Annual FPG and HbA1c variations have a strong association with diabetic nephropathy in patients

with type 2 diabetes. Whether intervention for reducing glucose variation should be administered
needs to be examined in a future study.

The present study is the first to demonstrate that annual

variation in HbA1c and FPG measurements can predict
diabetic nephropathy in 30- to 89-year-old patients with type
2 diabetes. An estimated HbA1c-CV greater than 13.44%
was associated with a 1.58-fold higher risk compared with
HbA1c-CV 6.68%, and an estimated FPG-CV >26.57%
was associated with an approximately 4.75-fold higher risk
compared with FPG-CV 15.99%. Our results demonstrated
that FPG-CV is a new and good measure of glucose
variation that can capture the association between oscillating
plasma glucose and diabetic nephropathy in addition to
HbA1c variation. These findings are relevant to the clinical
management of patients with type 2 diabetes. Managed
care has facilitated routine collection of HbA1c and FPG measurements, which should be availed for
glycemic
assessment. Whether intervention for reducing glucose
variation should be administered needs to be examined in a
future study.
Several plausible mechanisms can be hypothesized to
explain the association of HbA1c and FPG variations with
diabetic nephropathy. First, glucose variation may have an
impact on some mechanisms that affect diabetic nephropathy.
One possible mechanism involves glucose variation
that may produce free radicals activating the pathways
involved in the pathogenesis of diabetes complications.19
Ceriello et al19 reported that oscillating plasma glucose
poses more deleterious effects than constant high glucose on
endothelial function and oxidative-stress generation, which
are 2 key factors that result in cardiovascular complications
in diabetes.19 The other possible mechanism is that oscillating
plasma glucose may act directly on the kidney to
interrupt renal function. Instead of focusing on functional
and structural changes in the glomerulus, changes within
the tubulointerstitium were reported, which contributed to
progressive kidney diseases, including diabetic nephropathy.
Such tubulointerstitial changes were found in approximately
one third of type 2 diabetic patients in a biopsy
study.25 Cell growth, collagen synthesis, and cytokine
secretion in cultured human tubulointerstitial cells were
enhanced after intermittent exposure to high glucose rather
than constant exposure to high glucose.26 Second, glucose
variation may be a sign and not a cause of incident diabetic
nephropathy.
Finally, glucose variation might be an indication of poor
health, comorbidity, or complication that can result in
increased risk for diabetic nephropathy. The present study
considered baseline comorbidity and complication in the
regression models and excluded those who had comorbidity
and complication in the analysis to mitigate this possibility.
However, some residual confounding and uncontrolled
confounding factors may exist, such as biochemical markers
that were not considered in the study.

The findings of the present study have implications for

understanding nephropathy in diabetes. Moreover, annual
HbA1c-CV and FPG-CV may be included in the evaluation
of glucose control in patients with type 2 diabetes for better
prediction of diabetic nephropathy. Whether intervention for
reducing glucose variation should be administered needs to
be examined in a future study. Fluctuations in glycated hemoglobin (HbA1c) are correlated with the
development of nephropathy, but not retinopathy, in patients with type 2 diabetes, according to a new
study published online March 14 in Diabetes Care.

Recent research has suggested that HbA1c variability is an independent risk factor for the
development of diabetic retinopathy and nephropathy in people with type 1 diabetes, as well as
microalbuminuria in patients with type 2 diabetes, write Giuseppe Penno, MD, from the University of
Pisa, Italy, and colleagues. The aim of the current work was to examine these associations further in a
large cohort of subjects with type 2 diabetes from the Renal Insufficiency and Cardiovascular Events
(RIACE) Italian multicenter study.

This consisted of 15,933 white patients with type 2 diabetes. For this analysis, the researchers looked
at 3 to 5 HbA1c values from 8260 patients (52.6% of the entire RIACE cohort) that were collected
over a 2-year period before the participants entered the trial.

Patients' median age was 68 years, and the median duration of diabetes was 14 years (range, 7 to 23
years). Average HbA1c and HbA1c variability was calculated for each patient as the intraindividual
mean (HbA1c-MEAN) and standard deviation (HbA1c-SD), respectively.

Median and interquartile ranges of HbA1c-MEAN and HbA1c c-SD were 7.57% (range, 6.86% –
8.38%) and 0.46% (range, 0.29% – 0.74%), respectively.
HbA1c-SD added to HbA1c-MEAN was an independent correlate of microalbuminuria and stages 1
to 2 chronic kidney disease (CKD) and an independent predictor of macroalbuminuria, reduced
estimated glomerular filtration rate (eGFR), and stages 3 to 5 albuminuric CKD, whereas HbA1c-
MEAN was not correlated with these outcomes. The opposite was observed for diabetic retinopathy.

"This…analysis provides the first evidence of a wide spectrum of associations of average HbA1c and
HbA1c variability with microvascular complications in subjects with type 2 diabetes, thus suggesting
that different mechanisms might link glycemic control to microvascular abnormalities in these
individuals," say Penno et al.

The fact that the patients had had diabetes for a long time and therefore likely had a worse
cardiovascular-risk profile and a greater likelihood of having cardiovascular disease (CVD) is a
limitation of the study, the authors point out. But they also note the strengths of their study, including
the large cohort size, the contemporary data set, the completeness of the data, and the concurrent
analysis of diabetic retinopathy and nephropathy.

"In patients with type 2 diabetes, HbA1c variability affects albuminuria and albuminuric CKD
phenotypes independently of (or instead of) average HbA1c, even after adjustment for known risk
factors for microvascular complications. On the contrary, HbA1c variability has no effects on diabetic
retinopathy, which is mainly dependent on HbA1c," they conclude.

This study was supported by the Research Foundation of the Italian Society of Diabetology and the
Diabetes, Endocrinology, and Metabolism Foundation, Eli Lilly, Takeda, Chiesi Farmaceutici, and
Boehringer-Ingelheim.