Long-Term Glucose-Lowering Therapy Lowers Cardiovascular Risk in Diabetes

A nationwide cohort study published in The Lancet Regional Health – Europe found that long-term adherence trajectories to noninsulin glucose-lowering medication were associated with meaningful differences in cardiovascular outcomes among adults with newly diagnosed type 2 diabetes (T2D).¹

Using group-based trajectory modeling of pharmacy dispensing data from nearly 80,000 Danish adults, investigators identified 3 distinct adherence patterns and found that those with persistently low adherence had a 27% higher rate of major cardiovascular events than those who sustained high adherence over a decade.¹

Study Design and Adherence Trajectories

Investigators analyzed data from 79,510 Danish adults with newly diagnosed T2D who initiated noninsulin glucose-lowering medication between 2005 and 2012. Medication adherence was estimated from pharmacy dispensing records using the proportion of days covered, and group-based trajectory modeling was applied to repeated monthly adherence measures to characterize longitudinal patterns rather than relying on static, single-point metrics.¹

Three long-term adherence trajectories emerged: high adherence (41% of the cohort), intermediate adherence (33%), and low adherence (26%). The high-adherence group showed a decline beginning 4 years after treatment initiation, the intermediate group showed stable but moderate adherence, and the low-adherence group showed an early decline that persisted throughout follow-up.¹

Compared with the low-adherence group, individuals with high adherence were younger (median age, 59 years vs 63 years), more frequently male (60% vs 50%), and more often free of comorbidities other than diabetes at baseline (87.8% vs 83.7%). They were also more likely to live with others, have higher socioeconomic status, and use multiple glucose-lowering medication classes during follow-up.¹

Cardiovascular Outcomes Over a Decade

The primary outcome was a composite of ischemic heart disease, stroke, or heart failure. Over a median follow-up of 10 years, 15,276 cardiovascular events occurred. Crude cardiovascular disease (CVD) incidence rates per 1000 person-years were 30.1 in the low-adherence group, 23.3 in the intermediate-adherence group, and 19.7 in the high-adherence group.¹

After adjustment for demographic, clinical, social, and behavioral factors, the adjusted hazard ratio (HR) for the composite cardiovascular outcome was 1.07 (95% CI, 1.03-1.12) for intermediate adherence and 1.27 (95% CI, 1.21-1.33) for low adherence compared with high adherence. Using restricted mean survival time analysis, individuals in the high-adherence group remained free of cardiovascular events for an average of 220 additional days (95% CI, 204-237) over 10 years compared with those in the low-adherence group.¹

When cardiovascular outcomes were examined separately, the strongest association was observed for ischemic heart disease, with an adjusted HR of 1.45 (95% CI, 1.37-1.54) for low adherence compared with high adherence. Low adherence, but not intermediate adherence, was also associated with a higher stroke rate (HR, 1.24; 95% CI, 1.15-1.34). No significant associations were observed for heart failure, which investigators attributed to differing underlying pathophysiology and potentially lower statistical power due to fewer events.¹

Early-Onset Diabetes and Younger Adults at Greatest Risk

Stratified analyses showed that the relative impact of low adherence was greatest among younger individuals. Among adults younger than 55 years, low adherence was associated with a 51% higher rate of cardiovascular events (HR, 1.51; 95% CI, 1.38-1.65) compared with high adherence. In analyses restricted to early-onset CVD, defined as events occurring before age 55 years, low adherence was associated with a 73% higher rate of events compared with high adherence (HR, 1.73; 95% CI, 1.54-1.94).¹

The authors noted that younger adults with T2D face higher lifetime cardiovascular risk and more years of potential life lost, underscoring the importance of early and sustained adherence support in this population. Sensitivity analyses, including inverse probability of treatment weighting and models forcing 4 or 5 adherence trajectory groups, produced results consistent with the primary findings.¹

Broader Context: Newer Agents and Glycemic Targets

Separate analyses of cardiovascular outcome trials have examined how specific drug classes and glycemic targets relate to cardiovascular risk in T2D, offering additional context for the adherence findings above. A systematic review and meta-analysis of cardiovascular outcome trials and real-world cohort studies found that sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor (GLP-1) agonists provided comparable cardiovascular and kidney benefits regardless of patients' baseline statin or lipid-lowering therapy status, suggesting these agents' benefits are not simply additive to lipid control.²

A separate network meta-analysis of 126 randomized controlled trials found that among SGLT-2 inhibitors, GLP-1 receptor agonists, and pioglitazone specifically, achieving a hemoglobin A_1C of 7.0% or lower was associated with a modestly reduced risk of major adverse cardiovascular events compared with levels above 7.0%, without an effect on all-cause mortality.³

Taken together with the adherence trajectory findings, this body of evidence points to sustained engagement with glucose-lowering therapy, across drug classes, as a meaningful lever for long-term cardiovascular risk reduction in T2D.

REFERENCES

1. Nielsen LB, Bartholdy A, Nguyen TL, et al. Long-term adherence to glucose-lowering therapy and cardiovascular risk in type 2 diabetes: a nationwide cohort study. Lancet Reg Health Eur. 2026;68:101795. Published 2026 Jul 31. doi:10.1016/j.lanepe.2026.101795

2. Kunutsor SK, Seidu BS, Seidu S. Cardiovascular effectiveness of newer glucose-lowering agents, with and without baseline lipid-lowering therapy in type 2 diabetes: A systematic meta-analysis of cardiovascular outcome trials and real-world evidence. Prim Care Diabetes. 2024;18(6):589-598. doi:10.1016/j.pcd.2024.09.007

3. de Carvalho LSF, Nogueira ACC, Bonilha I, et al. Glucose-Lowering and the Risk of Cardiovascular Events With Antidiabetic Therapies: A Systematic Review and Additive-Effects Network Meta-Analysis. Front Cardiovasc Med. 2022;9:876795. Published 2022 Apr 29. doi:10.3389/fcvm.2022.876795