A Systematic Review and Meta-Analysis

[Posted 1/Mar/2024]

AUDIENCE: Nephrology, Internal Medicine

KEY FINDINGS: Lower eGFR and greater albuminuria were independently associated with increased risk of incident AF. CKD should be regarded as an independent risk factor for incident AF.

BACKGROUND: Atrial fibrillation (AF) and chronic kidney disease (CKD) often coexist. However, it is not known whether CKD is an independent risk factor for incident AF. Therefore, we evaluated the association between markers of CKD-estimated glomerular filtration rate (eGFR) and albuminuria-and incident AF.

DETAILS: Participants with measurement of eGFR and/or albuminuria who were not receiving dialysis.Selection Criteria for Studies: Cohort studies and randomized controlled trials were included that reported incident AF risk in adults according to eGFR and/or albuminuria. Age- or multivariate-adjusted risk ratios (RRs) for incident AF were extracted from cohort studies, and RRs for each trial were derived from event data. RRs for incident AF were pooled using random-effects models. 38 studies involving 28,470,249 participants with 530,041 incident AF cases were included. Adjusted risk of incident AF was greater among participants with lower eGFR than those with higher eGFR (eGFR <60 vs >=60 mL/min/1.73 m²: RR, 1.43; 95% CI, 1.30-1.57; and eGFR <90 vs >=90 mL/min/1.73 m²: RR, 1.42; 95% CI, 1.26-1.60). Adjusted incident AF risk was greater among participants with albuminuria (any albuminuria vs no albuminuria: RR, 1.43; 95% CI, 1.25-1.63; and moderately to severely increased albuminuria vs normal to mildly increased albuminuria: RR, 1.64; 95% CI, 1.31-2.06). Subgroup analyses showed an exposure-dependent association between CKD and incident AF, with the risk increasing progressively at lower eGFR and higher albuminuria

Copyright © Elsevier Ltd. All rights reserved.

Source: Ha, J. T., Freedman, S. B., Kelly, D. M., et al. (2024). Kidney Function, Albuminuria, and Risk of Incident Atrial Fibrillation: A Systematic Review and Meta-Analysis. American Journal of Kidney Diseases. Published: March, 2024. DOI: 10.1053/j.ajkd.2023.07.023.

National Cohort and Co-Sibling Study

[Posted 21/Apr/2025]

AUDIENCE: Cardiology, Ob/Gyn

KEY FINDINGS: In this large national cohort, women who experienced any of 5 major adverse pregnancy outcomes had increased risk for HF up to 46 years later. Women with adverse pregnancy outcomes need early preventive actions and long-term clinical care to reduce the risk of HF.

BACKGROUND: Adverse pregnancy outcomes, such as preterm delivery and hypertensive disorders of pregnancy, may be associated with higher future risks of heart failure (HF). However, the comparative effects of different adverse pregnancy outcomes on long-term risk of HF, and their potential causality, are unclear. The authors sought to examine 5 major adverse pregnancy outcomes in relation to long-term risk of HF in a large population-based cohort.

DETAILS: A national cohort study was conducted of all 2,201,638 women with a singleton delivery in Sweden in 1973-2015, followed up for HF identified from nationwide outpatient and inpatient diagnoses through 2018. Cox regression was used to compute HRs for HF associated with preterm delivery, small for gestational age, preeclampsia, other hypertensive disorders of pregnancy, and gestational diabetes, while adjusting for other adverse pregnancy outcomes and maternal factors. Co-sibling analyses assessed for potential confounding by shared familial (genetic or environmental) factors. In 48 million person-years of follow-up, 667,774 women (30%) experienced an adverse pregnancy outcome, and 19,922 women (0.9%) were diagnosed with HF (median age, 61 years). All 5 adverse pregnancy outcomes were independently associated with long-term increased risk of HF. With up to 46 years of follow-up after delivery, adjusted HRs for HF associated with specific adverse pregnancy outcomes were: gestational diabetes, 2.19 (95% CI: 1.95-2.45); preterm delivery, 1.68 (95% CI: 1.61-1.75); other hypertensive disorders, 1.68 (95% CI: 1.48-1.90); preeclampsia, 1.59 (95% CI: 1.53-1.66); and small for gestational age, 1.35 (95% CI: 1.31-1.40). All HRs remained significantly elevated (1.3- to 3.0-fold) even 30 to 46 years after delivery. These findings were only partially explained by shared familial factors. Women with multiple adverse pregnancy outcomes had further increases in risk (eg, up to 46 years after delivery, adjusted HRs associated with 1, 2, or ≥3 adverse pregnancy outcomes were 1.51 [95% CI: 1.47-1.56], 2.31 [95% CI: 2.19-2.45], and 3.18 [95% CI: 2.85-3.56], respectively).

