Combined associations of family history and self-management with age at diagnosis and cardiometabolic risk in 86,931 patients with type 2 diabetes: Joint Asia Diabetes Evaluation (JADE) Register from 11 countries

In 2019, 9.3% of the global adult population were affected by diabetes with 50% living in Asia [1]. The majority had type 2 diabetes (95%) characterized by varying degrees of insulin resistance and deficiency [2], often accompanied by clustering of cardiometabolic risk factors [3]. Delayed diagnosis and management of diabetes can lead to poor quality of life, multimorbidity, and premature mortality [4, 5]. Young-onset type 2 diabetes diagnosed before age of 40 has become increasingly prevalent [6]. The growing burden of young-onset type 2 diabetes is multifactorial, including but not limited to genetics, perinatal factors, childhood obesity, and unhealthy lifestyles [6, 7]. In the clinic-based Joint Asia Diabetes Evaluation (JADE) Register, 1 in 5 Asian adults had young-onset type 2 diabetes [8], who had worse control of cardiometabolic risk factors than their peers with late-onset disease [6, 9]. In these young people, decades of exposure to cardiometabolic risk factors can lead to premature complications and death with socioeconomic implications [10].

Family history (FamH) is a strong risk factor for type 2 diabetes [11], evidenced by a higher concordance rate among monozygotic than dizygotic twins [12, 13]. People with FamH of diabetes had early onset of type 2 diabetes [14‐18] and increased risks for hypertension, dyslipidemia, and obesity [19, 20]. Apart from shared genotypes, a FamH of diabetes might reflect shared behaviors and environment, such as lifestyles (physical inactivity, unhealthy diet, alcohol, and tobacco use) and socioeconomic status (education, employment, and household income) [20, 21]. On the other hand, some researchers had reported 40–80% reduced risk of type 2 diabetes associated with FamH, probably due to increased perceived risk and motivation to change lifestyles for mitigating risk [22].

Diabetes is a complex disease comprising of, but not limited to, genetic, perinatal, demographic, cognitive-psychosocial-behavioral, environmental, and ecological components with FamH being a proxy of some of these components [2], modified by self-management and access to care to influence age of diagnosis and clinical outcomes (Additional file 1: Figure S1) [2]. Despite this plausibility, there is a paucity of data on the interactive effects between FamH and behavioral factors on disease onset and cardiometabolic risks in type 2 diabetes. In this study, we hypothesize that FamH interacts with unhealthy lifestyles to bring forward age of diagnosis and together with suboptimal self-management, proxied by self-monitoring of blood glucose (SMBG), worsen control of cardiometabolic risk factors compared to those without FamH. We argue that while FamH per se is a non-modifiable risk factor, FamH can be used as a simple proxy to identify high-risk individuals for intensive lifestyle modification to delay disease onset and self-management support programs to improve control of cardiometabolic risk factors. We tested this hypothesis using data from a multicenter diabetes register in Asia with documentation of age of diagnosis, lifestyles, SMBG, and cardiometabolic risk factors.

A total of 113,184 patients with diabetes were enrolled in the JADE Register from 2007 to 2021. After excluding patients with type 1 diabetes (n=1567) or unclassified diabetes (n=8310) and incomplete FamH data (n=16,376), we included 86,931 (76.8%) patients with type 2 diabetes [mean±SD age: 56.6±11.6 years, 53.5% men] in our final analysis (Table 1). Overall, 59.5% of the patients reported a positive FamH, with mother-only FamH being most common (13.2%), followed by siblings-only FamH (11.5%) and father-only FamH (9.8%). Among the 11 countries/regions, the prevalence of FamH ranged from 39.1 to 85.3% (Fig. 1). Compared with the non-FamH group, the FamH group was younger without sex preponderance (Table 1). They had better education (middle school or above) and were more likely to be actively employed and perform regular SMBG, but less likely to report a healthy lifestyle (healthy diet, never or ex-smoker, never or occasional alcohol drinker) (adjusted p-values<0.05).

