Bonora 2000: Insulin Resistance Indices in Population Studies

Background

Dr. Enzo Bonora and colleagues at the University of Verona published this population-based study examining the relationship between insulin resistance indices and cardiovascular disease outcomes. This landmark study moved beyond diagnostic accuracy to demonstrate that QUICKI and HOMA-IR predict hard clinical outcomes — cardiovascular events and mortality.

Study Design

Population:

• •888 subjects from the Bruneck Study
• •Population-based cohort from northeastern Italy
• •Age 40-79 years at enrollment
• •Comprehensive metabolic phenotyping at baseline (1990)

Follow-up:

• •10-year prospective observation
• •Cardiovascular events: MI, stroke, cardiac death
• •All-cause mortality tracking
• •Complete follow-up in 97% of cohort

Baseline Assessments:

• •Fasting glucose and insulin (QUICKI, HOMA-IR calculation)
• •Euglycemic clamp in subset (n=158) for validation
• •Traditional CVD risk factors
• •Subclinical atherosclerosis by ultrasound

Validation of Fasting Indices

In Clamp Substudy (n=158):

Index	Correlation with Clamp M
QUICKI	r = 0.79
1/HOMA-IR	r = 0.72
Fasting insulin	r = -0.64

QUICKI showed strongest agreement with clamp-measured insulin sensitivity, consistent with prior studies.

Cardiovascular Outcomes

Event Rates by QUICKI Tertile:

QUICKI Tertile	CV Events (%)	Hazard Ratio
Highest (>0.37)	8.2%	Reference
Middle (0.32-0.37)	12.6%	1.5 (1.1-2.1)
Lowest (<0.32)	19.1%	2.3 (1.6-3.4)

Independent Predictors in Multivariate Model: Even after adjustment for traditional risk factors (LDL, HDL, BP, smoking, age, sex), insulin resistance indices remained significant:

• •QUICKI (per 0.01 decrease): HR 1.08 (1.04-1.12)
• •HOMA-IR (per unit increase): HR 1.09 (1.05-1.14)

Mortality Outcomes

All-Cause Mortality by Insulin Resistance:

QUICKI Category	10-Year Mortality	Relative Risk
Insulin Sensitive (>0.37)	9.4%	Reference
Intermediate	13.2%	1.4
Insulin Resistant (<0.32)	18.8%	2.0

Insulin resistance predicted mortality independent of glucose levels — a crucial finding indicating that IR is harmful even without frank diabetes.

Subclinical Atherosclerosis

Carotid Intima-Media Thickness (cIMT):

QUICKI Tertile	Mean cIMT (mm)
Highest	0.82 ± 0.18
Middle	0.91 ± 0.21
Lowest	1.02 ± 0.24

Strong association between insulin resistance and subclinical atherosclerosis, suggesting mechanism for CVD risk.

Mechanistic Discussion

The authors proposed multiple pathways linking insulin resistance to CVD:

1. •Dyslipidemia: IR drives TG-rich VLDL production
2. •Hypertension: Insulin affects renal sodium handling
3. •Endothelial dysfunction: IR impairs NO production
4. •Prothrombotic state: Elevated PAI-1 with IR
5. •Inflammation: hsCRP elevated in insulin resistant subjects

Clinical Implications

Risk Stratification:

• •QUICKI adds to traditional risk factors
• •Identifies high-risk individuals missed by glucose alone
• •Supports aggressive intervention in insulin resistant patients

Treatment Target:

• •Improving QUICKI may reduce CVD risk
• •Lifestyle intervention that improves IR may have CV benefit
• •Provides rationale for insulin-sensitizing therapies

Strengths

1. •Population-based: Generalizable findings
2. •Hard endpoints: CVD events and mortality (not just surrogates)
3. •Long follow-up: 10 years of observation
4. •Clamp validation: Subset confirmed index accuracy
5. •Multivariate analysis: Independent of traditional risk factors

Metabolic Health Perspective

The Bonora study provides powerful motivation for metabolic optimization:

Key Message: Insulin resistance predicts cardiovascular disease and death — even without diabetes. Improving QUICKI is not just a number game; it may reduce risk of heart attack, stroke, and premature death.

For Metabolic Health:

1. •QUICKI is a window into cardiovascular risk
2. •Improving from <0.32 to >0.37 associated with ~50% lower CV risk
3. •Lifestyle changes that improve QUICKI have evidence-based CV benefit
4. •Early intervention (before diabetes) is the optimal window

This study transformed QUICKI from a metabolic research tool into a clinically meaningful marker of cardiovascular risk, providing strong justification for its use in metabolic health optimization programs.