{
  "abstract": "Objective Sodium-glucose cotransporter 2 (SGLT2) inhibitors are guideline-recommended agents for treating heart failure (HF), but the role of metabolomic biomarkers in underlying mechanisms, particularly acylcarnitines, remains unclear. This study examined the associations of acylcarnitines with SGLT2 inhibition and incident HF.Methods This subcohort study included 2178 participants from the prospective China Kadoorie Biobank without cardiovascular disease, diabetes or cancer at baseline. Plasma levels of 40 acylcarnitines were quantified using targeted mass spectrometry-based platforms. The impact of genetically predicted random plasma glucose (RPG) via SGLT2 inhibition on acylcarnitines was assessed with Mendelian randomization (MR). The associations of acylcarnitines with HF risk were assessed using Cox proportional hazards models. Acylcarnitines were classified into short-, medium- and long-chain groups and analysed individually or summed as scores.Results Of the 2178 participants, the mean (SD) age was 53.2 (9.8) years. 13 incident HF cases occurred during a median follow-up of 10.5 years. SGLT2 inhibition was associated with higher levels of acylcarnitines, while higher levels of acylcarnitines were associated with reduced HF risk. An unweighted acylcarnitines score was associated with SGLT2 inhibition (β, 2.04 (0.29, 3.79) SD increase per 1 mmol/L lower genetic RPG via SGLT2 inhibition) and HF risk (HR, 0.97 (0.93, 0.99) per 1-SD higher of the score). Glucokinase activation, another antidiabetic agent used for comparison, showed weaker associations with acylcarnitines.Conclusion MR analysis indicated SGLT2 inhibition showed associations with acylcarnitines, which are also associated with HF risk. Our findings highlighted the potential involvement of acylcarnitines in the mechanisms between SGLT2 inhibitors and HF.",
  "authors": [
    {
      "affiliations": [
        "Department of Epidemiology & Biostatistics, Peking University School of Public Health, Beijing, China"
      ],
      "name": "Zhiyu Wu"
    },
    {
      "affiliations": [
        "Department of Epidemiology & Biostatistics, Peking University School of Public Health, Beijing, China"
      ],
      "name": "Shuyao Song"
    },
    {
      "affiliations": [
        "Department of Epidemiology & Biostatistics, Peking University School of Public Health, Beijing, China",
        "Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China"
      ],
      "name": "Jun Lv"
    },
    {
      "affiliations": [
        "Department of Epidemiology & Biostatistics, Peking University School of Public Health, Beijing, China",
        "Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China"
      ],
      "name": "Canqing Yu"
    },
    {
      "affiliations": [
        "Department of Epidemiology & Biostatistics, Peking University School of Public Health, Beijing, China",
        "Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China"
      ],
      "name": "Dianjianyi Sun"
    },
    {
      "affiliations": [
        "Department of Epidemiology & Biostatistics, Peking University School of Public Health, Beijing, China",
        "Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China"
      ],
      "name": "Pei Pei"
    },
    {
      "affiliations": [
        "Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), University of Oxford Nuffield Department of Population Health, Oxford, England, UK"
      ],
      "name": "Ling Yang"
    },
    {
      "affiliations": [
        "Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), University of Oxford Nuffield Department of Population Health, Oxford, England, UK"
      ],
      "name": "Yiping Chen"
    },
    {
      "affiliations": [
        "Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), University of Oxford Nuffield Department of Population Health, Oxford, England, UK"
      ],
      "name": "Iona Y Millwood"
    },
    {
      "affiliations": [
        "Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), University of Oxford Nuffield Department of Population Health, Oxford, England, UK"
      ],
      "name": "Robin G Walters"
    },
    {
      "affiliations": [
        "Liuyang Traditional Chinese Medical Hospital, Liuyang, China"
      ],
      "name": "Hong Guo"
    },
    {
      "affiliations": [
        "Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), University of Oxford Nuffield Department of Population Health, Oxford, England, UK"
      ],
      "name": "Xiaoming Yang"
    },
    {
      "affiliations": [
        "Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), University of Oxford Nuffield Department of Population Health, Oxford, England, UK"
      ],
      "name": "Dan Schmidt"
    },
    {
      "affiliations": [
        "China National Center for Food Safety Risk Assessment, Beijing, China"
      ],
      "name": "Junshi Chen"
    },
    {
      "affiliations": [
        "Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), University of Oxford Nuffield Department of Population Health, Oxford, England, UK"
      ],
      "name": "Zhengming Chen"
    },
    {
      "affiliations": [
        "Department of Epidemiology & Biostatistics, Peking University School of Public Health, Beijing, China",
        "Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China"
      ],
      "name": "Liming Li"
    },
    {
      "affiliations": [
        "Department of Epidemiology & Biostatistics, Peking University School of Public Health, Beijing, China",
        "Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China"
      ],
      "name": "Yuanjie Pang"
    }
  ],
  "title": "SGLT2 inhibition, acylcarnitines and heart failure: a Mendelian randomization study",
  "uid": "13eb0c50-d9ec-5102-8c95-6198e0af605d"
}