Figures 2 and 3 show the cumulative proportion defined by age at diagnosis across FamH groups. Overall, the FamH group was diagnosed 4.6 years earlier than the non-FamH group [mean (95% CI): 47.9 (47.8–48.0 years) vs. 52.5 (52.4–52.6) years] (Fig. 2). Patients with FamH affecting both parents with/without siblings had the earliest age at diagnosis [44.6 (44.5-44.8 years)], followed by FamH affecting single parent with/without siblings [47.7 (47.6-47.8 years)] and FamH affecting siblings only [51.5 (51.3-51.7 years)], with non-FamH group having the oldest age at diagnosis [52.5 (52.4-52.6 years)] (Fig. 3). The findings were consistent across the 11 countries/regions.

Figure 4 presents the combined associations of lifestyles and FamH with mean age at diagnosis. The non-FamH group with ≥2 healthy lifestyles had the oldest age at diagnosis [52.8 (52.7–52.9) years] while the FamH group with <2 healthy lifestyles had the earliest age at diagnosis [46.0 (45.8–46.2) years]. The FamH group with ≥2 healthy lifestyles had an age at diagnosis [48.2 (48.1–48.3) years] close to the non-FamH group with <2 healthy lifestyles [50.1 (49.8–50.5) years]. Similar patterns were observed in 11 Asian countries/regions. The results of sensitivity analysis (Additional file 1: Figure S2) including patients with type 2 diabetes diagnosed within 1 year before enrolment (n=8,556) were consistent with the overall analysis (n=86,931).

After adjusting for country, years of registration, demographics, education, employment status, lifestyles, SMBG, and medication use at registration, the FamH group had higher odds of hypertension (aOR 1.10, 95% CI 1.05–1.14) and dyslipidemia (aOR 1.19, 95% CI 1.13–1.26) but also higher odds of achieving the “A” goal (aOR 1.05, 95% CI 1.02–1.09), “B” goal (aOR 1.06, 95% CI 1.02–1.10), and ≥2 “ABC” goals (aOR 1.07, 95% CI 1.03–1.11), albeit with considerable inter-country variations (Fig. 5). Patients with affected parents with/without siblings also had higher adjusted odds of hyperglycemia, hypertension, and dyslipidemia compared to patients with affected siblings only (Fig. 6).

Self-management (healthy lifestyles plus SMBG) was associated with lower odds of hyperglycemia, hypertension, and dyslipidemia, and higher odds of attaining each “ABC” goal in both FamH and non-FamH groups, with greater strength of associations in the FamH group (Fig. 7F). The interaction term (FamH × self-management) was associated with lower odds of hypertension (aOR 0.90, 95% CI 0.82–0.98) and higher odds of achieving the “A” goal (aOR 1.10, 95% CI 1.00–1.20), “B” goal (aOR 1.20, 95% CI 1.10–1.31), “C” goal (aOR 1.18, 95% CI 1.08–1.28), and ≥ 2 “ABC” goals (aOR 1.19, 95% CI 1.08–1.30) (Additional file 1: Table S2). Subgroup analyses showed interaction between each behavior and FamH (Fig. 7A–D) except for SMBG with similar effect size in FamH and non-FamH group (Additional file 1: Table S2) while never or occasional use of alcohol was associated with lower odds of “A” and “B” goal achievement.

Based on hypothesis defined a priori, to the best of our knowledge, this is the first real-world evidence on the combined associations of  FamH and behavioral factors with  age at  diagnosis and control of cardiometabolic risk factors in Asian patients with type 2 diabetes. In this study, the proportion of patients with FamH of diabetes ranged from 39.1% in Vietnam to 85.3% in Malaysia, similar to the 40–60% prevalence of FamH reported from Korea, India, and Belgium [14‐17], Overall, the FamH group was diagnosed 4.6 years younger than the non-FamH group which was the same as that reported in a Korean study [14]. In Sydney, other researchers also showed earlier age of diagnosis by 1.7 years for every 10% increase in affected family members [29].