Copyright © American College of Cardiology Foundation. All rights reserved.

Source: Crump, C., Crump, J., and Crump, K. (20245). Adverse Pregnancy Outcomes and Long-Term Risk of Heart Failure in Women: National Cohort and Co-Sibling Study. J Am Coll Cardiol HF.. 2025; 3(4): 589–598. Published: April, 2025. DOI: 10.1016/j.jchf.2024.11.004.

[Posted 9/Apr/2025]

AUDIENCE: Endocrinology, Family Medicine

KEY FINDINGS: Study results indicate that PTM and unmodified IA-2ecA are predominantly present at late stages of T1D development in patients with clinical new-onset T1D.

BACKGROUND: Increasing evidence shows that pathogenic T cells in type 1 diabetes (T1D) that may have evaded negative selection recognize post-translationally modified (PTM) epitopes of self-antigens.

DETAILS: Authors have investigated the profiles of autoantibodies specifically targeting the deamidated epitopes of insulinoma antigen-2 extracellular domain (IA-2ec) to explore their relationship with T1D development. Authors compared the characteristics of autoantibodies targeting the IA-2ec Q > E epitopes (PTM IA-2ecA) as well as those targeting the IA-2ec unmodified epitopes (IA-2ecA) in participants across different stages of T1D development and in individuals with other types of diabetes and other kinds of autoimmunity. In patients with new-onset T1D, the prevalence of PTM IA-2ecA (26.1%) was significantly higher than that of IA-2ecA (19.5%; P < 0.0001). In a longitudinal newborn cohort, both IA-2ecAs were present, but they were rare in preclinical stage 1 T1D, and with much lower positivity in individuals with stage 3 T1D who had been closely followed from birth in a clinical study compared with patients diagnosed in routine clinical settings with overt symptoms. In participants with latent autoimmune diabetes in adults, type 2 diabetes, and celiac disease autoimmunity, authors did not observe significant positivity of either IA-2ecAs.

Copyright © The American Diabetes Association. All rights reserved.

Source: Jia, X., Wenzlau, J. M., Zhang, C., al. (2025). Strong Association of Autoantibodies Targeting Deamidated Extracellular Epitopes of Insulinoma Antigen-2 With Clinical Onset of Type 1 Diabetes. Diabetes. 2025; 74(4): 544-553. Published: March 20, 2025. DOI: 10.2337/db24-0571.

[Posted 13/Mar/2025]

AUDIENCE: Nephrology, Internal Medicine

KEY FINDINGS: Three years of treatment with tirzepatide in persons with obesity and prediabetes resulted in substantial and sustained weight reduction and a markedly lower risk of progression to type 2 diabetes than that with placebo.

BACKGROUND: Obesity is a chronic disease and causal precursor to myriad other conditions, including type 2 diabetes. In an earlier analysis of the SURMOUNT-1 trial, tirzepatide was shown to provide substantial and sustained reductions in body weight in persons with obesity over a 72-week period. Here, we report the 3-year safety outcomes with tirzepatide and its efficacy in reducing weight and delaying progression to type 2 diabetes in persons with both obesity and prediabetes.

DETAILS: Authors performed a phase 3, double-blind, randomized, controlled trial in which 2,539 participants with obesity, of whom 1,032 also had prediabetes, were assigned in a 1:1:1:1 ratio to receive tirzepatide at a once-weekly dose of 5 mg, 10 mg, or 15 mg or placebo. The current analysis involved the participants with both obesity and prediabetes, who received their assigned dose of tirzepatide or placebo for a total of 176 weeks, followed by a 17-week off-treatment period. The three key secondary end points, which were controlled for type I error, were the percent change in body weight from baseline to week 176 and onset of type 2 diabetes during the 176-week and 193-week periods. At 176 weeks, the mean percent change in body weight among the participants who received tirzepatide was -12.3% with the 5-mg dose, -18.7% with the 10-mg dose, and -19.7% with the 15-mg dose, as compared with -1.3% among those who received placebo (P<0.001 for all comparisons with placebo). Fewer participants received a diagnosis of type 2 diabetes in the tirzepatide groups than in the placebo group (1.3% vs. 13.3%; hazard ratio, 0.07; 95% confidence interval [CI], 0.0 to 0.1; P<0.001). After 17 weeks off treatment or placebo, 2.4% of the participants who received tirzepatide and 13.7% of those who received placebo had type 2 diabetes (hazard ratio, 0.12; 95% CI, 0.1 to 0.2; P<0.001). Other than coronavirus disease 2019, the most common adverse events were gastrointestinal, most of which were mild to moderate in severity and occurred primarily during the dose-escalation period in the first 20 weeks of the trial. No new safety signals were identified.

