Per-henrik H. Groop

Cardiovascular diabetology • January 18, 2025

Matias Seppälä, Heidi Lukander, Johan Wadén, Marika Eriksson, Valma Harjutsalo, Per-henrik Groop, Lena Thorn

Background Sedentary behavior, such as excessive sitting, increases risk of cardiovascular disease and premature mortality in the general population, but this has not been assessed in type 1 diabetes. Occupational sitting is increasingly ubiquitous and often constitutes the largest portion of daily sitting time. Our aim was to identify clinical factors associated with excessive occupational sitting in type 1 diabetes and, in a prospective setting, to explore its association with cardiovascular events and all-cause mortality, independent of leisure-time physical activity. Methods An observational follow-up study of 1,704 individuals (mean age 38.9 ± 10.1 years) from the Finnish Diabetic Nephropathy Study. Excessive occupational sitting, defined as ≥ 6 h of daily workplace sitting, was assessed using a validated self-report questionnaire. Data on cardiovascular events and mortality were retrieved from national registries. Multivariable logistic regression identified independently associated factors, while Kaplan-Meier curves and Cox proportional hazard models were used for prospective analyses. Results Factors independently and positively associated with excessive occupational sitting included a high occupational category [OR 6.53, 95% CI (4.09‒10.40)] and older age [1.02 (1.00‒1.03)], whereas negatively associated factors included current smoking [0.68 (0.50‒0.92)], moderate albuminuria [0.55 (0.38‒0.80)], and high leisure-time physical activity [0.52 (0.36‒0.74)]. During a median follow-up of 12.5 (6.5–16.4) years, 163 individuals (9.6%) suffered cardiovascular events, and during a median follow-up of 13.7 (9.4–16.6) years, 108 (6.3%) deaths occurred. Excessive occupational sitting increased cardiovascular event risk (hazard ratio [HR] 1.55 [95% CI 1.10‒2.18]) after adjustment for confounders and other covariates. Furthermore, in a stratified multivariable analysis among current smokers, excessive occupational sitting increased the risk of all-cause mortality (2.06 [1.02‒4.20]). Conclusions Excessive occupational sitting is associated with a higher risk of cardiovascular events and all-cause mortality in individuals with type 1 diabetes. This association persists regardless of leisure-time physical activity, after adjusting for independently associated variables identified in our cross-sectional analyses. These findings underscore the need to update physical activity guidelines to better address sedentary behavior and improve outcomes for individuals with type 1 diabetes. Targeting occupational sitting should be considered a key focus for interventions aimed at reducing overall sedentary time.

Cardiovascular Diabetology • February 25, 2025

Kaarina Rimpeläinen, Fanny Jansson Sigfrids, Daniel Gordin, Miira Klemetti, Valma Harjutsalo, Per-henrik Groop, Lena Thorn

Objective: Our aim was to assess how pre-eclampsia, gestational hypertension, and chronic (pre-pregnancy) hypertension, compared to no hypertensive disorders during pregnancy, impact development of cardiovascular disease and all-cause mortality in type 1 diabetes (T1D). Methods: We included 190 T1D women with median age of 29.4 (interquartile range 26.0-33.3) years at delivery between 1988 and 1994 at the Helsinki University Hospital, and who were later re-examined within the Finnish Diabetic Nephropathy Study. Of these, 43 (22.6%) had had pre-eclampsia, 32 (16.8%) gestational hypertension, 20 (10.5%) chronic hypertension, and 95 (50.0%) had remained normotensive during the index pregnancy. We retrieved follow-up data on cardiovascular events and mortality from national registries until the end of 2020. Results: During a median 27.9 (25.4-30.7) years of follow-up, 46 (24.2%) experienced a composite cardiovascular event and 25 (13.2%) died from any cause. In Cox regression analysis, the risk of a cardiovascular event was increased for chronic hypertension [hazard ratio, HR 3.45 (95% CI 1.25-9.54)], gestational hypertension [HR 3.63 (1.55-8.51)], and pre-eclampsia [HR 5.07 (2.31-11.11)] compared with the non-hypertension group, after adjustment for delivery age and age at T1D onset. The corresponding risk of all-cause mortality was increased for chronic hypertension [HR 3.31 (1.06-10.35)] and pre-eclampsia [HR 2.92 (1.07-7.98)], but not for gestational hypertension [HR 1.26 (0.33-4.85)]. After further adjustment for diabetic kidney disease or diabetic retinopathy as a time-dependent covariate, the association with cardiovascular disease remained for pre-eclampsia and gestational hypertension, while for mortality, none of the associations were significant. Conclusions: Hypertension during pregnancy is associated with increased risk of cardiovascular events during long-term follow-up in women with T1D, with pre-eclampsia conferring the highest risk. For all-cause mortality, chronic hypertension and pre-eclampsia, but not gestational hypertension, increases the risk of death, yet not independently of diabetic kidney disease.

