Glycated hemoglobin and cardiovascular risk in diabetes mellitus: Evolving evidence beyond glycemic control

Table 1 Summary of various trials evaluating glycated hemoglobin and cardiovascular outcome

Ref.	Design and population	HbA1c exposure or contrast	Cardiovascular outcome	Main finding
Selvin et al[12]	Meta-analysis of observational studies in diabetes	Per 1% higher HbA1c	Composite CVD	Pooled relative risk 1.18 for CVD in type 2 diabetes
UKPDS 33[23]	RCT; newly diagnosed type 2 diabetes	Intensive 7.0% vs conventional 7.9%	Diabetes-related and vascular endpoints	12% lower any diabetes-related endpoint; 25% lower microvascular risk; no clear macrovascular benefit during trial
UKPDS 34[24]	RCT; overweight, newly diagnosed type 2 diabetes	Metformin 7.4% vs conventional 8.0%	Diabetes-related death and mortality	32% lower any diabetes-related endpoint; 42% lower diabetes-related death; 36% lower all-cause mortality
UKPDS 80[31]	Post-trial follow-up	Prior intensive vs prior conventional control	MI and death	Emergent legacy benefit: 15% lower MI and 13% lower all-cause death; metformin subgroup retained larger benefits
ACCORD[4]	RCT; long-standing, high-risk type 2 diabetes	Target < 6.0% vs standard 7.0%-7.9%	Composite major adverse cardiovascular events and death	No convincing primary cardiovascular gain; mortality increased with intensive strategy
ADVANCE/ADVANCE-ON[5,27]	RCT and observational follow-up	Intensive strategy targeting ≤ 6.5%	Vascular events, mortality	Reduced microvascular events; no durable macrovascular or mortality benefit in follow-up
VADT/15-year follow-up[3,28]	RCT and extended follow-up; veterans with long-standing type 2 diabetes	Median 6.9% vs 8.4%	Major cardiovascular events	Neutral at trial end; delayed reduction in major CVD events on longer follow-up
TECOS secondary analysis[14]	Secondary analysis; type 2 diabetes with established ASCVD	Baseline and time-varying HbA1c	HF hospitalisation, death, non-HF cardiovascular events	U-shaped association; lowest risk around HbA1c 7%

CVD: Cardiovascular disease; HbA1c: Glycated hemoglobin; HF: Heart failure; MI: Myocardial infarction; RCT: Randomised controlled trial; UKPDS: United Kingdom Prospective Diabetes Study.