In this study, we retrospectively analyzed patients with newly diagnosed T2DM in Korea. Our study demonstrated that patients with YOD are at a higher risk of developing CKD than those with LOD after adjusting for their clinically distinct characteristics. Patients with YOD were characterized by poor metabolic risk factors such as high BMI, high fasting glucose levels, smoking, heavy drinking, and low physical activity; however, they shared some favorable metabolic characteristics, including a lower prevalence of hypertension, dyslipidemia, and low income. The risk of developing CKD was consistently higher in patients with YOD than in those with LOD (OR: 1.7) when clinically distinct variables were adjusted (Table 2). The higher risk of CKD development in patients with YOD was consistent in the subgroup analysis and was especially prominent in non-smoking patients with a low BMI (Table 3).
Our results suggest that patients with YOD are an important subpopulation of T2DM cases, with respect to their renal outcome. Diabetic nephropathy is a progressive disorder that may result in end-stage renal disease (ESRD), in which patients require renal replacement therapy. Patients with CKD are also increased in risk of mortality, fluid retention, uncontrolled blood pressure, electrolyte imbalance (hyperkalemia, hyperphosphatemia), and osteoporosis, which increase the medical and socioeconomic burden. Our study suggests that patients who develop T2DM at an early age may require intensive medical treatment and more-frequent screening for renal complications. In the subgroup analysis, a low BMI and non-smoking status were more important risk factors for CKD development in YOD. Among patients with YOD, hypertension or dyslipidemia, and the use of sulfonylurea were more common in those who developed CKD. Low-BMI and non-smoking populations are generally regarded as low-risk metabolic groups. Our data suggest that, although patients may have a low BMI or do not smoke, they should require more medical attention for renal complications if they develop T2DM at an early age. Our data also suggest that patients with YOD who have concomitant hypertension or dyslipidemia should be aware of the potential development of nephropathy 30.
At this point, we do not fully understand the mechanism by which sulfonylurea use is associated with an increased incidence of CKD in YOD. Because sulfonylurea is prescribed commonly in Korea to patients who do not reach optimal glycemic targets despite using metformin and DPP-IV inhibitors, we speculate that a higher proportion of sulfonylurea usage may be related to hyperglycemia in patients with YOD. In addition, sulfonylurea-associated hypoglycemia may contribute to the increased development of CKD 31. However, because we did not measure the prevalence of hypoglycemia in our participants, we do not have data to verify our hypothesis. Anti-diabetic agents, such as SGLT2 inhibitors or GLP1 receptor agonists, have been shown to delay the progression of CKD (microalbuminuria, GFR) 32–35. Liraglutide, dulaglutide, and dapagliflozin have been shown to be safe, even in adolescents 36–38. Thus, patients with YOD may benefit from the early use of these anti-diabetic agents instead of sulfonylurea. Future well-designed clinical studies are needed to test this hypothesis.
Despite the increasing prevalence, the clinical course of YOD is poorly understood, particularly with respect to renal outcomes. Previous studies reported high comorbidity of nephropathy in patients with YOD. Patients with YOD have a higher incidence of renal complications than patients with Type 1 diabetes (T1DM) of similar age 39. Compared with LOD, the prevalence of nephropathy is higher in YOD at any given age 40,41. However, whether the risk of developing nephropathy is fundamentally different for patients with YOD compared to those with LOD remains inconclusive 7. Pavkov et al. longitudinally analyzed 1856 Pima Indians and demonstrated that the incidence of ESRD did not differ between patients with early-onset diabetes and LOD 40. However, the definition of early-onset diabetes in that study was different from that used in our study. In that study, patients who were diagnosed with T2DM under the age of 20 years were defined as having YOD, whereas patients diagnosed aged 20–55 years were defined as having LOD. Therefore, we suggest that the LOD group in that study might have included some patients who share the same clinical characteristics of YOD. Chan et al. studied 9509 Chinese patients and reported that, at any given age, patients with YOD are at an increased risk of developing CKD compared to patients with LOD 41. The authors also showed that, when adjusted for the duration of diabetes, the incidence of CKD was even higher in patients with LOD than in those with YOD. However, their cohort included a significant portion of patients already diagnosed with diabetes at the time of enrollment (baseline mean duration of diabetes: YOD = 6 years, LOD = 5 years), with the baseline GFR being lower in patients with LOD (96.9 ± 32.0 mL/min/1.73 m2) than in patients with YOD (125.1 ± 36.7 mL/min/1.73 m2). Because the incidence of CKD was defined in this study as a GFR < 60 mL/min/1.73 m2, the possibility of overestimating the relative risk cannot be excluded. Recently, Wu et al. studied 436,744 newly diagnosed (Hong Kong Diabetes Surveillance Database, HKDSD) and 16,979 already diagnosed (Hong Kong Diabetes Register) T2DM patients in China. Consistent with our study, the authors maintained that the increased risk of CKD in YOD can be attributed to both increased exposed diabetic condition and aggressiveness of disease 42.
