -4.28) mmHg, -6.10 (-7.61, -4.58) mmHg, and + 4.39 (3.38, 5.39) bpm, respectively. Adverse events were mild, with no difference in orthostatic hypotension between volenrelaxin and placebo. CONCLUSION: Volenrelaxin was well-tolerated, safe and suitable for weekly SC dosing. Volenrelaxin showed a sustained improvement in kidney perfusion upon repeated dosing, supporting further clinical development in chronic kidney disease and chronic heart failure. Clinical trial registration: NCT04768855.
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BACKGROUND AND HYPOTHESIS: Finerenone, a non-steroidal mineralocorticoid receptor antagonist, improved kidney, and cardiovascular outcomes in patients with CKD and T2D in two Phase 3 outcome trials. The FIND-CKD study investigates the effect of finerenone in adults with CKD without diabetes. METHODS: FIND-CKD (NCT05047263 and EU CT 2023-506897-11-00) is a randomized, double-blind, placebo-controlled Phase 3 trial in patients with CKD of non-diabetic aetiology. Adults with a urinary albumin-creatinine ratio (UACR) of ≥ 200 to ≤3500 mg/g and eGFR ≥ 25 to <90 mL/min/1.73 m2 receiving a maximum tolerated dose of a renin-angiotensin-system (RAS) inhibitor were randomized 1:1 to once daily placebo or finerenone 10 or 20 mg depending on eGFR above or below 60 mL/min/1.73 m2. The primary efficacy outcome is total eGFR slope, defined as the mean annual rate of change in eGFR from baseline to Month 32. Secondary efficacy outcomes include a combined cardiorenal composite outcome comprising time to kidney failure, sustained ≥57% decrease in eGFR, hospitalization for heart failure, or cardiovascular death, as well as separate kidney and cardiovascular composite outcomes. Adverse events are recorded to assess tolerability and safety. RESULTS: Across 24 countries, 3231 patients were screened and 1584 were randomized to study treatment. The most common causes of CKD were chronic glomerulonephritis (57.0%) and hypertensive/ischaemic nephropathy (29.0%). Immunoglobulin A nephropathy was the most common glomerulonephritis (26.3% of the total population). At baseline, mean eGFR and median UACR were 46.7 mL/min/1.73 m2 and 818.9 mg/g, respectively. Diuretics were used by 282 participants (17.8%), statins by 851 (53.7%), and calcium channel blockers by 794 (50.1%). SGLT2 inhibitors were used in 16.9% of patients; these individuals had a similar mean eGFR (45.6 vs 46.8 mL/min/1.73 m2) and slightly higher median UACR (871.9 vs 808.3 mg/g) compared to those not using SGLT2 inhibitors at baseline. CONCLUSIONS: FIND-CKD is the first Phase 3 trial of finerenone in patients with CKD of non-diabetic aetiology.
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OBJECTIVE: Kidney transplantation is the gold standard therapeutic alternative for patients with end-stage renal disease; nevertheless, it is not without potential complications leading to considerable morbidity and mortality such as post-transplant diabetes mellitus (PTDM). This narrative review aims to comprehensively evaluate PTDM in terms of its diagnostic approach, underlying pathophysiological pathways, epidemiological data, and management strategies. METHODS: Articles were retrieved from electronic databases using predefined search terms. Inclusion criteria encompassed studies investigating PTDM diagnosis, pathophysiology, epidemiology, and management strategies. RESULTS: PTDM emerges as a significant complication following kidney transplantation, influenced by various pathophysiological factors including peripheral insulin resistance, immunosuppressive medications, infections, and proinflammatory pathways. Despite discrepancies in prevalence estimates, PTDM poses substantial challenges to transplant. Diagnostic approaches, including traditional criteria such as fasting plasma glucose (FPG) and HbA1c, are limited in their ability to capture early PTDM manifestations. Oral glucose tolerance test (OGTT) emerges as a valuable tool, particularly in the early post-transplant period. Management strategies for PTDM remain unclear, within sufficient evidence from large-scale randomized clinical trials to guide optimal interventions. Nevertheless, glucose-lowering agents and life style modifications constitute primary modalities for managing hyperglycemia in transplant recipients. DISCUSSION: The complex interplay between PTDM and the transplant process necessitates individualized diagnostic and management approaches. While early recognition and intervention are paramount, modifications to maintenance immunosuppressive regimens based solely on PTDM risk are not warranted, given the potential adverse consequences such as increased rejection risk. Further research is essential to refine management strategies and enhance outcomes for transplant recipients.
