Age at diagnosis, glycemic trajectories, and responses to oral glucose-lowering drugs in type 2 diabetes in Hong Kong: A population-based observational study.

Background Lifetime glycemic exposure and its relationship with age at diagnosis in type 2 diabetes (T2D) are unknown. Pharmacologic glycemic management strategies for young-onset T2D (age at diagnosis <40 years) are poorly defined. We studied how age at diagnosis affects glycemic exposure, glycemic deterioration, and responses to oral glucose-lowering drugs (OGLDs). Methods and findings In a population-based cohort (n= 328,199; 47.2% women; mean age 34.6 and 59.3 years, respectively, for young-onset and usual-onset [age at diagnosis >= 40 years] T2D; 2002-2016), we used linear mixed-effects models to estimate the association between age at diagnosis and A1C slope (glycemic deterioration) and tested for an interaction between age at diagnosis and responses to various combinations of OGLDs during the first decade after diagnosis. In a register-based cohort (n= 21,016; 47.1% women; mean age 43.8 and 58.9 years, respectively, for young- and usual-onset T2D; 2000-2015), we estimated the glycemic exposure from diagnosis until age 75 years. People with young-onset T2D had a higher mean A1C (8.0% [standard deviation 0.15%]) versus usual-onset T2D (7.6% [0.03%]) throughout the life span (p< 0.001). The cumulative glycemic exposure was >3 times higher for young-onset versus usual-onset T2D (41.0 [95% confidence interval 39.1-42.8] versus 12.1 [11.8-12.3] A1C-years [1 A1C-year = 1 year with 8% average A1C]). Younger age at diagnosis was associated with faster glycemic deterioration (A1C slope over time +0.08% [0.078-0.084%] per year for age at diagnosis 20 years versus +0.02% [0.016-0.018%] per year for age at diagnosis 50 years;p-value for interaction <0.001). Age at diagnosis >= 60 years was associated with glycemic improvement (-0.004% [-0.005 to -0.004%] and -0.02% [-0.027 to -0.0244%] per year for ages 60 and 70 years at diagnosis, respectively;p-value for interaction <0.001). Responses to OGLDs differed by age at diagnosis (p-value for interaction <0.001). Those with young-onset T2D had smaller A1C decrements for metformin-based combinations versus usual-onset T2D (metformin alone: young-onset -0.15% [-0.105 to -0.080%], usual-onset -0.17% [-0.179 to -0.169%]; metformin, sulfonylurea, and dipeptidyl peptidase-4 inhibitor: young-onset -0.44% [-0.476 to -0.405%], usual-onset -0.48% [-0.498 to -0.459%]; metformin and alpha-glucosidase inhibitor: young-onset -0.40% [-0.660 to -0.144%], usual-onset -0.25% [-0.420 to -0.077%]) but greater responses to other combinations containing sulfonylureas (sulfonylurea alone: young-onset -0.08% [-0.099 to -0.065%], usual-onset +0.06% [+0.059 to +0.072%]; sulfonylurea and alpha-glucosidase inhibitor: young-onset -0.10% [-0.266 to 0.064%], usual-onset: 0.25% [+0.196% to +0.312%]). Limitations include possible residual confounding and unknown generalizability outside Hong Kong. Conclusions In this study, we observed excess glycemic exposure and rapid glycemic deterioration in young-onset T2D, indicating that improved treatment strategies are needed in this setting. The differential responses to OGLDs between young- and usual-onset T2D suggest that better disease classification could guide personalized therapy. Author summaryWhy was this study done? Young-onset type 2 diabetes (diagnosed before age 40 years) is an aggressive disease, associated with higher risks of mortality and other complications compared with usual-onset type 2 diabetes (diagnosed at age 40 years or after). Although exposure to hyperglycemia is a key risk factor for type 2 diabetes complications, the magnitude of this exposure over a lifetime has never been quantified. Because young people were excluded from randomized control trials of oral glucose-lowering drugs, it is unknown whether these drugs are effective for treating young-onset type 2 diabetes. What did the researchers do and find? Young-onset type 2 diabetes was associated with over triple the exposure to hyperglycemia from diagnosis until age 75 years compared with usual-onset type 2 diabetes. Diabetes progressed much faster in young-onset type 2 diabetes compared with usual-onset type 2 diabetes. Compared with usual-onset type 2 diabetes, people with young-onset type 2 diabetes had smaller responses to most metformin-based drug combinations and greater responses to other combinations containing sulfonylureas. What do these findings mean? Excess exposure to hyperglycemia and rapid disease progression in young-onset T2D call for better treatment strategies. The differential responses to oral glucose-lowering drugs between young- and usual-onset T2D suggest that better disease classification could guide personalized therapy.