Copyright © Massachusetts Medical Society. All rights reserved.

Source: Jastreboff, A. M., le Roux, C. W., Stefanski, A., et al. (2024). Tirzepatide for Obesity Treatment and Diabetes Prevention. NEJM. 2025; 392(10): 958-971. Published: March, 2025. DOI: 10.1056/NEJMoa241081.

[Posted 3/Mar/2025]

AUDIENCE: Endocrinology, Family Medicine

KEY FINDINGS: The FDA has resolved the shortage of semaglutide injection products, a glucagon-like peptide 1 (GLP-1) medication, meeting US demand, ending a nearly 3-year shortage. Patients and prescribers may still see intermittent and limited localized supply disruptions as the products move through the supply chain from the manufacturer and distributors to local pharmacies.

BACKGROUND: FDA has determined the shortage of semaglutide injection products, a glucagon-like peptide 1 (GLP-1) medication, is resolved. Semaglutide injection products have been in shortage since 2022 due to increased demand.

DETAILS: FDA confirmed with the drug's manufacturer that their stated product availability and manufacturing capacity can meet the present and projected national demand. Patients and prescribers may still see intermittent and limited localized supply disruptions as the products move through the supply chain from the manufacturer and distributors to local pharmacies.

To avoid unnecessary disruption to patient treatment, the agency does not intend to take action against compounders for violations of the FD&C Act arising from conditions that depend on semaglutide injection products’ inclusion on FDA’s drug shortage list:

• For a state-licensed pharmacy or physician compounding under section 503A of the FD&C Act: compounding, distributing or dispensing semaglutide injection products that are essentially a copy of an FDA-approved product within 60 calendar days from today's announcement, until April 22, 2025.
• For outsourcing facilities under section 503B of the FD&C Act: compounding, distributing or dispensing semaglutide injection products that are essentially a copy of an FDA-approved drug product within 90 calendar days from today’s announcement, until May 22, 2025. FDA may still take action regarding violations of any other statutory or regulatory requirements, such as to address findings that a product may be of substandard quality or otherwise unsafe.

Current shortage status of other GLP-1 products (as of February 21, 2025):

FDA continues to actively monitor drug availability and is currently working to determine whether the demand or projected demand for each drug in shortage exceeds the available supply.

• Dulaglutide injection: In shortage. Manufacturer has reported all presentations are available.
• Liraglutide injection: In shortage. Manufacturer has reported two presentations are available, and three have limited availability.

Source: FDA cLarifies Policies for Compounders as National GLP-1 Supply Begins to Stabilize. FDA. Published: February, 21, 2025.

[Posted 21/Oct/2024]

AUDIENCE: Nephrology, Internal Medicine

KEY FINDINGS: P2Y2R was significantly expressed in human and mouse polycystic kidneys. Deletion and antagonism of P2Y2R reduced cyst enlargement in an ADPKD mouse model.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by multiple bilateral kidney cysts that gradually enlarge, resulting in a decline in kidney function. Cyst growth is significantly driven by ATP-dependent chloride secretion mediated by the ion channel TMEM16A. This pathway is further augmented in advanced stages of the disease by hypoxia and activation of hypoxia-inducible factor (HIF)-1α. The mechanisms by which ATP leads to activation of TMEM16A and how HIF-1α contributes to cyst growth in vivo have remained elusive.

DETAILS: Mice with an inducible tubule-specific deletion of Pkd1 were compared with mice with an additional codeletion of the purinergic receptor P2y2r. Furthermore, animals were challenged by pharmacological activation of HIF-1α and Pkd1-deficient mice were treated with suramin, an antagonist of purinergic signaling. In addition, expression of P2Y2R, TMEM16A, and HIF-1α was analyzed in nephrectomy samples from 27 patients with ADPKD. Genetic deletion of P2y2r significantly inhibited cyst growth in vivo. In addition, aggravation of the polycystic phenotype mediated by pharmacological activation of HIF-1α was reduced by deletion of P2y2r. Application of suramin to pharmacologically inhibit purinergic signaling also suppressed cyst enlargement in vivo. Analysis of kidney samples from 27 patients with ADPKD revealed significant expression of P2Y2R at the luminal site of the cyst-lining epithelium.

Copyright © American Society of Nephrology. All rights reserved.

Source: Kraus, A., Skoczynski, K., Brotsch. M., et al. (2024). P2Y2R and Cyst Growth in Polycystic Kidney Disease. Journal of the American Society of Nephrology. 2024; 35(10):p 1351-1365. Published: October, 2024. DOI: 10.1681/ASN.0000000000000416.