Cardiovascular and Kidney Outcomes Across the Glycemic Spectrum
Open accessAbstract
Background Treatment guidelines for prediabetes primarily focus on glycemic control and lifestyle management. Few evidence-based cardiovascular and kidney risk-reduction strategies are available in this population. Objectives This study sought to characterize cardiovascular and kidney outcomes across the glycemic spectrum. Methods Among participants in the UK Biobank without prevalent type 1 diabetes, cardiovascular disease, or kidney disease, Cox models tested the association of glycemic exposures (type 2 diabetes [T2D], prediabetes, normoglycemia) with outcomes (atherosclerotic cardiovascular disease [ASCVD], chronic kidney disease [CKD], and heart failure), adjusting for demographic, lifestyle, and cardiometabolic risk factors. Results Among 336,709 individuals (mean age: 56.3 years, 55.4% female), 46,911 (13.9%) had prediabetes and 12,717 (3.8%) had T2D. Over median follow-up of 11.1 years, 6,476 (13.8%) individuals with prediabetes developed ≥1 incident outcome, of whom only 802 (12.4%) developed T2D prior to an incident diagnosis. Prediabetes and T2D were independently associated with ASCVD (prediabetes: adjusted HR [aHR]: 1.11; 95% CI: 1.08-1.15; P < 0.001; T2D: aHR: 1.44; 95% CI: 1.37-1.51; P < 0.001), CKD (prediabetes: aHR: 1.08; 95% CI: 1.02-1.14; P < 0.001; T2D: aHR: 1.57; 95% CI: 1.46-1.69; P < 0.001), and heart failure (prediabetes: aHR: 1.07; 95% CI: 1.01-1.14; P = 0.03; T2D: aHR: 1.25; 95% CI: 1.14-1.37; P < 0.001). Compared with hemoglobin A1c (HbA1c) <5.0%, covariate-adjusted risks increased significantly for ASCVD above HbA1c of 5.4%, CKD above HbA1c of 6.2%, and heart failure above HbA1c of 7.0%. Conclusions Prediabetes and T2D were associated with ASCVD, CKD, and heart failure, but a substantial gradient of risk was observed across HbA 1c levels below the threshold for diabetes. These findings highlight the need to design risk-reduction strategies across the glycemic spectrum.
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These three comorbidities are frequently caused by metabolic risk, which is frequently driven by obesity and its associated risk factors, and the incidence of all three conditions rises with increasing A1C levels.
“These three comorbidities are frequently caused by metabolic risk, which is frequently driven by obesity and its associated risk factors, and the incidence of all three conditions rises with increasing A1C levels (17).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [17]
The Results (Incident Disease Outcomes; page unavailable) show that risk of ASCVD, CKD, and heart failure generally increased across HbA1c levels, though the thresholds for significantly increased adjusted risk differed by condition. The Results (Study Cohort; page unavailable) also report higher BMI and other cardiometabolic risk factors in participants with prediabetes or T2D. These associations do not establish that metabolic risk frequently causes the three conditions or that obesity drives that risk. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe incidence of ASCVD, heart failure, and CKD rises with increasing A1C levels.
“the incidence of all three conditions rises with increasing A1C levels (19).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [19]
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- Authors
- Honigberg, M. C., Zekavat, S. M., Pirruccello, J. P., Natarajan, P., & Vaduganathan, M.
- Affiliations
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Honigberg, Michael C.
- ORCID
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2021-08
- Volume
- 78
- Issue
- 5
- Pages
- 453-464
- ISSN
- 0735-1097 (ISSN-L)
- PMC
- PMC8324525
- OpenAlex
- W3157902107
- Cited by
- 108
- References
- 34
- Citations by year
- 2026: 21 · 2025: 22 · 2024: 22 · 2023: 26 · 2022: 15 · 2021: 2
- FWCI
- 12.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Alexion Pharmaceuticals
- National Heart, Lung, and Blood Institute (R01HL142711, R01HL148050, R01HL148565, R01HL151283, T32HL094301-07)
- Baxter Healthcare Corporation
- Boehringer Ingelheim
- Cytokinetics
- Amgen
- Fondation Leducq (TNE-18CVD04)
- Massachusetts General Hospital
- Novartis
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- prediabetes, type 2 diabetes, HbA1c, glycemic control, atherosclerotic cardiovascular disease, chronic kidney disease, heart failure, cardiovascular risk, kidney disease risk, normoglycemia, UK Biobank, incident disease risk, cardiometabolic risk factors, lifestyle intervention, diabetes prevention, risk mitigation strategies
- MeSH terms
- Aged, Blood Glucose, Cardiovascular Diseases, Female, United Kingdom, Humans, Kidney Diseases, Male, Middle Aged, Prediabetic State, Biological Specimen Banks
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