Discussion
In this study, we demonstrated that most FLP-CGM-derived metrics related to intraday and interday glucose variability are significantly associated with the severity of DR or albuminuria, even after adjusting for various risk factors in 999 outpatients with type 2 diabetes. Notably, these metrics remain predictive factors for determining the severity of albuminuria after adjusting for HbA1c levels.
A pooled subanalysis of population-based studies demonstrated that the prevalence of any DR in patients with diabetes during 2000–2008 was substantially lower than the prevalence observed before 2000.26 The relative reduction in the prevalence of any DR from 49.6% to 24.8% may reflect improvements in medical care and management of diabetes and DR-related risk factors, including blood pressure, as well as early disease identification and medical provider awareness. In that study,26 the prevalence of any DR and PDR in patients with type 2 diabetes during 1980–2008 was 27.2% and 2.6%, respectively. Our study demonstrated that the prevalence of any DR was 22.2% and PDR was 3.9%. Given that risk factors for DR such as blood glucose and blood pressure were relatively well controlled in our study, the prevalence of DR in our study is reasonable.
The Japan Diabetes Complications Study demonstrated that HbA1c is the strongest risk factor for development and progression of DR, while longer duration of diabetes, systolic blood pressure, and BMI are positively associated with incident DR.27 In fact, previous studies have demonstrated that improvement in HbA1c levels is associated with reduced risk of DR development and progression in patients with type 2 diabetes.6 7 In accordance with those findings, our study indicated that HbA1c is positively associated with DR severity, even after adjusting for several risk factors. On the other hand, a recent study demonstrated that TIR3.9–10 mmol/L based on seven-point glucose testing is inversely associated with the risk of DR progression in patients with type 1 diabetes.28 Similarly, another cross-sectional study demonstrated that CGM-derived TIR3.9–10 mmol/L is inversely associated with DR severity, independent of HbA1c levels in patients with type 2 diabetes.17 Our study also demonstrated that FLP-CGM-derived TIR3.9–10.0 mmol/L is inversely associated with DR severity, even after adjusting for several possible risk factors in patients with type 2 diabetes. However, associations between TIR3.9–10 mmol/L as well as other FLP-CGM-derived metrics including SD, MAGE, TAR>10 mmol/L, TAR>13.9 mmol/L, HBGI, MODD, and IQR and DR severity did not reach statistical significance after adjusting for HbA1c levels.
A possible explanation for the discrepant findings may be differences in characteristics of patients between our studies and the other two previous studies. First, the subjects of a prior study28 were patients with type 1 diabetes treated with insulin, which is completely different from our subjects. In addition, TIR3.9–10mmol/L derived from seven-point blood glucose testing reflects one-daytime values; it does not reflect the overnight period and has limited ability to assess intraday and inter-glycemicinterday glucose variability. The subjects of the other prior study17 were hospitalized for the treatment of diabetes. They were mainly treated with insulin and had hospital meals during a few days of CGM measurement. Thus, these patients are anticipated to have lower TIR3.9–10mmol/L despite substantially higher HbA1c levels. Accordingly, that data may not be generalizable to outpatients with type 2 diabetes under their usual living conditions.
Recently, SGLT-2 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and GLP-1 receptor agonists have been frequently used for patients with type 2 diabetes. These drugs are reported to decrease glucose fluctuations without increasing the risk of hypoglycemia.29 Not surprisingly, our subjects had lower HbA1c levels and were more likely to have lower SD and MAGE and higher TIR3.9–10mmol/L, because a higher proportion used DPP-4 inhibitors and SGLT-2 inhibitors than those in a previous study.29 Thus, it could be difficult to detect the impact of glycemic variability on DR severity independent of HbA1c levels in our study subjects. However, it should be noted that FLP-CGM-derived metrics related to intraday and interday glucose variability were still significantly associated with DR severity after adjusting for possible risk factors other than HbA1c. These findings highlight the substantial role of intraday and interday glucose variability in the pathogenesis of DR. Although FLP-CGM-derived metrics are unlikely to be more useful than HbA1c in terms of predicting DR severity, HbA1c alone might not provide information on intraday and interday glucose variability. Accordingly, our data suggest FLP-CGM-derived metrics might be important complements to HbA1c.
