CGM-measured Glucose Variability Associated with Diabetes Micro- and Macrovascular Complications

Glycemic variability and low time in range were associated with retinopathy, nephropathy, neuropathy, and CVD in a cohort of more than 20 000 persons, most with T2D.

Daily glycemic variability as measured by continuous glucose monitoring (CGM) may contribute to a range of complications seen in type 2 diabetes (T2D), with time in range (TIR) proving to be the most consistent measure, according to findings from a recent study published in the Journal of Clinical Endocrinology and Metabolism.

Researchers led by Elif I Ekinci, PhD, department of medicine at the University of Melbourne, and the department of endocrinology at Austin Health, Heidelberg, Victoria, Australia write that while Hb A1c (A1c) has remained the gold standard for clinical assessment of risk for diabetes complications, evidence is accumulating that demonstrates short term, and in the case of this study, intradaily fluctuations in glucose levels, contribute significantly to overall management of hyperglycemia and disease control.

To gain a better understanding specifically of the relationship between CGM-derived metrics of glycemic variability and diabetes complications, Eckinci et al conducted a systematic literature search from January 1, 2010 to August 22, 2020 of the PubMed and Embase databases.

The team's final analysis was based on 34 publications comprising 20 852 participants. Within this group, 663 had type 1 diabetes (T1D), 19 909 had T2D, 192 had latent autoimmune diabetes of adulthood, and there were 88 control patients who did not have diabetes.

Nephropathy. Six of the 34 studies, 1563 participants, addressed nephropathy. Five studies investigated albuminuria and 4 of those found statistically significant associations with glycemic variability. Those associations were found with glycemic TIR in the 2 largest studies (n = 866 and n = 281).

Retinopathy. Another 6 studies with a total of 6599 patients evaluated the association between CGM metrics and retinopathy. Of those studies, 5 assessed established retinopathy and 4 of those found statistically significant associations with glycemic variability. Results of the 2 largest studies in this group n = 3262 and n = 3119) demonstrated the associations for standard deviation (SD) of blood glucose levels and reduced TIR. Retinal changes associated with glycemic variation in T1D were particularly noted with low blood glucose index.

Neuropathy. In 7 studies, peripheral neuropathy and irregular nerve conduction were associated with SD, mean amplitude of glycemic excursions (MAGE), and reduced TIR.

Macrovascular complications. The review found 13 studies that addressed CGM-derived metrics of glycemic variability and macrovascular disease, defined as cardiovascular [CV], cerebrovascular, and peripheral vascular disease. The largest, a prospective cohort study of 6225 patients, found TIR associated with CV disease and all-cause mortality.

Eckinci and colleagues identified 22 of the 34 studies in which associations were explored between CGM metrics and diabetes complications after adjustment for A1c. In 19, several metrics of variability remained associated with diabetes after the adjustment, ie, MAGE, TIR, coefficient of variation for glucose, and time-below-range. The team also round that adjustment for A1c resulted in 5 studies in loss of significance for a CGM metric of variability.

Primary limitations to their review, according to the authors, include the considerable heterogeneity among studies across key variables, precluding the possibility of performing a meta-analysis. Also, the majority of the studies were cross-sectional, limiting the ability to demonstrate causality. Finally, proxy measures were used in many studies to infer the presence of disease.

The investigators write that while their findings appear to support an association between greater glycemic variability and lower TIR and micro- and macrovascular complications of diabetes, more research is needed.

They call in particular for longitudinal studies, meta-analyses, and randomized controlled trials, to more clearly evaluate relationships between these CGM-derived metrics "and all diabetes complications, especially in type 1 diabetes. Future studies should also consider the impact of closed-loop pump therapy on the development of diabetes complications."

Reference: Yapanis M, James S, Craig ME, O’Neal D, Ekinci EI. Complications of diabetes and metrics of glycaemic management derived from continuous glucose monitoring. J Clin Endocrinol Metab. Published online January 30, 2022. doi: 10.1210/clinem/dgac034