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Glycated Hemoglobin Directly Impacts Cardiovascular Disease Risk

Aug 4, 2018

Reducing glycated hemoglobin — HbA1c  — may be new goal of therapy to prevent coronary artery disease and other subtypes.

According to many observational studies, there seems to be a strong link between type 2 diabetes and cardiovascular disease. Mendelian randomization studies suggest a positive causal relation of dysglycemia and coronary artery disease. In a two-sample Mendelian randomized study, the relation of HbA1c with CVD and its subtypes was assessed using genetic predictors of HbA1c from one of the world’s largest biobanks, the UK Biobank.

Meta-analysis of Glucose and Insulin-Related Traits Consortium (MAGIC) includes a meta-analysis of genome-wide association study (GWAS) of HbA1c in 159,540 adults without diabetes. Of these participants, 123,665 were of European descent. The mean age of the population of participants was 50 years old or older. Single nucleotide polymorphisms (SNPs) reaching significance in the European ancestry was 43 but 39 were ultimately retained. The UK Biobank recruited more than 500,000 participants. These participants completed a questionnaire and a physical assessment. The mean age of the participants was 56.9 years old. The genotyping of SNPs was done using the Haplotype Reference Consortium panel. Only participants genetically verified to be of white British descent were analyzed to reduce confounding. The CardioGRAMplusC4D is a meta-analysis of GWAS of CAD-case subjects.

CAD was defined as having one of the following: diagnosis of myocardial infarction, acute coronary syndrome, chronic stable angina or coronary stenosis. Primary outcomes were CVD and its subtypes. Subtypes included ischemic stroke, hemorrhagic stroke, and CAD. CVD, CAD, and stroke mortality were considered secondary outcomes.

Of the 502,642 participants in the UK Biobank, 392,038 remained for analysis. 158,601 of these participants had CVD, 29,293 had CAD, and 9,042 experienced strokes. There were 2,313 CVD deaths from the year 2006 to 2016. Based on the GWAS catalog, 13 SNPs were related to potential causes of CAD. Using inverse variance weighting in 38 SNPs, CAD risk was higher with higher HbA1c measures. The association between stroke and its subtypes was found to be heterogenous even though the CI’s were wide. There was a positive association between HbA1c and CAD in the CARDIoGRAMplusC4D using inverse variance weighting. Regardless of the SNP selection, there were detrimental effects of HbA1c on CAD. Due to a low mortality rate in the UK Biobank, the association between HbA1c and with CVD, CAD, and stroke mortality were not clear.

Although precise estimates could not be made, this study, along with others, suggests that there is a close relationship between CVD and HbA1c. CAD is likely to be influenced or caused by HbA1c. Therefore, reducing HbA1c may be a new goal of therapy to prevent CAD and other subtypes of CVD. More studies are needed to further identify the mechanisms in which this pathology occurs and to confirm the causal relationship.

Practice Pearls:

  • HbA1c, glycated hemoglobin, likely causes subtypes of CVD.
  • Type 2 diabetes has been observed to have a strong association with CAD.
  • Higher HbA1c values are associated with higher risk of CAD regardless of genotyping.
  • HbA1c may be a potential new target in prophylactic therapy of CAD.


Yeung, Shiu Lun Au, et al. “The Impact of Glycated Hemoglobin (HbA1c) on Cardiovascular Disease Risk: A Mendelian Randomization Study Using UK Biobank.” Diabetes Care, 2018, p. dc180289., doi:10.2337/dc18-0289.

Amanda Cortes, 2019 LECOM School of Pharmacy PharmD Candidate