Subject(s)
Diabetes Mellitus , Kidney Transplantation , Humans , Kidney Transplantation/adverse effects , Risk Factors , Diabetes Mellitus/etiology , Diabetes Mellitus/epidemiology , Diabetes Mellitus/therapy , Kidney Failure, Chronic/therapy , Kidney Failure, Chronic/surgery , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/adverse effects , Blood Glucose/metabolism , Postoperative Complications/etiology , Postoperative Complications/therapy , Postoperative Complications/epidemiology , Postoperative Complications/diagnosis , Hypoglycemic Agents/therapeutic use , Glucose Tolerance Test , Insulin ResistanceABSTRACT
BACKGROUND: The cardiorenal effects of sodium-glucose cotransporter 2 inhibition (empagliflozin 25 mg QD) combined with angiotensin-converting enzyme inhibition (ramipril 10 mg QD) were assessed in this mechanistic study in patients with type 1 diabetes with potential renal hyperfiltration. METHODS: Thirty patients (out of 31 randomized) completed this double-blind, placebo-controlled, crossover trial. Recruitment was stopped early because of an unexpectedly low proportion of patients with hyperfiltration. Measurements were obtained after each of the 6 treatment phases over 19 weeks: (1) baseline without treatment, (2) 4-week run-in with ramipril treatment alone, (3) 4-week combined empagliflozin-ramipril treatment, (4) a 4-week washout, (5) 4-week combined placebo-ramipril treatment, and (6) 1-week follow-up. The primary end point was glomerular filtration rate (GFR) after combination treatment with empagliflozin-ramipril compared with placebo-ramipril. GFR was corrected for ramipril treatment alone before randomization. At the end of study phase, the following outcomes were measured under clamped euglycemia (4 to 6 mmol/L): inulin (GFR) and para-aminohippurate (effective renal plasma flow) clearances, tubular sodium handling, ambulatory blood pressure, arterial stiffness, heart rate variability, noninvasive cardiac output monitoring, plasma and urine biochemistry, markers of the renin-angiotensin-aldosterone system, and oxidative stress. RESULTS: Combination treatment with empagliflozin-ramipril resulted in an 8 mL/min/1.73 m2 lower GFR compared with placebo-ramipril treatment (P=0.0061) without significant changes to effective renal plasma flow. GFR decrease was accompanied by a 21.3 mL/min lower absolute proximal fluid reabsorption rate (P=0.0092), a 3.1 mmol/min lower absolute proximal sodium reabsorption rate (P=0.0056), and a 194 ng/mmol creatinine lower urinary 8-isoprostane level (P=0.0084) relative to placebo-ramipril combination treatment. Sodium-glucose cotransporter 2 inhibitor/angiotensin-converting enzyme inhibitor combination treatment resulted in additive blood pressure-lowering effects (clinic systolic blood pressure lower by 4 mm Hg [P=0.0112]; diastolic blood pressure lower by 3 mm Hg [P=0.0032]) in conjunction with a 94.5 dynes × sex/cm5 lower total peripheral resistance (P=0.0368). There were no significant changes observed to ambulatory blood pressure, arterial stiffness, heart rate variability, or cardiac output with the addition of empagliflozin. CONCLUSIONS: Adding sodium-glucose cotransporter 2 inhibitor treatment to angiotensin-converting enzyme inhibitor resulted in an expected GFR dip, suppression of oxidative stress markers, additive declines in blood pressure and total peripheral resistance. These changes are consistent with a protective physiologic profile characterized by the lowering of intraglomerular pressure and related cardiorenal risk when adding a sodium-glucose cotransporter 2 inhibitor to conservative therapy. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02632747.
Subject(s)
Blood Pressure Monitoring, Ambulatory , Ramipril , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Angiotensins , Blood Pressure , Double-Blind Method , Glomerular Filtration Rate , Glucose , Humans , Ramipril/pharmacology , Ramipril/therapeutic use , Sodium , Sodium-Glucose Transporter 2ABSTRACT
Glucagon-like peptide-1 receptor agonists reduce albuminuria and may stabilize the estimated glomerular filtration rate (eGFR) in people with type 2 diabetes (T2D). In this post hoc analysis of the SUSTAIN 6/PIONEER 6 trials encompassing 6480 participants at high cardiovascular risk (semaglutide, 3239 participants; placebo, 3241 participants), we investigated the effects of semaglutide versus placebo on eGFR decline. Pooled data by treatment were evaluated for annual eGFR change (total annual eGFR slope in ml/min per 1.73 m2) from baseline to end of treatment and time to persistent eGFR reductions of 30%, 40%, 50% and 57% or more, including subgroup analyses by baseline eGFR (30 to under 60 or 60 and over ml/min per 1.73 m2). In the overall population, the estimated treatment difference (ETD; semaglutide versus placebo) in annual eGFR slope was significant at 0.59 ml/min per 1.73 m2 (95% confidence interval 0.29; 0.89). The ETD was numerically largest in the 30 to under 60 ml/min per 1.73 m2 eGFR subgroup, 1.06 ml/min per 1.73 m2 (0.45; 1.67), but no significant interaction was observed for treatment effect by subgroup. Hazard ratios (semaglutide versus placebo) for time to persistent eGFR decline were under 1.0 for all eGFR thresholds in the overall population; and were numerically lower in the baseline eGFR 30 to under 60 ml/min per 1.73 m2 subgroup versus the overall population, although no significant interaction was observed for treatment effect by subgroup. Thus, pooled analyses of clinical trial data in patients with T2D suggest that semaglutide may reduce the rate of eGFR decline.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Humans , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/drug therapy , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Risk Factors , Kidney , Hypoglycemic Agents/adverse effectsABSTRACT
BACKGROUND: The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established. METHODS: In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. RESULTS: A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo. CONCLUSIONS: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.).