A large number of subjects and homogeneity of ethnicity are two strengths of our study. We analyzed 83,032 (YOD = = 7,345) patients newly diagnosed with Type 2 diabetes to determine the risk of CKD development. Previous studies suggest that the heterogeneity of the incidence and clinical characteristics of YOD is dependent on ethnicity 7,43. The participants in our study comprised patients in Korea only. Importantly, the baseline GFR was lower in the LOD group (91.33 ± 36.64 mL/min/1.73 m2) compared with the YOD group (98.92 ± 45.06 mL/min/1.73 m2) in our cohort. However, the risk of CKD was higher in patients with YOD than in those with LOD, even after adjusting for clinically distinct variables. Therefore, we speculate the relative CKD risk in the YOD group would not be overestimated in our study.
Here, the risk of developing CKD was consistently higher in patients with YOD than in those with LOD, even as clinically distinct variables were serially adjusted. In particular, a higher risk of CKD development in the YOD group was more prominent in the non-smoking or low-BMI subgroups. These results suggest that patients with YOD may have different pathogenicity from that of LOD; these could have contributed to the difference in CKD development 44. However, we could not measure important parameters, such as HbA1c or C-peptide levels, which may potentially affect the renal outcome. We also could not measure the variability of some metabolic parameters (fasting plasma glucose, blood pressure, and cholesterol), which can also affect renal outcomes 45. In this study, we defined the development of CKD as the presence of more than two consecutive measurements of GFR < 60 mL/min/1.73 m2. Although a similar definition has been used in previous studies to define diabetic nephropathy, we admit that patients with micro- or macro-albuminuria with GFR > 60 mL/min/1.73 m2 were potentially included in this study 41,46. We defined the diagnosis of Type 2 diabetes as the time point when anti-diabetic medication was first prescribed to those who attained diabetes-related ICD-10 codes (E11–14) at least once per year during the observational period. For this reason, there could be a time difference between the actual T2DM onset and the time point defined by the T2DM diagnosis. However, since patients with LOD tend to start medication later than patients with YOD, we speculate that this technical barrier would not have biased our results. We enrolled patients newly diagnosed with T2DM by considering patients who started oral hypoglycemic agents and excluded patients with T1DM. Therefore, minor forms of diabetes, such as steroid-induced diabetes, pancreatitis, pancreatectomy-induced diabetes, monogenic diabetes, or latent autoimmune diabetes in adults could have been included in our study. However, considering the large number of patients analyzed (n = 84,384), we suggest that the inclusion of patients with minor forms of diabetes would not have biased the overall conclusion of our study.
In summary, among the Korean population, patients with YOD are at an increased risk of developing CKD compared with patients with LOD. The risk of developing CKD in patients with YOD is higher than that in patients with LOD, even after adjusting for clinically distinct characteristics that include age, sex, BMI, smoking, heavy drinking, regular physical activity, low income, hypertension, aspirin use, fasting glucose levels, insulin use, and the number of oral hypoglycemic agents. This suggests that for patients who develop T2DM at an early age more attention is required for the development and prevention of renal complications.