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.

Table 2 Various guidelines and their summaries about glycated hemoglobin and cardiovascular risk

Guideline or consensus source	Glycaemic target statement	Cardiovascular implication
ADA standards 2025[51]	HbA1c < 7% is appropriate for many non-pregnant adults; targets should be individualised, with more stringent or less stringent goals according to safety and burden	HbA1c remains important, but glycaemic goals should not be pursued at the cost of severe hypoglycaemia or excessive treatment burden
ADA/European Association for the Study of Diabetes consensus 2022[47]	HbA1c remains central to monitoring, but target-setting should be person-centred and tailored to comorbidity, duration, patient preference, and treatment risk	In ASCVD, HF, or chronic kidney disease, drug selection should prioritise organ protection, not HbA1c lowering alone
European Society of Cardiology diabetes/CVD guideline 2023[57]	Glycaemic management should be personalised within comprehensive cardiovascular risk reduction	HbA1c should be interpreted within broader CVD prevention, with strong emphasis on therapies proven to reduce ASCVD, HF, and renal events

ADA: American Diabetes Association; CVD: Cardiovascular disease; HbA1c: Glycated hemoglobin; HF: Heart failure.