AIMS/HYPOTHESIS Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk. METHODS GIP concentrations were successfully measured during OGTTs in two independent populations (Malmö Diet Cancer-Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD. RESULTS In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 × 10-5) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD. CONCLUSIONS/INTERPRETATION In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5-9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.

中文翻译：

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葡萄糖依赖性促胰岛素肽和心血管事件和死亡率的风险：一项前瞻性研究。

目的/假说正在出现葡萄糖依赖性促胰岛素肽（GIP）和/或GIP受体（GIPR）参与心血管生物学的证据。我们假设，与胰高血糖素样肽1（GLP-1）相比，GIP对心血管生物学有不良影响，因此我们研究了GIP和GLP-1浓度对心血管疾病（CVD）和死亡风险的影响。方法在总共8044名受试者的两个独立人群（马尔默饮食癌症-心血管队列[MDC-CC]和波坦尼亚的糖尿病患病率，预测和预防[PPP-Botnia]）中，OGTT期间成功测量了GIP浓度。在MDC-CC中测量GLP-1（n = 3625）。CVD的发生率和死亡率通过国家/地区登记册或调查表进行评估。进一步，使用与GIP相关的遗传变异体rs1800437作为工具变量，对GIP途径和预后（冠状动脉疾病[CAD]和心肌梗塞）之间的两次孟德尔随机（2SMR）分析进行了分析。使用CAD作为暴露变量和GIP作为结果变量进行了另外的反向2SMR，其工具变量由114种已知的CAD遗传风险变体构成。结果在荟萃分析中，较高的GIP空腹水平与较高的总死亡率（HR [95％CI] = 1.22 [1.11，1.35]； p = 4.5×10-5）和CVD死亡（HR [95]相关％CI] 1.30 [1.11，1.52]； p ＝ 0.001）。因此，2SMR分析显示GIP浓度升高与CAD和心肌梗塞有关，另外2SMR反向显示CAD对GIP水平无明显影响，因此，证实了GIP仅对CAD可能产生的影响。结论/解释在两项基于社区的前瞻性研究中，在随访的5-9年内，GIP水平升高与全因和心血管疾病死亡的风险更高，而GLP-1水平与过度风险无关。有必要进行进一步的研究以确定GIP本身对心血管的影响。