What is the clinical evidence from this study?

Study design: Cohort. Population: Cardiovascular disease risk (n=3983). Intervention: High long-term fasting insulin variability vs. Low long-term fasting insulin variability. Primary outcome: Fatal and nonfatal cardiovascular events (HR 1.65, 95% CI 1.13-2.39, p=0.009).

What does this research mean for the field?

High long-term fasting insulin variability during young adulthood before the onset of diabetes increases the risk of cardiovascular disease by 65% and all-cause mortality by 97% in later life. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

March 8, 2025Open Access

Association of long-term insulin variability before the onset of diabetes with cardiovascular outcomes in later life: Findings from the coronary artery risk development in young adults (CARDIA) study

Key Result

High long-term fasting insulin variability during young adulthood increased the risk of cardiovascular disease by 65% (HR 1.65) and all-cause mortality by 97% (HR 1.97) compared to low variability.

Study Design

Type

Cohort (n=3,983)

Multicenter

Yes

Structured PICO

Does high long-term fasting insulin variability increase the risk of incident cardiovascular disease and all-cause mortality in young adults before the onset of diabetes?

Population

3,983 young adults aged 18 to 30 years with at least three fasting insulin measurements before the onset of diabetes (CARDIA study participants)

Intervention

High long-term fasting insulin variability (high tertile of average real variability [ARV] and standard deviation [SD] of insulin)

Comparator

Low long-term fasting insulin variability (low tertile of insulin ARV)

Outcome

Incident cardiovascular disease (CVD) and all-cause mortalityhard clinical

High long-term fasting insulin variability in young adulthood before diabetes onset is independently associated with an increased risk of future cardiovascular disease and all-cause mortality.

Main Result

Effect estimate: HR 1.65 (95% CI 1.13-2.39)

Absolute Event Rate: 2.92% vs 1.22%

p-value: p=0.009

Limitations

The study specifically recruited black and white participants, so conclusions may not be generalizable to other racial and ethnic groups.
Coronary artery calcification (CAC) was not assessed at baseline, so it is not known with certainty that CAC developed over the years.
As an observational study, there may be residual and unknown confounding factors despite multiple adjustments.

Abstract

• Long-term insulin variability helps to identify the risk of CVD and all-cause mortality. • Long-term insulin variability was associated with the degree but not the presence of CAC. • Minimizing insulin variability helps to prevent cardiovascular risks in later life. The important effects of variability of some physiological/biological characteristics (such as LDL cholesterol, blood pressure) on cardiovascular outcomes have been elucidated, while the role of insulin variability is undefined. To investigate the associations of long-term fasting insulin variability during young adulthood before the onset of diabetes with subsequent cardiovascular outcomes in middle age. We included 3,983 CARDIA (Coronary Artery Risk Development Study in Young Adults) participants aged 18 to 30 years with at least three fasting insulin measurements. Intra-individual fasting insulin variability was defined by the average real variability (ARV) of insulin and standard deviation (SD) of insulin during 30-year follow-up. The presence and the degree of coronary artery calcification (CAC) were assessed by computed tomography at year 25. Incident cardiovascular disease (CVD) and all-cause mortality were adjudicated. After multivariable adjustment, comparing high versus low tertile of insulin ARV, the hazard of CVD increased by 65% (HR, 1.65; 95% CI, 1.13-2.39) and all-cause mortality by 97% (HR, 1.97; 95% CI, 1.38-2.82). Higher tertile of insulin ARV was associated with significantly worse degree of CAC (β =0.1; 95% CI, 0.03-0.18) but not with the presence of CAC ( P =0.197). Similar results were also observed in insulin SD. High long-term insulin variability in young adulthood before the onset of diabetes was associated with an increased risk of CVD and all-cause mortality in later life, independent of average FG, HOMA-IR and other established cardiovascular risk factors. Long-term insulin variability was associated with the degree but not the presence of CAC.

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