New health screening data from South Korea suggest that while antidiabetic treatment administered promptly after the threshold for type 2 diabetes is crossed may improve survival rates, cardiovascular benefits remain promising but unproven.
Study: Timing of antidiabetic drug initiation and risk of cardiovascular events and death. Image credit: Anastasiya Artcomma / Shutterstock
In a recent study published in the journal JAMA network openresearchers investigated the association between the timing of antidiabetic drug (ADM) initiation and the risk of major major cardiovascular events (MACE) and death in people who newly reach laboratory diagnostic thresholds for type 2 diabetes (T2D).
T2D is characterized by chronic hyperglycemia, which increases the risk of cardiovascular disease (CVD) and death. Cardiovascular complications constitute the main cause of death in T2D patients, and their reduction remains a central treatment goal. Ideally, regular screening facilitates timely diagnosis and treatment. Despite this, T2D often remains undetected for years due to no or mild symptoms, delaying treatment.
A recent 24-year post-trial follow-up of the UK Prospective Diabetes Study found that good glycemic control at the time of T2D diagnosis, especially if near euglycemia was achieved within the first year, was associated with lower risk of mortality and myocardial infarction (MI), with benefits persisting even after subsequent glycemic deterioration. Based on previous evidence, recent guidelines recommend prompt pharmacological intervention at the time of T2D diagnosis. Nevertheless, evidence regarding the consequences of specific ADM initiation timing on MACE and mortality is limited.
About research
In this study, researchers investigated the association between the timing of ADM initiation and the risk of death and MACE in people who newly reached laboratory diagnostic thresholds for T2D. In this study, we conducted targeted trial emulation to evaluate health examination data from the Gangbuk Samsung Health Survey (KSHS) related to Korean health insurance claims from 2013 to 2022.
KSHS participants who newly crossed diagnostic thresholds of fasting plasma glucose (FPG) ≥126 mg/dL or glycated hemoglobin (HbA1c) ≥6.5% were included. Time 0, the cohort entry date, is the date on which these HbA1c or FPG values were first recorded. Individuals with a T1D diagnosis or ADM prescription before time 0 were excluded. The team defined four treatment strategies. ADM starts 3, 6, and 12 months after month 0, but not within 12 months (control).
ADMs include metformin, glucagon-like peptide-1 receptor agonists, sulfonylureas, insulin, meglitinides, alpha-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and thiazolidinediones. The primary outcome of this study was a modified composite of the three-point MACE (stroke, MI, and all-cause mortality), with all-cause mortality assessed as a separate secondary outcome. Follow-up continued for 5 years from the occurrence of the first outcome or until the study end date.
The researchers followed a clone sensor weight approach to emulate a prespecified hypothesis test. They cloned participants into four treatment strategies and applied artificial censorship whenever deviations from the assigned strategy occurred. The team then calculated the inverse probability of censoring weights to adjust the data for potential selection bias introduced by artificial censoring.
Additionally, the team used Kaplan-Meier survival probabilities to calculate 5-year absolute risk differences and risk ratios between treatment strategies. Subgroup analyzes were performed by age, sex, presence of prevalent CVD, year of cohort entry, baseline estimated glomerular filtration rate (eGFR), and baseline glycemic status. Additionally, multiple sensitivity analyzes were performed to assess the robustness of the results.
Survey results
The study included 23,452 participants with an average age of 48.2 years, of whom 75.3% were male. Of these, participants 3,651, 5,057, 6,988, and 18,521 adhered to their assigned strategies to initiate ADM within 3 months, 6 months, and 12 months, respectively, and did not initiate ADM. At baseline, 24% of participants had hypertension and approximately 21% were using angiotensin receptor antagonists.
Mean FPG and HbA1c at time 0 were 141.8 mg/dL and 6.9%, respectively. In total, 21% of participants started ADM during the 12-month grace period, while 53.3% did not start treatment during the 5-year follow-up period. Among the ADM classes that participants started within 12 months, DPP-4 inhibitors accounted for the largest proportion (33.1%), followed by metformin (30.7%) and SGLT-2 inhibitors (11.8%).
The 5-year absolute MACE risk was numerically lower with earlier ADM initiation and increased from 0.46% to 1.43% with delayed initiation, but the relative risk estimate for MACE was not statistically significant. Furthermore, participants who started ADM within 3 months had the lowest absolute risk of all-cause mortality over 5 years. Participants who started ADM within 6 and 12 months had comparable all-cause mortality risks, whereas the control group had the highest risk. The risk of death was significantly lower when treatment was started within 3 and 12 months than when treatment was not started within 12 months, but the 6-month estimate did not reach statistical significance.
Previous initiation of ADM showed stronger point estimates for cardiovascular effects for women, participants younger than 65 years, and participants with prevalent CVD. Of note, ADM initiation earlier than 12 months was not associated with reduced risk in participants without baseline CVD compared with controls. Sensitivity analyzes generally supported the robustness of these results, but the authors cautioned that subgroup results should not be overstated due to limited sample size and low number of events.
conclusion
Overall, starting ADM within 12 months of exceeding the diagnostic threshold for T2D was associated with a lower risk of all-cause mortality, with the clearest reduction observed for initiation within 3 months. Furthermore, participants with prevalent CVD had higher point estimates of reduced MACE and mortality risk with early initiation of ADM. Overall, given the observational nature of the study, the small number of events, and the relatively young, predominantly male health screening cohort, larger population-based studies are needed to confirm these results.
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