Change in hbA1c following treatment with and the short-term risk of major adverse cardiovascular outcomes

Abstract Background Post-hoc analyses from glucagon-like peptide-1 receptor agonist (GLP1-RA) trial populations have shown a benefit on cardiovascular outcomes from reduction in glycated hemoglobin (HbA1c). It is of interest to see if this finding translates into a cohort of real-world GLP1-RA users. Purpose To study among new GLP1-RA users, how reaching a Hba1c below 53 mmol/mol six months after initiation affects the risk of major adverse cardiovascular outcomes (MACE), compared with a HbA1c above 53 mmol/mol. Methods We included new GLP1-RA users six months after initiation of treatment, with an available HbA1c value 0-6 months before and 0-6 months after GLP1-RA initiation, from the Danish registries between 2010-2022. HbA1c levels pre- and post-treatment were categorized as above 53 mmol/mol or below 53mmol/mol. The primary outcome was defined as a composite of myocardial infarction, stroke, and all-cause death. Patients were followed from index (6 months after GLP1-RA initiation) until the outcome, a total of 1 years, or end-of-study (31.12.21), whichever comes first. Crude 1-year risks were compared using the Kaplan Meier estimator, or the Aalen Johansen estimator if competing risk was present. The effect of HbA1c below 53 mmol/mol versus a HbA1c above 53 mmol/mol on MACE was estimated using a Cox regression model adjusted for age, sex, educational level, baseline comorbidities, type 2 diabetes duration, and baseline cardiovascular disease including heart failure. Hospitalization for hyperglycemia was also evaluated using a Cox regression. Results A total of 4,081 new GLP1-RA users (median age: 58y [IQR:50;66], 52% males) were included, 3,090 had a post-treatment HbA1c below 53 mmol/mol and 991 had a post-treatment Hba1c above 53 mmol/mol. During a median follow-up of 1 year (IQR:1.0,1.0), the crude 1-year risk of MACE in persons with a HbA1c below 53 mmol/mol was 6.4% (95% confidence interval [CI]: 5.5;7.2) and 9.5% (7.7;11.3) in persons with HbA1c above 53 mmol/mol, yielding a hazard rate of 0.69 (0.54;0.88). No interaction between pre-and post HbA1c was found (p=0.59). The hazard rate of hospitalization for hypoglycemia was 0.76 (0.45:1.23) for persons reaching HbA1c level below 53 mmol/mol compared to patients with a HbA1c above 53 mmol/mol, with no interaction between pre- and post HbA1c observed (p =0.052). Conclusion A HbA1c level below 53 mmol/mol, among GLP1-RA users reduced the 1-year rate of MACE and did not significantly increase the 1-y