Home / Resources / Articles / Hyperglycemia Impact on Micro- and Macrovascular Disease

Hyperglycemia Impact on Micro- and Macrovascular Disease

May 1, 2021
Editor: Steve Freed, R.PH., CDE

Author: Deonna Andrews, PharmD Candidate 2020 of Florida Agricultural & Mechanical University College of Pharmacy and Pharmaceutical Sciences 

High glucose levels, even in the normoglycemic range, may potentiate microvascular complications.  

Hyperglycemia can lead to a multitude of health complications. In persons with diabetes, and even in those without, it has been observed to lead to ischemic heart disease. Also, in people with diabetes, a high glucose level is a definitive risk factor for microvascular disease. Although this is known, it is uncertain if hyperglycemia increases the risk of peripheral micro- and macrovascular diseases in the general population. Additionally, it is unknown whether the extent of this same risk varies between vascular compartments.   


Previous studies have found complications of microvascular dysfunction in people with prediabetes, such as retinopathy and neuropathy. However, these findings can be misleading due to the accompanying cardiometabolic risk factors such as obesity, hyperlipidemia, and hypertension.    

To definitively assess whether high glucose levels in the normoglycemic range and higher have a causal effect on a disease, researchers performed this study. This includes considering all evidential information such as mechanistic studies, longitudinal epidemiological studies, genetic Mendelian randomization studies, and randomized controlled trials. This study took a distinctive approach to use Mendelian randomization. This epidemiological approach will address causality using a random assortment of alleles at conception to circumvent confounding and reverse causation.   

The objective of this observational study was to evaluate whether hyperglycemia in the normoglycemic range had a causal effect on the risk of retinopathy, neuropathy, nephropathy, chronic kidney disease, peripheral arterial disease, and myocardial infarction. Of note, myocardial infarction was included as a positive control for the genetic instrument to confirm the association between the genetic instrument and the risk of myocardial infarction.   

The study population was 117,193 individuals from two cohorts of the general Danish population, participants in the Copenhagen City Heart Study and the Copenhagen General Population Study. From there, researchers tested five different areas that included: whether random plasma glucose levels at baseline were prospectively associated with risk of disease; how specific variants of genes affected glucose levels; genetic variants associated with high glucose levels with risk of disease; analysis of instrumental variables to obtain causal risk estimates per 1 mmol/L (18 mg/dL) higher glucose levels; using a two-sample Mendelian randomization design with summary-level data based on 26 genetic variants associated with fasting glucose levels in individuals without diabetes. Researchers found the endpoints on the diagnoses of retinopathy, peripheral neuropathy, diabetic nephropathy, peripheral arterial disease, chronic kidney disease, and myocardial infarction.   

Researchers were able to ascertain that glucose levels in the normoglycemic range and higher were associated with high risks of retinopathy, neuropathy, diabetic nephropathy, peripheral artery disease, and myocardial infarction, all of which were determined with a p <0.001. Genetic causality analysis yielded the following: risk ratio for a 1 mmol/L higher glucose level was 2.01 (95% CI 1.18–3.41) for retinopathy, 2.15 (1.38–3.35) for neuropathy, 1.58 (1.04–2.40) for diabetic nephropathy, 0.97 (0.84–1.12) for estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, 1.19 (0.90–1.58) for PAD, and 1.49 (1.02–2.17) for myocardial infarction. Observation of this stepwise increase in the risk of vascular disease with increasing glucose levels within the normoglycemic range or higher led researchers to believe that the proposition of an elevated glucose level has a causal role in the pathogenesis of the microvascular disease.   

To conclude, hyperglycemia within the normal range in the general population is linked to the development of microvascular and macrovascular diseases. Limitations of this study include that the glucose measured in both participating groups was obtained from samples from participants in a nonfasted state, and oral glucose tolerance tests were not performed.  

Practice Pearls: 

  • Hyperglycemia was associated with higher risks of all endpoints, which was also observed for glucose levels within the normal range.  
  • This study observed the stepwise correlation between hyperglycemia and the risks of developing micro- and macrovascular complications using Mendelian randomization.  
  • Although limitations exist, this study minimized residual confounding and reversed causation due to many participants and highly valid data.   


Emanuelsson, Frida, et al. Impact of Glucose Level on Micro- and Macrovascular Disease in the General Population: A Mendelian Randomization Study. Diabetes Care, American Diabetes Association, Feb 13, 2020, care.diabetesjournals.org/content/early/2020/02/12/dc19-1850. 


Deonna Andrews, PharmD Candidate 2020 of Florida Agricultural & Mechanical University College of Pharmacy and Pharmaceutical Sciences