A Population-Based Cohort Study

[Posted 24/May/2023]

AUDIENCE: Endocrinology, Ob/Gyn

KEY FINDINGS: Gestational glucose intolerance, including conditions not meeting gestational diabetes criteria of the two-step strategy, confers a high risk of type 2 diabetes in young adulthood. These conditions should be recognised as risk factors for type 2 diabetes, especially among women with abnormal fasting glucose concentrations during pregnancy.

BACKGROUND: The risk of type 2 diabetes among women with glucose intolerance during pregnancy that does not meet gestational diabetes criteria requires further investigation. We aimed to explore the associations between various degrees of gestational glucose intolerance and the risk of type 2 diabetes in young adulthood.

DETAILS: For this population-based cohort study, the national Israeli conscription database was linked to Maccabi Healthcare Services (MHS), the second-largest state-mandated health provider in Israel. Researcghers included 177,241 women who underwent a pre-recruitment evaluation at adolescence (age 16-20 years), 1 year before mandatory military service, and later underwent, from Jan 1, 2001, to Dec 31, 2019, two-step gestational diabetes screening with a 50 g glucose challenge test (GCT) based on a threshold of 140 mg/dL (7.8 mmol/L), followed as needed by a 100 g oral glucose tolerance test (OGTT). Abnormal OGTT values were defined according to the Carpenter-Coustan thresholds: 95 mg/dL (5.3 mmol/L) or higher in the fasting state; 180 mg/dL (10.0 mmol/L) or higher at 1 h; 155 mg/dL (8.6 mmol/L) or higher at 2 h; and 140 mg/dL (7.8 mmol/L) or higher at 3 h. The primary outcome was incident type 2 diabetes in the MHS diabetes registry. Cox proportional hazards models were applied to estimate adjusted hazard ratios (HRs) with 95% CIs for incident type 2 diabetes. During a cumulative follow-up of 1,882,647 person-years, and with a median follow-up of 10.8 (IQR 5.2-16.4) years, 1262 women were diagnosed with type 2 diabetes. Crude incidence rates of type 2 diabetes were 2.6 (95% CI 2.4-2.9) per 10,000 person-years in women with gestational normoglycaemia, 8.9 (7.4-10.6) per 10,000 person-years in women with an abnormal GCT and normal OGTT, 26.1 (22.4-30.1) per 10,000 person-years in women with one abnormal OGTT value (in the fasting state or 1 h, 2 h, or 3 h post-challenge), and 71.9 (66.0-78.3) per 10,000 person-years in women with gestational diabetes. After adjustment for sociodemographic characteristics, adolescent BMI, and age at gestational screening, the risk of type 2 diabetes was higher, compared to the gestational normoglycaemia group, in women with an abnormal GCT and normal OGTT (adjusted hazard ratio [HR] 3.39 [95% CI 2.77-4.16]; p<0.0001), in women with one abnormal OGTT value (9.11 [7.64-10.86]; p<0.0001), and in women with gestational diabetes (24.84 [21.78-28.34]; p<0.0001). The risk of type 2 diabetes was modestly increased in women with isolated elevated fasting glucose (adjusted HR 11.81 [95% CI 8.58-16.25]; p<0.0001), and in women with gestational diabetes and an abnormal fasting glucose (38.02 [32.41-44.61]; p<0.0001).

Copyright © Elsevier Ltd. All rights reserved.

Source: Bardugo, A., Bendor, C. D., Rotem, R. S., et al. (2023). Glucose Intolerance In Pregnancy and Risk Of Early-Onset Type 2 Diabetes: A Population-Based Cohort Study. The Lancet. 2023; 11(5): 333-344. Published: May, 2023. DOI: 10.1016/S2213-8587(23)00062-1.

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 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.