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. 2021 Aug 3;78(5):453-464.
doi: 10.1016/j.jacc.2021.05.004. Epub 2021 May 17.

Cardiovascular and Kidney Outcomes Across the Glycemic Spectrum: Insights From the UK Biobank

Michael C Honigberg  1 , Seyedeh M Zekavat  2 , James P Pirruccello  3 , Pradeep Natarajan  4 , Muthiah Vaduganathan  5
Affiliations

Cardiovascular and Kidney Outcomes Across the Glycemic Spectrum: Insights From the UK Biobank

Michael C Honigberg et al. J Am Coll Cardiol. .

Abstract

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 HbA1c levels below the threshold for diabetes. These findings highlight the need to design risk-reduction strategies across the glycemic spectrum.

Keywords: atherosclerotic cardiovascular disease; heart failure; prediabetes; prevention; type 2 diabetes.

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Conflict of interest statement

Funding Support and Author Disclosures Dr Honigberg is supported by a grant from the National Heart, Lung, and Blood Institute (T32HL094301-07). Dr Natarajan is supported by grants from the National Heart, Lung, and Blood Institute (R01HL142711, R01HL148050, R01HL148565, R01HL151283), Fondation Leducq (TNE-18CVD04), and a Hassenfeld Scholar Award from Massachusetts General Hospital; has received grant support from Amgen, Apple, Boston Scientific, and Novartis; has received personal fees from Apple, Blackstone Life Sciences, Genentech, and Novartis; and Dr Natarajan’s spouse has been employed by Vertex, all unrelated to the present work. Dr Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, and Relypsa; has had speaking engagements with Novartis and Roche Diagnostics; and has participated on clinical endpoint committees for studies sponsored by Galmed and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

FIGURE 1
FIGURE 1. Proportion of the Study Sample With ≥1 Primary Study Outcome
One or more different primary study outcomes (incident atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure) occurred in 21,769 (7.9%) individuals with normoglycemia, 6,476 (13.8%) with prediabetes, and 3,017 (23.7%) with type 2 diabetes over a median follow-up period of 11.1 years.
FIGURE 2
FIGURE 2. Incident ASCVD, Heart Failure, and CKD by Baseline Diabetes Status
The “high-risk prediabetes” category was defined as individuals with prediabetes who were current or former smokers and who had medication-adjusted systolic blood pressure, medication-adjusted non–high-density lipoprotein cholesterol, and C-reactive protein each in the top tertile of the study sample (corresponding to adjusted systolic blood pressure ≥148 mm Hg [ie, ≥133 mm Hg for individuals on antihypertensive therapy], adjusted non-high-density lipoprotein cholesterol ≥189.5 mg/dL [ie, ≥128.9 mg/dL for those on cholesterol-lowering therapy], and C-reactive protein ≥2.07 mg/L). All other individuals with prediabetes were classified as belonging to the “other prediabetes” category. ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease.
CENTRAL ILLUSTRATION
CENTRAL ILLUSTRATION. Incident Atherosclerotic Cardiovascular Disease, Heart Failure, and Chronic Kidney Disease by Baseline Hemoglobin A1c Level
A 3- to 4-fold gradient of cardiovascular and kidney disease risk was observed between HbA1c ≥7.0% and HbA1c <5.0%. HbA1c = hemoglobin A1c
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Comment in

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