Aim: To investigate the observational and causal associations between glucose levels in the nondiabetic range and risk of vascular diseases in the general population.
Methods: We included 112,457 nondiabetic individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study and assessed their prospective risk of retinopathy, neuropathy, diabetic nephropathy, peripheral arterial disease (PAD), and myocardial infarction (MI) as a function of increasing glucose levels. We used Mendelian randomization (MR) to assess a potential causal effect of high glucose levels on the vascular endpoints using genetic variants known to be associated with elevated glucose levels. We replicated our analyses in a 2-sample MR design using glucose data from the MAGIC consortium and vascular endpoint data from the UK Biobank.
Results: Observationally, glucose levels in the nondiabetic range and higher were associated with increased risks of retinopathy, neuropathy, diabetic nephropathy, PAD, and MI (p trend for all <0.001). In genetic, causal analyses risk ratios for a 1 mmol/L higher glucose were 2.01 (95% confidence interval: 1.18-3.41) for retinopathy, 2.15 (1.38-3.35) for neuropathy, 1.58 (1.04-2.40) for diabetic nephropathy, 1.19 (0.90-1.58) for PAD, and 1.49 (1.02-2.17) for MI. Summary level data from the MAGIC consortium and the UK Biobank gave similar results.
Conclusion: In this general population, glucose levels in the nondiabetic range and higher were prospectively associated with a high risk of retinopathy, neuropathy, diabetic nephropathy, PAD, and MI. These associations were causal for retinopathy, neuropathy, diabetic nephropathy, and MI, but causality could not be confirmed for PAD. These findings suggest that elevated glucose levels in the nondiabetic range is an important risk factor for microvascular diseases.
F. Emanuelsson: None. S. Marott: None. A. Tybjaerg-Hansen: None. B.G. Nordestgaard: None. M. Benn: None.
Danish Council for Independent Research