Glycemic variability (GV) refers to changes in blood glucose or other related biomarkers during a set period of time. The long-term form of GV is all too familiar to HCPs, as glycosylated hemoglobin (HbA1C) has long been the gold standard for measuring glycemic control. Nevertheless, with the rise of continuous glucose monitoring (CGM), interest has focused on another risk factor in patients with type-1 and type-2 diabetes: short-term GV.

 

Impact of short-term GV

 

Research findings, reported in Cardiovascular Diabetology, suggest that long-term GV and short-term GV (ie, within-day and between-day variability) correlate with a higher risk of diabetic macrovascular and microvascular changes, as well as hypoglycemia and mortality rates.

Zhou Z, Sun B, Huang S, et al. Glycemic variability: adverse clinical outcomes and how to improve it? Cardiovasc Diabetol. 2020;19(1):102.

 

The relevance of short-term GV—and specifically, time in range (TIR)— was explored by Chinese researchers publishing in Diabetes Care.

Lu J, Wang C, Shen Y, et al. Time in range in relation to all-cause and cardiovascular mortality in patients with type 2 diabetes: a prospective cohort study. Diabetes Care. 2021;44(2):549–555.

In a large, prospective study, they found that TIR measured by CGM during hospitalization was inversely correlated with long-term risks or all-cause cardiovascular disease mortality in patients with type-2 diabetes. 

 

“These results support the validity of TIR as a surrogate marker of long-term adverse clinical outcomes and an endpoint in future clinical trials,” they wrote.

In most patients, TIR is inversely associated with HbA1C levels and predicts chronic diabetes complications, including retinopathy and microalbuminuria. For most people, TIR >70% is acceptable, with the glucose range being between 70 and 180 mg/dL.

With the increased adoption of CGM, experts suggest TIR will become an increasingly important biomarker in assessing disease. It’s still unclear, however, whether TIR values that are not in range represent changes in insulin secretion, metabolism, and/or sensitivity.

Meneses, MJ, Patarrão, RS, Pinheiro, T, et al. Leveraging the future of diagnosis and management of diabetes: From old indexes to new technologies. Eur J Clin Invest. 2023; 53:e13934.

 

 

Impact of long-term GV

 

US researchers for the Look AHEAD study, published in BMJ Open Diabetes Research & Care, evaluated the association between long-term variations in HbA1C and cardiovascular disease and death.

Kaze AD, Santhanam P, Erqou S, et al. Long-term variability of glycemic markers and risk of all-cause mortality in type 2 diabetes: the Look AHEAD study. BMJ Open Diabetes Res Care. 2020;8(2):e001753

 

 

They found that, for participants in the highest quartile of the standard deviation of HbA1C, there was a 2.10-fold increased risk in all-cause mortality vs participants in the lowest quartile. Furthermore, those individuals in the top quartile had a 1.66-fold higher risk of all-cause mortality vs those in the bottom quartile.

 

Why is GV dangerous?

 

The reasons underlying the pathophysiologic damage done by GV remain unclear. The Look AHEAD investigators, however, hypothesized that blood glucose fluctuations could worsen oxidative stress, thus leading to endothelial dysfunction and atherosclerosis. Glucose fluctuations could also trigger the release of inflammatory cytokines, which mediate diabetes complications.

The authors noted that “fluctuating blood glucose has cytotoxic effects in the pancreas, leading to a significant reduction of glucose-mediated insulin secretion, beta cells’ apoptosis, and mitochondrial alterations, perpetuating the vicious cycle of worsening glycemic control and complications of diabetes.”

 

Leveraging TIR in practice

 

The Advanced Technologies & Treatments for Diabetes (ATTD) has promoted the use of TIR in concert with HbA1C levels when making clinical decisions in patients with both type-1 and type-2 diabetes.

Wright EE Jr, Morgan K, Fu DK, et al. Time in range: how to measure it, how to report it, and its practical application in clinical decision-making. Clin Diabetes. 2020;38(5):439–448.

 

 

Other experts have recommended establishing a pattern for at least 10 days, preferably 14 days.

Gabbay MAL, Rodacki M, Calliari LE, et al. Time in range: a new parameter to evaluate blood glucose control in patients with diabetes. Diabetol Metab Syndr. 2020;12:22.

 

 

One key to gathering CGM readings is the increased utilization of CGM technology. The authors of the article in Cardiovascular Diabetology advocated adoption of this new approach of glucose monitoring in clinical practice, in order to provide a more comprehensive assessment of GV. 

They believe that future developments in new technologies, such as CGM systems and flash glucose monitoring, and indices for better deciphering and defining of GV, will contribute to improved understanding of the clinical relevance of GV in the management of diabetes.