How glycemic variability can help predict diabetes complications and other issues

By Naveed Saleh, MD, MS | Fact-checked by Barbara Bekiesz
Published May 1, 2023

Key Takeaways

  • Short-term glycemic variability (GV) is measured by time in range (TIR) via continuous glucose monitoring (CGM). It predicts diabetic complications, hypoglycemia, and death.

  • Fluctuations in levels of blood glucose could worsen oxidative stress and inflammation, both of which contribute to heart disease and death. 

  • Experts recommend making clinical decisions based on hemoglobin A1C (HbA1C) levels, which represent long-term GV, as well as on TIR.

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.[]

The relevance of short-term GV—and specifically, time in range (TIR)— was explored by Chinese researchers publishing in Diabetes Care.[] 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 end point in future clinical trials,” they wrote.

TIR refers to the amount of time in which a patient with diabetes lies within target glucose ranges. It is the most frequently used CGM metric. 

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.[]

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.[] 

They found that, for participants in the highest quartile of 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.[] 

Maintaining a range of 70–180 mg/dL for more than 70% of the time was recommended.

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

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.

What this means for you

In addition to HbA1C, which measures long-term GV, short-term GV measures such as TIR can help guide treatment decisions. With the increased adoption of CGM, the assessment of TIR is becoming more popular. Both long- and short-term GV are linked to diabetic complications and death and should be considered. 

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