According to serial cross-sectional studies of patients with diabetes who participated in the National Health and Nutrition Examination Surveys, the prevalence of albuminuria declined progressively from 20.8% in 1988–1994 to 15.9% in 2009–2014.30 Higher prevalence of treatment with antidiabetic agents, renin–angiotensin system inhibitors, and statins may account for the reduction in the prevalence of albuminuria. On the other hand, an in vitro study showed that intermittent treatment of high blood glucose levels increases apoptosis of mesangial cells by increasing levels of inflammatory cytokines and oxidative stress, leading to the development of DN.31 However, there are limited data about the clinical impact of intraday and interday glucose variability on the presence or progression of albuminuria in patients with type 2 diabetes. Two previous studies conducted by the same group did not show a significant association between CGM-derived metrics of intraday and interday glucose variability and the presence of albuminuria independent of HbA1c levels in patients with type 2 diabetes with HbA1c levels of more than 8%.32 33 In contrast, our study clearly showed close relationships between FLP-CGM-derived metrics related to intraday and interday glucose variability and the severity of albuminuria, even after adjusting for various possible risk factors including HbA1c, in patients with type 2 diabetes. The reason that those studies yielded conflicting results is not clear, but it may be due to differences in the characteristics of subjects or use of antidiabetic agents among studies. Previous studies enrolled patients with inadequately controlled type 2 diabetes; thus, the prevalence of albuminuria was relatively high, approximately 40%. In contrast, our subjects had a substantially lower prevalence of albuminuria (27%) and were more likely to be taking SGLT-2 inhibitors, DPP-4 inhibitors, and GLP-1 receptor agonists. Taken together, our data suggest that intraday and interday glucose variabilities are important targets in terms of reducing the risk of albuminuria in patients treated according to the current consensus about diabetes treatment.34
HbA1c is recognized as a gold standard for treatment target. A few studies have demonstrated strong associations between HbA1c levels and diabetic microvascular complications.4 5 However, HbA1c alone may not adequately reflect an individual’s glycemic variation and risk of hyperglycemia and hypoglycemia. In this regard, the ATTD Congress recommended TIR as a key metric of glycemic management in clinical practice.15 Our results showed that TIR3.9–10 mmol/L, TAR>10 mmol/L, and TAR>13.9 mmol/L are significantly associated with the severity of albuminuria, even after adjusting for possible risk factors including HbA1c levels. On the other hand, a recent study demonstrated that severe hypoglycemia is a predictor of worsening renal dysfunction in patients with type 2 diabetes.35 However, in addition to LBGI, TBR<3.9 mmol/L and TBR<3.0 mmol/L were not associated with the severity of albuminuria in our study. Mild hypoglycemia, low frequency of hypoglycemic events, or both may not be involved in the development of albuminuria. Alternatively, the relatively low frequency of hypoglycemic events and short duration of hypoglycemia observed in our study may account for this finding. Taken together, based on FLP-CGM-derived metrics, focusing on improving hyperglycemia may be important to reduce the risk of albuminuria development. However, HbA1c alone does not provide enough information. Indeed, a previous study demonstrated that lower renal function (eGFR <60 mL/min/1.73 m2) is strongly correlated with a higher prevalence of anemia in the general population.36 Modest reductions in hemoglobin due to a shorter erythrocyte lifespan may affect the accuracy of HbA1c. In patients with more advanced DN, evaluating FLP-CGM-derived metrics could serve as a therapeutic target complementary to HbA1c.
Our study found that FLP-CGM-derived metrics related to glucose variability are associated with the severity of albuminuria, which is different from DR, even after adjusting for HbA1c levels. Although the exact reason for these findings is not clear, we postulated one scenario. Atherosclerosis of the intrarenal and extrarenal arteries and microangiopathy of the glomerular capillaries, afferent arterioles, and efferent arterioles are considered to contribute to the progression of glomerular lesions in DN.37 38 Previous studies have demonstrated that glucose fluctuation is more significantly associated with atherosclerotic-related diseases than the degree of hyperglycemic exposure as indicated by HbA1c levels in patients with type 2 diabetes.39 40 Thus, it is possible that atherosclerosis of the intrarenal and extrarenal arteries caused by glucose variability may also accelerate renal damage. Therefore, glucose variability is more likely to be associated with the pathogenesis of DN than DR.
The strengths of this study included its relatively large sample size and multicenter study design. Our study had certain limitations. First, the cross-sectional study design made it impossible to evaluate whether FLP-CGM-derived metrics had a causal relationship with diabetic microvascular complications. In this regard, we are currently conducting a long-term follow-up study in the same cohort that focuses on FLP-CGM-derived metrics and onset of outcomes such as primary cardiovascular disease and diabetic microvascular complications. Second, FLP-CGM-derived metrics were evaluated based on FLP-CGM measurements during a limited time. Thus, FLP-CGM-derived metrics may not represent overall glycemic control of subjects. In order to attain the best measurements of glucose fluctuations with FLP-CGM at baseline, we only recruited patients with stable control. In addition, we employed a blind CGM system that prevented subjects from altering their lifestyle behaviors based on the results of glucose readings. Third, we did not assess the accuracy of interstitial glucose levels obtained with the FLP-CGM system by comparing them with capillary glucose levels or venous glucose levels. Previous studies demonstrated some discrepancies in glucose levels obtained with the FLP-CGM system and conventional glucose measurements.41–44 Thus, our findings should be interpreted with caution. Fourth, we only recruited Japanese patients with type 2 diabetes. These constraints may limit the generalizability of our results. Finally, some potential conventional risk factors for DR were not included in the multivariate regression analysis. Previous studies reported that inflammation and homocysteine contribute to DR progression.45 46 This point should also be addressed in a future study.