Subject(s)
Atherosclerosis/drug therapy , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Cardiovascular Diseases/epidemiology , Diabetes Mellitus, Type 2/drug therapy , Hospitalization/statistics & numerical data , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Aged , Atherosclerosis/complications , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Cardiovascular Diseases/mortality , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/complications , Double-Blind Method , Female , Humans , Male , Middle Aged , Placebos/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/administration & dosage , Sodium-Glucose Transporter 2 Inhibitors/adverse effectsABSTRACT
Concerns about hyperkalemia may result in the underuse of established and novel therapies that improve kidney and/or cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Hyperkalemia-related issues are of particular relevance in patients with CKD, who are commonly receiving other hyperkalemia-inducing agents such as renin-angiotensin-aldosterone system inhibitors and nonsteroidal mineralocorticoid receptor antagonists. In contrast, sodium/glucose transporter 2 (SGLT2) inhibitors mitigate the risk of serious hyperkalemia in clinical trials. We aim to review recent evidence surrounding the risk of hyperkalemia in patients with T2DM and CKD treated with established and novel therapies for diabetic kidney disease, focusing on SGLT2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists. We conclude that SGLT2 inhibitors can be used safely in patients with T2DM at high CV risk with CKD without increasing the risk of hyperkalemia. Routine potassium monitoring is generally required when finerenone is used as a kidney- and CV-protective agent in patients with T2DM. Based on existing data, when added to the standard of care, combining SGLT2 inhibitors with finerenone is safe and has the potential to exert additional cardiorenal benefits in patients with diabetic kidney disease. The use of potassium binders should be considered to enable optimal doses of guideline-based therapies for patients with diabetic kidney disease to maximize the kidney and CV benefits.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Hyperkalemia , Renal Insufficiency, Chronic , Sodium-Glucose Transporter 2 Inhibitors , Humans , Hyperkalemia/etiology , Hyperkalemia/drug therapy , Mineralocorticoid Receptor Antagonists/therapeutic use , Mineralocorticoid Receptor Antagonists/pharmacology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetic Nephropathies/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/chemically induced , PotassiumABSTRACT
AIM: To assess the efficacy and safety of sotagliflozin, a dual inhibitor of sodium-glucose co-transporters 1 and 2, in adults with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD3). MATERIALS AND METHODS: This phase 3, randomized, placebo-controlled trial evaluated sotagliflozin 200 and 400 mg in 787 patients with T2D and an estimated glomerular filtration rate of 30-59 ml/min/1.73m2 . The primary objective was superiority of week 26 HbA1c reductions with sotagliflozin versus placebo. Secondary endpoints included changes in other glycaemic and renal endpoints overall and in CKD3 subgroups. RESULTS: At 26 weeks, the placebo-adjusted mean change in HbA1c (from a baseline of 8.3% ± 1.0%) was -0.1% (95% CI: -0.2% to 0.05%; P = .2095) and -0.2% (-0.4% to -0.09%; P = .0021) in the sotagliflozin 200 and 400 mg groups, respectively. Significant reductions in fasting plasma glucose and body weight, but not systolic blood pressure, were observed. Among patients with at least A2 albuminuria at week 26, the urine albumin-creatinine ratio (UACR) was reduced with both sotagliflozin doses relative to placebo. At week 52, UACR was reduced with sotagliflozin 200 mg in the CKD3B group. Adverse events (AEs), including serious AEs, were similar between the treatment groups. CONCLUSIONS: After 26 weeks, HbA1c was significantly reduced with sotagliflozin 400 but not 200 mg compared with placebo in this CKD3 cohort. UACR in patients with at least A2 albuminuria was reduced with each of the two doses at 26 weeks, but changes were not sustained at week 52. The safety findings were consistent with previous reports (NCT03242252).
