The Long Term Effects of Early Glycemic Control in Patients with Diabetes 

Minimization of secondary diabetic complications among key effects of early glycemic control in type 2 diabetes patients.   

As most of us know, type 2 diabetes can be considered a lifestyle disease with a slow progression towards many clinical complications. Many people with diabetes are unaware of their current level of glycemic control, which can pose a significant risk of developing secondary complications. Because hyperglycemia does not always manifest in immediate attention-requiring symptoms, patients with undiagnosed diabetes are at a higher risk of secondary complications such as retinopathies, nephropathies, neuropathies, and cardiovascular disease that develop slowly over multiple years when compared to those who have an understanding of their level of glycemic control from an early stage in the disease. 

A recent study conducted in Japan aimed to observe the relationship between diabetic progression and incidence of secondary micro and macrovascular complications. Previous studies have already determined the correlation between HbA1c levels and progression of diabetes, leading the researchers of this newer study to use HbA1c readings as a marker for the level of control patients with diabetes have over their disease state. A total of 1547 patients with type 2 diabetes were enrolled throughout the late 1990s and were followed up yearly until 2017 (maximum follow up of 22 years) and included in the primary analysis. A total of three cohorts were analyzed throughout the study and compared to disease progression: those who developed diabetic retinopathy, those who developed diabetic kidney disease, and those who developed cardiovascular disease. Patients with diabetes who had any of the three aforementioned secondary complications before enrollment were excluded from the study. The average patient enrolled in this study represented the typical patient you would see with long-term diabetes: the average age of 56 years old who had been diagnosed with diabetes for between 5 and 6.5 years with an HbA1c value of between 8% and 8.1% with normal renal function. Baseline characteristics were not significantly different between the three study cohorts.  

A primary endpoint for each cohort was defined within the study protocol. The endpoint for the first study cohort (diabetic retinopathy) was defined as the incidence of mild to moderate non-proliferative diabetes–associated retinopathy as diagnosed by licensed ophthalmologists; study patients had yearly eye exams as recommended by current American Diabetes Association (ADA) guidelines. The endpoint for the second study cohort (diabetic kidney disease) was the incidence of an estimated glomerular filtration rate (eGFR) decline of more than 40% from baseline. The endpoint for the third and final study cohort (cardiovascular disease) was defined as the incidence of any myocardial infarction, the procedure of the coronary artery, or any stroke requiring hospitalization.  

The primary endpoint was met in 28.3% of patients within the diabetic retinopathy cohort, 21.3% of patients within the diabetic kidney disease cohort, and 11.9% of patients within the cardiovascular disease cohort with a median time-to-event of 7.9 years, 9.7 years, and 10.4 years, respectively. The relationship between disease progression through measured HbA1c levels and incidence of secondary vascular complications was reported through multivariate Cox proportional hazard regression models adjusted for baseline characteristics.  

It was found that baseline HbA1c values of 1% or higher above a goal of <7% resulted in a 33% increased risk for developing mild to moderate diabetic retinopathy and a 29% increased risk for developing diabetic kidney disease (p<0.0001 for both outcomes). Baseline HbA1c values were not a significant predictor of cardiovascular disease (p=0.07). However, time-dependent HbA1c values were a significant predictor during the early follow-up period (1-3 years). They gradually became less predictive and more constant as time went on throughout the study period (19-22 years). Ultimately, the researchers of this study from Japan found that patients with diabetes and receiving medications for glycemic control are most likely to develop secondary complications within the first ten years of therapy initiation that may decrease over time. Diabetic retinopathy is the most prevalent secondary complication, followed by diabetic kidney disease, then cardiovascular disease. 

Practice Pearls: 

• Early initiation and sustained treatment of glycemic control therapy are crucial for the prevention of secondary diabetic complications. 
• Early glycemic control may not be the only preventative measure for the prevention of cardiovascular disease in patients with diabetes. 
• Future international studies with the same design and protocol are warranted to generalize results to the greater population. 

Reference for “The Long Term Effects of Early Glycemic Control in Patients with Diabetes”:
Takao T, Matsuyama Y, Suka M, et al. Analysis of the duration and extent of the legacy effect in patients with type 2 diabetes: A real-world longitudinal study. Journal of Diabetes and It’s Complications 2019; [Epub ahead of print]. DOI: 10.1016/j.jdiacomp.2019.05.005 

Adam Chalela, B.S. Doctor of Pharmacy Candidate USF College of Pharmacy 

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