Intensive lifestyle intervention in type 2 diabetes and risk of incident coronary artery disease for the common haptoglobin phenotypes: the Look AHEAD study

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Abstract

Background

Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Disease Risk in Diabetes (ACCORD) participants with the haptoglobin (Hp) 2-2 phenotype only. It remains unknown whether Hp phenotype modifies the effect of an intensive lifestyle intervention (ILI) on CAD in type 2 diabetes.

Methods

Haptoglobin phenotype was measured in 4542 samples from the Action for Health in Diabetes (Look AHEAD) study. Cox regression models assessed the effect of ILI (focused on weight loss from caloric restriction and physical activity) versus diabetes support and education (DSE) on CAD events in each phenotype group, and within pre-specified subgroups including race/ethnicity, sex, history of cardiovascular disease, diabetes medication use, and diabetes duration.

Results

1590 (35%) participants had the Hp2-2 phenotype. The ILI did not lower glycated hemoglobin (%HbA1c) to < 6.5% in either phenotype, with a peak significant difference between treatment arms of 0.5% [non-Hp2-2] and 0.6% [Hp2-2]. The cumulative CAD incidence was 13.4% and 13.8% in the DSE arm and 12.2% and 13.6% in the ILI arm for non-Hp2-2 and Hp2-2 groups, respectively. Compared to DSE, the ILI was not associated with CAD among participants without (HR = 0.95, 95% CI 0.78–1.17) or with (0.89, 0.68–1.19) the Hp2-2 phenotype (p-interaction between Hp phenotype and ILI = 0.58). After Bonferroni correction, there were no significant results among any subgroups.

Conclusions

Hp phenotype did not modify the effect of the weight loss ILI on risk of CAD in Look AHEAD, potentially because it did not substantially impact glycemic control among participants with or without the Hp2-2 phenotype. Further research is needed to determine if these results are conclusive.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12933-024-02164-8.

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Most cited references 33

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Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies

The Emerging Risk Factors Collaboration, George Smith (2011)

Summary Background Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances. Methods We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. Findings Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8·49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2·00 (95% CI 1·83–2·19) for coronary heart disease; 2·27 (1·95–2·65) for ischaemic stroke; 1·56 (1·19–2·05) for haemorrhagic stroke; 1·84 (1·59–2·13) for unclassified stroke; and 1·73 (1·51–1·98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40–59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10–12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3·90 mmol/L and 5·59 mmol/L. Compared with fasting blood glucose concentrations of 3·90–5·59 mmol/L, HRs for coronary heart disease were: 1·07 (0·97–1·18) for lower than 3·90 mmol/L; 1·11 (1·04–1·18) for 5·60–6·09 mmol/L; and 1·17 (1·08–1·26) for 6·10–6·99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. Interpretation Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease. Funding British Heart Foundation, UK Medical Research Council, and Pfizer.

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Is Open Access

Introduction to the Analysis of Survival Data in the Presence of Competing Risks

Peter C Austin, Douglas S Lee, Jason P. Fine (2016)

Supplemental Digital Content is available in the text.

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Effects of intensive glucose lowering in type 2 diabetes.

J L Probstfield, William T. Friedewald, J Bigger … (2008)

Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001). As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.) 2008 Massachusetts Medical Society

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Author and article information

Contributors

Leah E. Cahill: leah.cahill@dal.ca

Journal

Journal ID (nlm-ta): Cardiovasc Diabetol

Journal ID (iso-abbrev): Cardiovasc Diabetol

Title: Cardiovascular Diabetology

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2840

Publication date (Electronic): 24 February 2024

Publication date PMC-release: 24 February 2024

Publication date Collection: 2024

Volume: 23

Electronic Location Identifier: 82

Affiliations

[1 ]Department of Medicine, Dalhousie University, ( https://ror.org/01e6qks80) Halifax, Canada

[2 ]GRID grid.413292.f, ISNI 0000 0004 0407 789X, QEII Health Sciences Centre, Nova Scotia Health Authority, ; Halifax, Canada

[3 ]Department of Epidemiology and Prevention, Wake Forest University School of Medicine, ( https://ror.org/0207ad724) Winston-Salem, USA

[4 ]Department of Community Health and Epidemiology, Dalhousie University, ( https://ror.org/01e6qks80) Halifax, Canada

[5 ]Rappaport Faculty of Medicine, Technion Israel Institute of Technology, ( https://ror.org/03qryx823) Haifa, Israel

[6 ]Department of Biostatistics and Data Science, Wake Forest University School of Medicine, ( https://ror.org/0207ad724) Winston-Salem, USA

[7 ]Department of Epidemiology, University of Alabama at Birmingham, ( https://ror.org/008s83205) Birmingham, USA

[8 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Nutrition, , Harvard T. H. Chan School of Public Health, ; Boston, USA

[9 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Epidemiology, , Harvard T. H. Chan School of Public Health, ; Boston, USA

[10 ]Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, ( https://ror.org/0207ad724) Winston-Salem, USA

Article

Publisher ID: 2164

DOI: 10.1186/s12933-024-02164-8

PMC ID: 10894470

PubMed ID: 38402400

SO-VID: e28b2e68-3127-4113-9ea1-32ea23aa8def

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 10 January 2024

Date accepted : 14 February 2024

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;

Award ID: DK057136

Award Recipient : Mark A. Espeland

Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;

Award ID: PJT173471

Award Recipient : Leah E. Cahill

Custom metadata

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: coronary artery disease,epidemiology,genetic association,glycated hemoglobin,haptoglobin phenotype,type 2 diabetes mellitus

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: coronary artery disease, epidemiology, genetic association, glycated hemoglobin, haptoglobin phenotype, type 2 diabetes mellitus

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Intensive lifestyle intervention in type 2 diabetes and risk of incident coronary artery disease for the common haptoglobin phenotypes: the Look AHEAD study

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Abstract

Background

Methods

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Conclusions

Supplementary Information

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Cardiovascular Innovations and Applications

Most cited references 33

Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies

Introduction to the Analysis of Survival Data in the Presence of Competing Risks

Effects of intensive glucose lowering in type 2 diabetes.

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Cited by 2

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