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.

[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.

[Posted 2/Sep/2024]

AUDIENCE: Internal Medicine, Nursing

KEY FINDINGS: Scientists from the University of Copenhagen have detected lipid biomarkers in children and teenagers with obesity that indicate an increased risk of developing type 2 diabetes, liver and heart disease as adults. A one-year lifestyle intervention lowered the levels of these lipid biomarkers, which demonstrates the importance of early intervention for children with obesity.

BACKGROUND: The number of children and teens with obesity is increasing worldwide, with over 250 million expected to be affected by 2030. It is a major public health crisis, as children with obesity risk developing insulin resistance, fatty liver, and high blood pressure, which may lead to diseases such as cardiovascular disease, type 2 diabetes and liver disease, later in life.

DETAILS: Scientists think these diseases can be triggered by changes in the body's lipids -- a wide range of fats and oils in the body including triglycerides and cholesterol that serve many purposes including energy storage and cellular signalling. But it is still not well understood how lipid species change in children with obesity, and how they are linked to early cardiometabolic complications.

Now, scientists at the University of Copenhagen have discovered that lipid species linked to cardiometabolic disease in adults are strongly associated with cardiometabolic risk factors in children and teenagers with obesity. The findings could pave the way for tests that serve as an early warning system for cardiometabolic disease.

"Our study shows that the impact of cardiometabolic associated lipid species emerges early in life in children with obesity, particularly affecting liver function and glucose metabolism. These risk lipid species could potentially be explored further as biomarkers for diagnosing or predicting cardiometabolic risk in children at high risk, offering new insights for early detection and intervention," says Postdoc Yun Huang from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, and co-first author of the study in Nature Medicine.

Early intervention reverses cardiometabolic disease risk

The scientists made their discoveries by drawing on the HOLBAEK Study biobank of more than 4,000 children with and without obesity. at the Children's Obesity Clinic at Holbaek Hospital. Together with scientists at Steno Diabetes Center Copenhagen, they harnessed powerful mass spectrometry technology to map hundreds of individual lipid species, each with distinct structures and functions, providing a detailed picture of lipid metabolism. By analyzing the differences in the lipid profiles of 958 children with overweight or obesity and 373 who had normal weight, they gained deep insight into obesity altered lipid profiles and their link to cardiometabolic risk, and the ability to detect excessive fat in the liver.

Copyright © ScienceDaily or by other parties, where indicated. All rights reserved.

Source: University of Copenhagen - The Faculty of Health and Medical Sciences (2024). A Simple Blood Test Warns of Possible Cardiometabolic Complications for Children With Obesity. ScienceDaily. 2024; Published: September 20, 2024. DOI: 10.1038/s41591-024-03279-x.

A Cohort Study of Patients From the TEMPO 3:4 Trial

[Posted 3/Sep/2024]

AUDIENCE: Nephrology, Internal Medicine

KEY FINDINGS: Visceral adiposity that can be quantified by MRI in the coronal plane using a deep learning segmentation model independently associates with more rapid kidney growth and improves classification of rapid progression in individuals with a normal BMI. Tolvaptan efficacy decreases with increasing visceral adiposity.

BACKGROUND: Body mass index (BMI) is an independent predictor of kidney disease progression in individuals with autosomal dominant polycystic kidney disease (ADPKD). Adipocytes do not simply act as a fat reservoir but are active endocrine organs. Authors hypothesized that greater visceral abdominal adiposity would associate with more rapid kidney growth in ADPKD and influence the efficacy of tolvaptan.

DETAILS: 1,053 patients enrolled in the TEMPO 3:4 tolvaptan trial with ADPKD and at high risk of rapid disease progression. In fully adjusted models, the highest tertile of visceral adiposity was associated with greater odds of annual change in TKV of >=7% versus v5% (odds ratio [OR], 4.78 [95% CI, 3.03-7.47]). The association was stronger in women than men (interaction P < 0.01). In linear mixed models with an outcome of percent change in TKV per year, tolvaptan efficacy (% change in TKV) was reduced with higher visceral adiposity (3-way interaction of treatment * time * visceral adiposity, P = 0.002). Visceral adiposity significantly improved classification performance of predicting rapid annual percent change in TKV for individuals with a normal BMI (DeLong's test z score: -2.03; P = 0.04). Greater visceral adiposity was not associated with estimated glomerular filtration rate (eGFR) slope in the overall cohort; however, visceral adiposity was associated with more rapid decline in eGFR slope (below the median) in women (fully adjusted OR, 1.06 [95% CI, 1.01-1.11] per 10 unit increase in visceral adiposity) but not men (OR, 0.98 [95% CI, 0.95-1.02]).

Copyright © Elsevier Ltd. All rights reserved.

Source: Nowak, K. L., Moretti, F., Bussola, N., et al. (2024). Visceral Adiposity and Progression of ADPKD: A Cohort Study of Patients From the TEMPO 3:4 Trial. Am J Kidney Dis. 2024; 84(3): 275-285. Published: September, 2024. DOI: XXXX.