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Prediabetes Equals Diabetes 

May 9, 2020

Author: Steve Freed, R.PH., CDE

Current studies are showing that micro and macro complications begin at prediabetes. Should we conclude that prediabetes equals diabetes and begin earlier treatment?

Elevated blood glucose levels indicative of prediabetes appear to be associated with increased risks for retinopathy, peripheral neuropathy, and also diabetic nephropathy, according to Emanuelsson et al. (p.894). As a result, they suggest that screening for micro- and macrovascular complications should be recommended for individuals with raised blood glucose or prediabetes. The diagnosis for prediabetes is fasting blood glucose of 100-125mg/dL, and a postprandial reading of 140 to 199, which are considered normal.  We can see from the results of this study that all the complications begin even at the lower levels of blood glucose. The conclusions come from an analysis of 117,000 individuals who had blood glucose levels determined along with genotyping for a series of genes previously associated with elevated blood glucose. The investigators also looked at various micro- and macrovascular endpoints to determine the risks associated with elevated glucose levels. And, crucially, they used Mendelian randomization and validation in further cohorts to determine causality. In total, about 820,000 individuals were considered in the analysis. The authors found that, on an observational level, increasing glucose levels were associated with higher risks for both micro and macrovascular complications. Based on genetics and causal analyses (Mendelian randomization), they found risk ratios for an 18mg/dL. ( 1-mmol/L) increase in blood glucose of 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, and 1.49 (1.02–2.17) for myocardial infarction. Risks for estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (indicating kidney disease) and peripheral arterial disease (PAD) were neither increased nor decreased with raised blood glucose. Validation in the cohorts further confirmed the associations with retinopathy, neuropathy, nephropathy, and myocardial infarction but not PAD and was refuted for eGFR. The study shows a causal impact of glycemia on the risk of microvascular disease in individuals from the general population. This risk is present at glucose levels within what is currently considered the normal or prediabetic range.  

The American Diabetes Association recommends screening for prediabetes in adults with obesity or overweight and with risk factors for diabetes. However, this screening does not include examinations for microvascular complications. Future targeted screening may identify individuals who already have microvascular complications and those at very high risk for developing complications, who may benefit the most from risk factor modifications and treatment. 

The study was designed to evaluate whether high glucose levels in the normoglycemic range and higher have a causal genetic effect on the risk of retinopathy, neuropathy, nephropathy, chronic kidney disease (CKD), peripheral arterial disease (PAD), and myocardial infarction (MI; positive control) in the general population. 

The results showed that the glucose levels in the normoglycemic range and higher were associated with high risks of retinopathy, neuropathy, diabetic nephropathy, PAD, and MI (all P for trend <0.001).  Summary-level data from the MAGIC, the CKDGen Consortium, and the UK Biobank gave a genetic risk ratio of 4.55 (95% CI 2.26–9.15) for retinopathy, 1.48 (0.83–2.66) for peripheral neuropathy, 0.98 (0.94–1.01) for eGFR <60 mL/min/1.73 m2, and 1.23 (0.57–2.67) for PAD per 1 mmol/L higher glucose level. 

To prevent glycemic deterioration as early as possible, in addition to being a risk factor for diabetes and cardiovascular disease, the data suggest that an elevated glucose level below the diabetes cutoff is a significant risk factor for microvascular disease. Screening for retinopathy, neuropathy, diabetic nephropathy and additional risk factors such as obesity, hyperlipidemia, and hypertension might be indicated in individuals with prediabetes. 

Previous observational studies have shown that retinopathy, neuropathy, and signs of microvascular dysfunction are prevalent in individuals with prediabetes. Observational findings may be confounded by concomitant cardiometabolic risk factors such as obesity, hyperlipidemia, and hypertension. The finding of a stepwise increase in the risk of vascular disease with increasing glucose levels within the normoglycemic range or higher support the idea that an elevated glucose level per se has a causal role in the pathogenesis of the microvascular disease, as do levels below the diabetes cutoff. This is in line with the general understanding of the natural history of type 2 diabetes as a continuous process of declining β-cell function and increasing relative insulin deficiency, leading to a continuous increase in glucose that is initiated years before the diabetes threshold is reached. Randomized controlled trials have shown that lifestyle changes and treatment with glucose-lowering drugs can reduce the progression from prediabetes to diabetes. Recent 30-year follow-up data from a study of 577 Chinese individuals showed that lifestyle interventions in individuals with prediabetes reduce long-term risks of diabetes, a composite of microvascular complications, cardiovascular disease, cardiovascular mortality, and all-cause mortality. The effects of lifestyle intervention are not likely to be due to glucose-lowering alone but to several beneficial metabolic effects. The findings highlight the importance of early detection of glycemia and screening for prediabetes in asymptomatic individuals through the use of risk assessment tools—such as the one currently provided by the American Diabetes Association  


Practice Pearls:  

  • Having blood glucose in the prediabetes range considered normal has shown to begin the complications of diabetes much earlier than thought. 
  • We need to be more proactive at the first signs of prediabetes. That means any fasting glucose reading above 100mg or a random reading of above 139mg/dL. 
  • These findings suggest that elevated glucose levels should be identified as an essential risk factor for micro- and macrovascular disease in the general population and that screening for microvascular disease may be recommended, along with screening for additional cardiovascular risk factors, in individuals with prediabetes. 
  • Maybe it is time to just call prediabetes, diabetes, which would provide for much earlier treatment. 


Reference for “Prediabetes Equals Diabetes”:

Diabetes Care 2020 Apr; 43(4): 894-902.https://doi.org/10.2337/dc19-1850 


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