Early diabetes drug treatment links to better survival after diagnosis thresholds

by · News-Medical

New Korean health-screening data suggest prompt antidiabetic treatment after type 2 diabetes thresholds are crossed may improve survival, while the cardiovascular benefits remain promising but unproven.

In a recent study published in the journal JAMA Network Open, researchers investigated associations between the timing of antidiabetic medication (ADM) initiation and the risk of major adverse cardiovascular events (MACE) and mortality in people newly meeting laboratory diagnostic thresholds for type 2 diabetes (T2D).

T2D is characterized by chronic hyperglycemia that contributes to a higher risk of cardiovascular disease (CVD) and death. Cardiovascular complications constitute the major cause of death among T2D patients, and their mitigation remains a central therapeutic goal. Ideally, regular screening facilitates timely diagnosis and treatment. Nevertheless, T2D is often undetected for years due to absent or mild symptoms, delaying treatment.

A recent 24-year posttrial follow-up of the UK Prospective Diabetes Study found that better glycemic control at T2D diagnosis was associated with lower risk of mortality and myocardial infarction (MI), particularly when near normoglycemia was achieved within the first year, and the benefits remained even after subsequent glycemic deterioration. Building on previous evidence, recent guidelines recommend prompt pharmacological intervention at the time of T2D diagnosis. Nonetheless, there is limited evidence on the outcomes of specific ADM initiation timing on MACE and mortality.

About the Study

In the present study, researchers explored associations between ADM initiation timing and the risk of mortality and MACE in people newly meeting laboratory diagnostic thresholds for T2D. This study implemented a target trial emulation to assess health screening data from the Kangbuk Samsung Health Study (KSHS) linked to health insurance claims in Korea between 2013 and 2022.

KSHS participants who newly exceeded diagnostic thresholds, with fasting plasma glucose (FPG) ≥ 126 mg/dL or glycated hemoglobin (HbA1c) ≥ 6.5%, were included. Time 0, or the cohort entry date, was the date when 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 initiation at 3, 6, and 12 months from time 0, and no initiation within 12 months (control).

ADMs included metformin, glucagon-like peptide-1 receptor agonists, sulfonylureas, insulin, meglitinides, α-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and thiazolidinediones. The study’s primary outcome was a modified composite of three-point MACE (stroke, MI, and all-cause mortality), with all-cause mortality assessed as a separate coprimary outcome. Follow-up continued for 5 years from the first outcome occurrence or until the study end date.

The researchers emulated a prespecified hypothetical trial following a clone-censor-weight approach. They cloned participants into the four treatment strategies and applied artificial censoring whenever deviations from the assigned strategy occurred. Next, the team calculated inverse probability of censoring weights and adjusted the data for potential selection bias introduced by artificial censoring.

Further, the team calculated five-year absolute risk differences and risk ratios between treatment strategies using Kaplan-Meier survival probabilities. Subgroup analyses were conducted by age, sex, presence of prevalent CVD, cohort entry year, baseline estimated glomerular filtration rate (eGFR), and baseline glycemic status. In addition, multiple sensitivity analyses were performed to assess the robustness of the results.

Findings

The study included 23,452 participants with a mean age of 48.2 years, of whom 75.3% were male. Of these, 3,651, 5,057, 6,988, and 18,521 participants adhered to their assigned strategies for ADM initiation within three, six, and 12 months, and no initiation, respectively. At baseline, 24% of participants had hypertension, and approximately 21% used angiotensin receptor blockers.

The mean FPG and HbA1c at time 0 were 141.8 mg/dL and 6.9%, respectively. In total, 21% of participants initiated ADM over 12 months of the grace period, while 53.3% did not initiate treatment during the five-year follow-up. Among ADM classes initiated within 12 months by participants, DPP-4 inhibitors accounted for the largest proportion (33.1%), followed by metformin (30.7%) and SGLT-2 inhibitors (11.8%).

The five-year absolute MACE risk was numerically lower with earlier ADM initiation, increasing from 0.46% to 1.43% as initiation was delayed, although relative risk estimates for MACE were not statistically significant. Further, participants who initiated ADM within three months had the lowest five-year absolute risk of all-cause mortality. Participants with ADM initiation within six and 12 months had comparable all-cause mortality risks, whereas controls had the highest risk. Mortality risk was significantly lower for initiation within 3 months and within 12 months than for no initiation within 12 months, whereas the 6-month estimate did not reach statistical significance.

Earlier ADM initiation showed stronger point estimates for cardiovascular benefit for females, participants under 65 years, and those with prevalent CVD. Notably, ADM initiation earlier than 12 months was not associated with a lower risk among participants without baseline CVD compared to controls. Sensitivity analyses generally supported the robustness of these results, although the authors cautioned that subgroup findings should not be overstated due to limited sample sizes and low event counts.

Conclusions

Taken together, ADM initiation 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 three months. Moreover, participants with prevalent CVD showed stronger point estimates for lower MACE and mortality risk with earlier initiation of ADM. Overall, larger population-based studies are required to corroborate these results, given the observational nature of the study, low event counts, and the relatively young, predominantly male health-screening cohort.

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