Cardiovasc Diabetol: Multidimensional Characterization of Prediabetes in the Project Baseline Health Study

Background: Prediabetes affects more than one-third of the U.
S.
population and is associated with an increased risk of diabetes and cardiovascular disease (CVD) and higher health care utilization and costs
.
However, prediabetes includes dysglycemia, including impaired fasting glucose, impaired glucose tolerance, and impaired/elevated hemoglobin A1c (HbA1c), as well as a wide range of clinical, chemical, molecular, and pathophysiological abnormalities that are associated with progression to more severe associated with various risks of clinically identifiable diabetes and CVD
.
Identifying abnormalities associated with different glycemic states (euglycemic control, prediabetes, and diabetes) in the general U.
S.
population may help identify causal pathways for development and progression to more severe disease states
.
In addition, identifying abnormalities associated with "high risk" prediabetes, or features associated with a higher risk of progression to diabetes/CVD and complications based on clinical, chemical, molecular and pathophysiological data, will allow for more targeted and Effective preventive interventions
.

The Project Baseline Health Study (ClinicalTrials.
gov NCT 03154346) (PBHS) is a unique, multicenter, prospective cohort study utilizing advanced technology and digital capabilities for recruitment and data collection
.
The PBHS study conducted in-depth phenotyping during in-person study visits, including medical history, physical function measures, imaging, and biospecimen collection, as well as longitudinal digital health data, survey data, and annual follow-up
.

OBJECTIVE: While prediabetes has been described through traditional cohort studies, in this study we used a variety of novel approaches collected in the PBHS study to compare participants with prediabetes with those with normal glycemic control or with diabetes comparison
.
In addition, we identified biomarkers associated with progression from prediabetes to diabetes and reversal of prediabetes to normoglycemic control
.

Methods: The Project Baseline Health Study (PBHS) was a multisite prospective cohort study of 2502 adults with in-depth clinical phenotyping through imaging, laboratory tests, clinical assessments, medical history, personal devices, and surveys
.
Participants were classified by diabetes status (diabetes [DM], prediabetes [preDM], or no diabetes [noDM]) at each visit based on blood glucose, HbA1c, medication, and self-report
.
Principal component analysis (PCA) was performed to create factors for cross-sectional comparisons across groups using linear models
.
Logistic regression was used to determine factors associated with progression from preDM to DM and reversal from preDM to noDM
.

Results: At enrollment, 1605 participants had noDM544 had preDM352 had diabetes
.
After 4 years of follow-up, 52 preDM patients developed DM and 153 patients reverted to noDM
.
Principal component analysis identified clusters of clinical variables consisting of 33 factors; these were tested along with eight individual variables identified a priori as of interest
.
Six PCA factors and six prior variables were significantly different (q < 0.
05) between noDM and preDM and DM after adjustment for false discovery rates for multiple comparisons
.
Of these, two factors (one including glucose measurements and one including anthropometric measurements and physical function) showed a monotonic/graded relationship between groups, as did three a priori variables: ASCVD risk, coronary calcium, and triglycerides ( all q < 10-21)
.
Four factors differed significantly between preDM and noDM but were consistent or similar between DM and preDM: red blood cell index (q = 8 × 10-10), lung function (q = 2 × 10-6), chronic disease Risk (q = 7 × 10-4) and cardiac function (q = 0.
001), as well as diastolic function (q = 1 × 10-10), sleep efficiency (q = 9 × 10-6), and sleep duration (q = 6 × 10-5) prior variables
.
Two factors were associated with progression from prediabetes to diabetes: anthropometric measurements and physical function (OR [95% CI]: 0.
6 [0.
5, 0.
9], q = 0.
04), heart failure and c-reactive protein (OR [95% CI] : 1.
4 [1.
1, 1.
7], q = 0.
02)
.
Anthropometric and physical function factors were also associated with reversion from prediabetes to noDM: (OR [95% CI]: 1.
9 [1.
4, 2.
7], q = 0.
02) and leukocyte index factors (OR [95% CI]: 0.
6 [ 0.
4, 0.
8), q = 0.
02), and the a priori variables ASCVD risk score (OR [95% CI]: as 0.
7 [0.
6, 0.
9] for every 0.
1 increase in CVD score, q = 0.
02) and triglycerides (OR [ 95% CI]: 0.
9 [0.
8, 1.
0]) for every 25 mg/dl increase in q = 0.
05
.

Table 1.
Baseline characteristics of the Project Baseline Health Study (PBHS) cohort

Table 2 Composition of principal component analysis factors

Table 3 PCA factors significantly associated with diabetes group, sorted by overall significance

Table 4 Prior-defined individual variables associated with the diabetes group, ordered by overall significance

Table 5 Factors and individual a priori variables associated with progression from prediabetes to diabetes

CONCLUSIONS: PBHS participants with preDM exhibited pathophysiological changes in cardiac, pulmonary, and hematological markers as well as decreases in physical function and sleep markers before DM; some changes predicted an increased risk of progression to diabetes
.
Factors that measure body markers and physical function are the most important factors associated with progression to diabetes and reversal to non-diabetic diabetes
.
Future research may determine whether these changes shed light on pathways to diabetes and related complications, and whether they can be used to identify individuals at high risk of developing diabetes for targeted preventive interventions
.

Original source: Chatterjee R, Kwee LC, Pagidipati N, et al.
Multi-dimensional characterization of prediabetes in the Project Baseline Health Study.
Cardiovasc Diabetol 2022 Jul 18;21(1)