The FamH plus unhealthy lifestyle group had the earliest age at diagnosis (46.0 years) while the non-FamH plus healthy lifestyle group had the oldest age at diagnosis (52.8 years). Interestingly, the FamH plus healthy lifestyle group (48.2 years) had similar age at diagnosis as the non-FamH plus unhealthy lifestyle group (50.1 years). This trend was found in both newly diagnosed patients and those with established diabetes. In part due to their younger age and active work-life, the FamH group was less likely to report healthy lifestyles with suboptimal control of cardiometabolic risk factors. While self-management (healthy lifestyle plus SMBG) was associated with better control of cardiometabolic risk factors and attainment of treatment goals in both FamH and non-FamH groups, this association was more marked in the FamH group with significant interaction. Although some researchers had specifically reported that healthy lifestyles might delay the onset of diabetes [30], no stratified analysis by FamH was reported.

The proportions of patients with FamH vary amongst different countries/regions. This might reflect different levels of public awareness regarding the familial nature of diabetes and access to early detection programs. Despite differences in national income levels, health systems and access to medicines, care, and support, the interactions between FamH and self-management on age at diagnosis and control of cardiometabolic risk factors were consistent across all participating Asian countries or areas. In our study, 1 in 3 patients reported a maternal history of diabetes with or without other affected family members. This accords with the known risk associations of maternal hyperglycemia with early-onset diabetes in the offspring [2, 31], likely attributable to intrauterine effects of maternal obesity and gestational diabetes [6]. Apart from shared environment, lifestyles, common and rare genetic factors [32], chronic hepatitis B infection, and hemoglobinopathy (affecting 6–10% of the Asian population) with familial clustering were associated with increased risk of diabetes. These risk associations might be due to low grade inflammation and oxidative stress, which might contribute to the familial clustering of diabetes [33, 34].

In our literature search, we did not find direct evidence suggesting that FamH raised awareness resulting in early screening and younger age of diagnosis. Some researchers had reported that African Americans with FamH were more aware of risk factors for diabetes and more likely to consume fruits and vegetables and engage in diabetes screening [35]. This might lead to a younger age of diagnosis, especially in healthcare systems with easy access to screening service. However, in our study, patients with FamH were less likely to report healthy lifestyles, which might interact with genetic factors to bring forward age at  diagnosis. On the other hand, compared with those without FamH, they were more likely to perform SMBG. Given the benefits of peer support on self-management [36], we hypothesize that mutual support among affected family members might motivate increased use of SMBG to control blood glucose. In the International Diabetes Mellitus Practice Survey recruiting patients outside Europe and North America, SMBG was the only factor associated with attainment of HbA_1c goal across all regions [27]. Data from the Taiwan Diabetes Registry also shows that SMBG was associated with higher odds of HbA_1c<7% in patients with recently diagnosed type 2 diabetes [35]. Qualitative analysis through direct interview may provide more insights on differences in behavioral determinants such as values, perspectives, and concerns between people with or without FamH [2].

A FamH of diabetes is a complex indicator of the multicausality of type 2 diabetes. While FamH and non-white ethnicity are well-known risk factors for type 2 diabetes, for the first time, our real-world evidence had quantified the age at diagnosis in patients with or without FamH and their associations with cardiometabolic risks, with potential modification by self-management. Given the legacy effect of glycemic control on future clinical events [40, 41], early detection of prediabetes in family members of affected patients for lifestyle intervention might delay onset of diabetes. In patients with familial diabetes, promoting self-management might be particularly effective in controlling cardiometabolic risk factors. These results supported the recommendation of implementing a data-driven integrated diabetes program to adopt a family-based approach to detect, prevent, and treat diabetes focusing on empowerment with ongoing support [42].