P6269Early glycemic changes after initiation of oral anti-diabetic medication and risk of major adverse cardiovascular events: results from a large primary care population of patients with type 2 diabetes
Authors: Ghouse J , Skov M W , Olesen M S , Holst A G , Nielsen J B 
Published: October 2019

Abstract

Background
Results from randomized trials in patients with type 2 diabetes have led to concerns regarding the safety and efficacy of aiming for normoglycemia.

Purpose
To determine the risk of major cardiovascular events (MACE) and death, associated with a large and rapid decline in HbA1C following first time initiation of an oral antidiabetic drug (OAD).

Methods
We included 10,518 primary care patients with T2D, who initiated an OAD for the first time. For each individual, we measured a decline in HbA1C, as the difference between the pre-treatment HbA1C (within 3 months before OAD initiation) and the post-treatment HbA1C (within 1.5–4.5 months after OAD initiation), divided by the time between the two measurements. The decline was reported in mmol/mol change per 3 months in HbA1C and categorized by the median decline into levels of steep (≤−9 mmol/mol [≤−0.8%]) and flat decline (>−11 mmol/mol per 3 mo. [> −1%]). Pre-treatment HbA1C was categorized by the median, into levels of low (48–70 mmol/mol) and high (>70 mmol/mol). Multiple Cox regression was used to study the effect of decline (steep vs. flat) on the outcome hazard rates separately for patients with low and high pre-treatment HbA1C, adjusted for age, sex, traditional cardiovascular risk factors, severe comorbidities, and concomitant medication treatment.

Results
During a median follow-up time of 7.7 years, 1,625 developed MACE and 2,323 died. We found that a steep decline vs. a flat decline was significantly associated with a decreased hazard for MACE, both in individuals high (Figure A; HR 0.81; 95% CI 0.69–0.94; P-value = 0.005) and low pre-treatment HbA1C (Figure A; HR 0.79; 95% CI 0.66–0.96; P-value = 0.015). The hazard of MACE was more pronounced on the short-term vs. long-term in individuals with high pre-treatment HbA1C (Figure A). We found no significant long-term association between combinations of pre-treatment HbA1C and decline categories and hazard of all-cause mortality. However, in patients with a low pre-treatment HbA1C, a steep slope was associated with an increased hazard of 1-year mortality (Figure B; HR 1.52; 95% CI 1.00–2.29; P-value = 0.048).

Conclusions
Using a primary-care population with T2D initiating an OAD for the first time, a combination of a high pre-treatment HbA1C and a large decline in HbA1C observed 3 months post-initiation, was associated with a decreased short-term risk of MACE, while a low pre-treatment HbA1C and a large decline was associated with an increased short-term risk of all-cause mortality. Although observational data have important limitations, our data indicate that clinicians might need to differentiate treatment with OADs based on the level of pre-treatment glycemia and be attentive to the magnitude of the HbA1C lowering observed three months post-initiation.

Acknowledgement/Funding
The Research Foundation at Copenhagen University Hospital, Rigshospitalet