Cardiovascular Diabetology • February 18, 2025

Rebecka Bergdal, Valma Harjutsalo, Per-henrik Groop, Stefan Mutter

Background: Hyperglycaemia and dyslipidaemia are well-known risk factors for coronary artery disease (CAD) in type 1 diabetes. The impact of long-term cumulative exposure to these risk factors is less explored. We investigated the relationship between cumulative glycaemic and lipid exposure and CAD in individuals with type 1 diabetes. Methods: This longitudinal study included 3495 adults with type 1 diabetes from the FinnDiane cohort, without end-stage kidney disease and no history of CAD or stroke at the study baseline. Total cumulative glycaemic exposure (CGEtot) and cumulative hyperglycaemic exposure (CGEhg), accounting only for time spent above an HbA1c of 53 mmol/mol (7%), were calculated from diabetes diagnosis. Results: During a median follow-up of 19.38 years, 534 participants had their first-ever CAD event. CGEhg (odds ratio 1.03 [95% CI 1.02-1.05], p < 0.001) and cumulative exposure to LDL cholesterol, triglycerides, and non-HDL cholesterol all significantly increased the odds for incident CAD. The highest tertile of CGEhg associated with a twofold odds increase for incident CAD. CGEtot was not significantly associated with CAD after adjusting for cumulative lipid exposure. Conclusions: Both hyperglycaemia and dyslipidaemia are independently associated with CAD in type 1 diabetes. These findings emphasize the importance of reaching an HbA1c below 53 mmol/mol (7%) and minimizing lipid exposure, as well as calling on health care professionals to not settle for suboptimal care, but to continue their support and encouragement towards better management of diabetes.

Cardiovascular Diabetology • February 18, 2025

Oliver Schnell, Jaime Almandoz, Lisa Anderson, Katharine Barnard Kelly, Tadej Battelino, Matthias Blüher, Luca Busetto, Doina Catrinou, Antonio Ceriello, Xavier Cos, Thomas Danne, Colin Dayan, Stefano Del Prato, Beatriz Fernández, Paola Fioretto, Thomas Forst, James Gavin, Francesco Giorgino, Per-henrik Groop, Igor Harsch, Hiddo J Heerspink, Lutz Heinemann, Mahmoud Ibrahim, Michel Jadoul, Sarah Jarvis, Linong Ji, Naresh Kanumilli, Mikhail Kosiborod, Ulf Landmesser, Sofia Macieira, Boris Mankovsky, Nikolaus Marx, Chantal Mathieu, Barbara Mcgowan, Tatjana Milenkovic, Othmar Moser, Dirk Müller Wieland, Nikolaos Papanas, Dipesh Patel, Andreas F Pfeiffer, Dario Rahelić, Helena Rodbard, Lars Rydén, Elke Schaeffner, C Spearman, Alin Stirban, Frank Tacke, Pinar Topsever, Luc Van Gaal, Eberhard Standl

