Prediabetes Subphenotyping: A Novel Approach to Type 2 Diabetes Prevention
New research proposes pathophysiology-based subphenotyping of individuals at increased risk for T2D; 6 are suggested to help refine screening, prevention, and treatment.
Prediabetes is widely recognized as predisposing patients to a higher probability of progression to type 2 diabetes (T2D) and the elevated glycemic condition itself increases risk of micro- and macrovascular complications.
But not all patients with prediabetes are alike.
German researchers recently proposed subphenotyping of patients at increased risk for T2D in an effort to improve screening, prevention, and treatment strategies. Their findings were reported recently on the preprint server MedRxiv, in the journal Nature Medicine, and a review article in Diabetes Therapy.
For a concise summary of the research and characteristics of the 6 prediabetes subphenotypes identified, click through the slides below.
A growing need. Only about 10% of patients with prediabetes progress to T2D each year, while others remain in the same intermediate hyperglycemic state during their lifespan or reverse to normal glucose tolerance. Still, the prevalence of prediabetes is thought to be rising, suggesting a greater need for effective screening and timely interventions.
Inadequate definitions. Intermediate hyperglycemia is indicative of elevated T2D risk, but the current definition of prediabetes does not reflect subphenotypes of pathophysiology or predict future metabolic trajectories. Causes of β-cell dysfunction and insulin resistance, as well as individual trajectories of hyperglycemia and subsequent complications, may be much more heterogeneous than previously thought.
Blood glucose is not enough. The current binary definition of T2D, based solely on blood glucose, cannot differentiate between patients with mild disease and those with more aggressive disease.
In search of a better tool. Researchers investigated whether determining prediabetes subphenotypes before the manifestation of T2D could improve detection of patients at risk for future diabetes and complications. Their novel subphenotyping approach used accurate measurements of insulin sensitivity and insulin secretion based on oral glucose tolerance test–derived variables and variables linked to diabetes pathogenesis. They incorporated a T2D polygenic risk score to assess genetic liability.
Six subphenotypes. The researchers identified 6 clusters of characteristics reflecting subphenotypes of prediabetes that place a person at increased risk for T2D: 1. persons at low risk; 2. slim persons at very low risk; 3. persons with β-cell failure and genetic risk factors at high risk; 4. obese persons at low risk; 5. persons with insulin resistance and fatty liver at high risk; and 6. persons with high levels of visceral fat, especially in the kidneys, at high risk. The clusters were replicated in a large prospective occupational cohort.
At the low end of risk. In clusters 1, 2, and 4, the risk of T2D and that of mortality were low compared with those in the other clusters. Most patients in cluster 2 were slim, and the risk of T2D complications was very low. Patients in cluster 4 were at low risk for T2D even though they were overweight; they had relatively healthy metabolisms because body fat was stored predominantly in subcutaneous rather than visceral depots.
Patients at higher risk. Patients in cluster 3, characterized by poor insulin secretion and moderately elevated visceral fat compartments, were at high risk for T2D, cardiovascular (CV) complications, and kidney disease; mortality risk was moderate. Persons in cluster 5 were at high risk for CV complications and nephropathy as well as T2D, with a relatively higher mortality rate. In cluster 6, patients were at increased risk for T2D, nephropathy, and mortality; T2D risk was lower than in clusters 3 and 5.
A closer look at the high-risk groups. The high incidence of T2D in cluster 3 might be explained by elevated genetic risk and low insulin secretion. Clusters 5 and 6 both are obese, high-risk subpopulations but with different risk profiles. Among all the groups, cluster 5 showed the highest risk of T2D, renal and vascular disease, and all-cause mortality.
The insulin-resistant group. High-risk cluster 6 patients reflect an insulin-resistant phenotype and were at high risk for microalbuminuria and chronic kidney disease. CV risk was not elevated. Glucose did not seem to be the major driver of clinical events.
How classification could translate into practice. Determination of prediabetes subphenotypes to detect at-risk patients could improve the use of interventions to delay or prevent T2D. For patients at low risk—clusters 1, 2, and 4—physicians may simply monitor them as often as their risk level dictates. For patients at higher risk—clusters 3, 5, and 6—immediate interventional measures may be needed, including aggressive lifestyle interventions for patients in clusters 3 and 5.
Very high risk may require medication. Appropriate pharmacologic therapies might be considered in selected patients with prediabetes, such as agents with proven cardiorenal benefit in T2DM, including glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors.