Subject(s)
Diabetes Mellitus, Type 2 , Renal Insufficiency, Chronic , Sodium-Glucose Transporter 2 Inhibitors , Adult , Humans , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Glycated Hemoglobin , Albuminuria/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/chemically induced , Double-Blind MethodABSTRACT
AIMS: Albuminuria is associated with abnormalities in the nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate pathway. We assessed safety and efficacy of the NO-independent sGC activator BI 685509 in patients with diabetic kidney disease and albuminuria. MATERIALS AND METHODS: In this Phase Ib trial (NCT03165227), we randomized patients with type 1 or 2 diabetes, estimated glomerular filtration rate (eGFR) 20-75 mL/min/1.73 m2 and urinary albumin:creatinine ratio (UACR) 200-3500 mg/g to oral BI 685509 (1 mg three times daily, n = 20; 3 mg once daily, n = 19; 3 mg three times daily, n = 20, after final titration) or placebo (n = 15) for 28 days. Changes from baseline in UACR in first morning void (UACRFMV ) and 10-hour (UACR10h ) urine (3 mg once daily/three times daily only) were assessed. RESULTS: Baseline median eGFR and UACR were 47.0 mL/min/1.73 m2 and 641.5 mg/g, respectively. Twelve patients had drug-related adverse events (AEs; 16.2%: BI 685509, n = 9; placebo, n = 3), most frequently hypotension (4.1%: BI 685509, n = 2; placebo, n = 1) and diarrhoea (2.7%: BI 685509, n = 2; placebo, n = 0). Four patients experienced AEs leading to study discontinuation (5.4%: BI 685509, n = 3; placebo, n = 1). Placebo-corrected mean UACRFMV decreased from baseline in the 3-mg once-daily (28.8%, P = 0.23) and three-times-daily groups (10.2%, P = 0.71) and increased in the 1-mg three-times-daily group (6.6%, P = 0.82); changes were not significant. UACR10h decreased by 35.3% (3 mg once daily, P = 0.34) and 56.7% (3 mg three times daily, P = 0.09); ≥50.0% of patients (UACR10h 3 mg once daily/three times daily) responded (≥20% UACR decrease from baseline). CONCLUSIONS: BI 685509 was generally well tolerated. Effects on UACR lowering merit further investigation.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Humans , Soluble Guanylyl Cyclase/pharmacology , Soluble Guanylyl Cyclase/therapeutic use , Albuminuria/drug therapy , Albuminuria/complications , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Glomerular Filtration Rate , Double-Blind MethodABSTRACT
AIM: To conduct a post hoc analysis to explore indices of hepatic steatosis/fibrosis and cardiorenal outcomes in the VERTIS CV study. MATERIALS AND METHODS: Patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease were randomized to ertugliflozin or placebo. Liver steatosis and fibrosis were assessed post hoc using the hepatic steatosis index (HSI) and fibrosis-4 (FIB-4) index to explore associations with cardiorenal outcomes (ertugliflozin and placebo data pooled, intention-to-treat analysis set). Cardiorenal outcomes (major adverse CV events [MACE]; hospitalization for heart failure [HHF]/CV death; CV death; HHF; and a composite kidney outcome) were stratified by baseline HSI and FIB-4 quartiles (Q1-Q4). Change in liver indices and enzymes over time were assessed (for ertugliflozin vs. placebo). RESULTS: Amongst 8246 participants, the mean age was 64.4 years, body mass index 32.0 kg/m2 , HSI 44.0 and FIB-4 score 1.34. The hazard ratios (HRs) for MACE, HHF/CV death, CV death, and HHF by FIB-4 score quartile (Q4 vs. Q1) were 1.48 (95% confidence interval [CI] 1.25, 1.76), 2.0 (95% CI 1.63, 2.51), 1.85 (95% CI 1.45, 2.36), and 2.94 (95% CI 1.98, 4.37), respectively (P < 0.0001 for all). With HSI, the incidence of HHF was higher in Q4 versus Q1 (HR 1.52 [95% CI 1.07, 2.17]; P < 0.05). The kidney composite outcome did not differ across FIB-4 or HSI quartiles. Liver enzymes and HSI decreased over time with ertugliflozin. CONCLUSION: In VERTIS CV, higher FIB-4 score was associated with CV events. HSI correlated with HHF. Neither measure was associated with the composite kidney outcome. Ertugliflozin was associated with a reduction in liver enzymes and HSI.