The 10th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on December 5-6, 2024. This year, discussions about cardiovascular (CV) and kidney outcome trials centered on the recent findings from studies involving empagliflozin (EMPACT-MI), semaglutide (STEP-HFpEF-DM and FLOW), tirzepatide (SURMOUNT-OSA and SUMMIT), and finerenone (FINEARTS-HF). These studies represent significant advances in reducing the risk of major adverse cardiovascular events (MACE) and improving metabolic outcomes in heart failure with preserved ejection fraction (HFpEF), chronic kidney disease (CKD), and obstructive sleep apnea (OSA). The congress also comprised sessions on novel and established therapies for managing HFpEF, CKD, and obesity; guidelines for managing CKD and metabolic dysfunction-associated steatotic liver disease (MASLD); organ crosstalk and the development of cardio-kidney-metabolic (CKM) syndrome; precision medicine and person-centered management of diabetes, obesity, cardiovascular disease (CVD) and CKD; early detection of type 1 diabetes (T1D) and strategies to delay its onset; continuous glucose monitoring (CGM) and automated insulin delivery (AID); cardiovascular autonomic neuropathy (CAN) and the diabetic heart; and the role of primary care in the early detection, prevention and management of CKM diseases. The contribution of environmental plastic pollution to CVD risk, the increasing understanding of the efficacy and safety of incretin therapies in the treatment of CKM diseases, and the latest updates on nutrition strategies for CKM management under incretin-based therapies were also topics of interest for a vast audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians, who actively engaged in online discussions. The 11th CVOT Summit will be held virtually on November 20-21, 2025 ( http://www.cvot.org ).

MedRxiv : The Preprint Server For Health Sciences • December 09, 2024

Anna Syreeni, Emma Dahlström, Laura Smyth, Claire Hill, Stefan Mutter, Yogesh Gupta, Valma Harjutsalo, Zhuo Chen, Rama Natarajan, Andrzej Krolewski, Joel Hirschhorn, Jose Florez, Per-henrik Groop, Amy Mcknight, Niina Sandholm

DNA methylation differences are associated with kidney function and diabetic kidney disease (DKD), but prospective studies are scarce. Therefore, we aimed to study DNA methylation in a prospective setting in the Finnish Diabetic Nephropathy Study type 1 diabetes (T1D) cohort. We analysed baseline blood sample-derived DNA methylation (Illumina's EPIC array) of 403 individuals with normal albumin excretion rate (early progression group) and 373 individuals with severe albuminuria (late progression group) and followed-up their DKD progression defined as decrease in eGFR to <60 mL/min/1.73m2 (early DKD progression group; median follow-up 13.1 years) or end-stage kidney disease (ESKD) (late DKD progression group; median follow-up 8.4 years). We conducted two epigenome-wide association studies (EWASs) on DKD progression and sought methylation quantitative trait loci (meQTLs) for the lead CpGs to estimate genetic contribution. Altogether, 14 methylation sites were associated with DKD progression (P<9.4×10-8). Methylation at cg01730944 near CDKN1C and at other CpGs associated with early DKD progression were not correlated with baseline eGFR, whereas late progression CpGs were strongly associated. Importantly, 13 of 14 CpGs could be linked to a gene showing differential expression in DKD or chronic kidney disease. Higher methylation at the lead CpG cg17944885, a frequent finding in eGFR EWASs, was associated with ESKD risk (HR [95% CI] = 2.15 [1.79, 2.58]). Additionally, we replicated meQTLs for cg17944885 and identified ten novel meQTL variants for other CpGs. Furthermore, survival models including the significant CpG sites showed increased predictive performance on top of clinical risk factors. Our EWAS on early DKD progression identified a podocyte-specific CDKN1C locus. EWAS on late progression proposed novel CpGs for ESKD risk and confirmed previously known sites for kidney function. Since DNA methylation signals could improve disease course prediction, a combination of blood-derived methylation sites could serve as a potential prognostic biomarker.