Optimizing Identification of Individual Diabetic Risk and Response to Therapy
Development of Type 2 Diabetes Mellitus
Type 2 diabetes (T2D) develops due to progressive insulin resistance and β-cell dysfunction over time.1 Insulin resistance (IR) is characterized by decreased liver, muscle, and adipose tissue sensitivity to insulin action. In response, β-cell insulin secretion increases to maintain relative glycemic stability. In this compensated state, blood glucose levels remain minimally elevated for many years. Over a variable time, progressive β-cell dysfunction occurs, leading to a decline in plasma insulin levels.
The combination of worsening IR and declining insulin levels are responsible for increasing hyperglycemia and the development of T2D.
Use of Glucose to Identify Diabetic Risk
Multiple expert organizations advocate identifying individual risk for developing T2D based on measurement of blood glucose levels.1,2 The American Diabetes Association (ADA) defines fasting glucose values less than 100 mg/dL as "normal", while values 100-125 mg/dL are considered "prediabetic". Fasting glucose of greater than or equal to 126 mg/dl on two separate occasions is indicative of diabetes. In the US, an estimated 88 million adults have prediabetes.3 Multiple population studies confirm the prediabetic cohorts experience a 5–10% annual risk of developing T2D.4-6
Multi-Ethnic Study of Atherosclerosis (n=5,314)
8-Year Risk of Diabetes
However, while progression to T2DM is associated with elevated glucose levels, the risk of individual progression over time varies widely at any given glucose value.2,8 Variable progression is particularly common among individuals with fasting glucose of 90-110 mg/dL.2,7 Many prediabetic patients, particularly those with glucose 100-110 mg/dL, do not progress to T2DM.2 Many others who are not prediabetic, particularly those with glucose 90-99 mg/dL, develop diabetes in a relatively short time (<8 years).7,9,10
Hence, blood glucose is a poor discriminator of individual T2D risk.
Use of Lipoprotein Insulin Resistance (LP-IR) Score to Identify Diabetic Risk
Among the earliest manifestations of IR, observed many years before the onset of hyperglycemia, are alterations in lipid and lipoprotein metabolism.11-12Specifically, insulin-resistant individuals have higher levels of the large very-low-density lipoprotein particles (VLDL-P), increased numbers of small LDL particles (LDL-P), lower levels of large HDL particles(HDL-P), as well as increased VLDL particle size and decreased LDL and HDL particle size.11 The LP-IR Score is a weighted combination of these lipoprotein variables that range from 0 (most insulin sensitive) to 100 (most insulin resistant).13
Prospective data from the Multi-Ethnic Study of Atherosclerosis (MESA) shows a significant graded relationship of NMR LP-IR Score with incident T2D.
Multi-Ethnic Study of Atherosclerosis (n=5,314)
8-Year Risk of Diabetes
Prospective data from the Multi-Ethnic Study of Atherosclerosis (MESA), Women's Health Study (WHS), and PREVEND confirm the significant predictive value of the NMR LP-IR Score even follow adjustment for confounder variables.
Use of Glucose and Lipoprotein Insulin Resistance (LP-IR) Score to Identify Diabetic Risk
Measures of glycemia and LP-IR are mutually related to the risk of developing T2D. The graph below shows new diabetes incidence (%) and hazard ratio (HR) for developing T2D over 20 years among women with high versus low HbA1C and LP-IR.
Women’s Health Study (n=25,925)
20-Year Risk of Diabetes
A similar relationship was found in the Multi-Ethnic Study of Atherosclerosis when fasting glucose and LP-IR were handled as continuous variables. As indicated in the graphs below, the risk for developing T2D increases with a higher (Red Line) versus lower (Green Line) LP-IR Score at any given glucose value. Additionally, at any LP-IR score, the risk for T2D increases with increasing fasting glucose.
Multi-Ethnic Study of Atherosclerosis (n=2,828)
Diabetic Risk Among Women
Multi-Ethnic Study of Atherosclerosis (n=2,486)
Diabetic Risk Among Men
Estimation of individual 8-Year Diabetic Risk requires both fasting glucose and LP-IR score.
The graph below demonstrates the gender-specific influences of fasting glucose and LP-IR on the 8-year risk of incident diabetes for men (white bars) and women (pink bars) followed in the Multi-Ethnic Study of Atherosclerosis.
Multi-Ethnic Study of Atherosclerosis (n=5,314)
8-Year Risk of Diabetes
William Cromwell, MD, FAHA, FNLA, is the Chief Medical Officer for Precision Health Reports. He is a leading expert in the management of metabolic disorders and lipoprotein disorders including diabetes management. Through our products, he extends his 30+ years of research and in-clinic experience to enable practicing healthcare providers across the U.S. to better deliver personalized care to their patients. Our analyses change the conversation from trying to explain data to instead having a meaningful conversation about a person’s individual risks of developing serious and costly cardiometabolic diseases.
References
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