Guest Editorial: Postprandial Dysmetabolism: Understanding the Impact of Elevated Postprandial Glucose and Triglycerides with the Potential to Prevent or Intervene Early

In 2019, the Centers for Disease Control and Prevention reported that prevalence for both obesity and overweight have continued to rise over the last eight years and are at an all-time high for adults and adolescents.(1) Approximately two-thirds of US adults are either obese (31%) or overweight (35%). Approximately one-third of US adolescents in grades 9-12 are obese (15%) or overweight (16%). Obesity in childhood and young adulthood is a predictor of weight difficulties in middle age and beyond. This pandemic is largely driven by poor diet quality and physical inactivity, although genetic predisposition and other lifestyle factors also play important roles.(2) Latency between eating occasions has declined in the US, leading to a nearly continuous postprandial state, except overnight while sleeping.

Overweight and obesity are associated with insulin resistance and chronic inflammation. Eventually, these may lead to pancreatic beta-cell dysfunction, producing impaired glucose tolerance and type II diabetes mellitus (T2D). Expanded adipose stores and insulin resistance result in chronically elevated circulating levels of free fatty acids. When the liver is exposed to these high levels of free fatty acids, it has only three options:  
(1) increase hepatic lipid oxidation,
(2) increase production of larger, triglyceride (TG)-enriched very-low-density lipoprotein particles or
(3) increase ectopic deposition of TG. Because hepatic lipid oxidation can only be increased to a modest extent, the excess of free fatty acids resulting from increased adiposity are generally converted to TG and thus contribute
to enhanced risks for fasting and postprandial hypertriglyceridemia and fatty liver (non-alcoholic fatty liver disease and non-alcoholic steatohepatitis).

The term postprandial dysmetabolism was coined by O’Keefe and Bell in 2007 to describe the combination of hypertriglyceridemia, hyperglycemia and hyperinsulinemia that often accompanies overweight, obesity and other insulin resistant conditions such as T2D and polycystic ovarian syndrome.(3)  A growing body of literature has developed that, taken together, supports the view that postprandial dysmetabolism contributes to the pathophysiology of cardiometabolic diseases, including atherosclerotic cardiovascular disease (ASCVD), microvascular diseases (retinopathy, neuropathy and nephropathy) and fatty liver.(4-8)

The main pathophysiologic mechanisms for the development of tissue damage with postprandial dysmetabolism are excessive glucose levels leading to the production of advanced glycation end products, and excessive TG-rich lipoproteins (from both the gut and the liver). These contribute, through a number of mechanisms, to pro-oxidative and inflammatory states, as well as increased coagulation and reduced fibrinolysis. Excess post-meal nutrients overburden electron transport, exceeding the metabolic capacity of muscle and adipose tissue mitochondria, and thus, result in increased production of reactive oxygen species. Remnants of TG-rich lipoproteins of both hepatic and intestinal origin enter the subendothelial space where they undergo oxidative and other types of modification, triggering uptake by macrophages and activation of inflammatory mechanisms. While both elevated levels of low-density-lipoprotein cholesterol (LDL-C) and TG-rich lipoprotein cholesterol are associated with higher levels of circulating inflammatory markers, such as high-sensitivity C-reactive protein, the relationship is roughly 5- to 6-fold stronger for the latter.(9)

Some obese individuals do not develop chronic inflammation and oxidative stress. It has been hypothesized that a ‘second hit’ or ‘multiple hits’ are necessary to induce these disturbances.(10) Along with chronic hyperglycemia and hypertriglyceridemia, other factors such as smoking (and other inhaled pollutants), chronic alcohol consumption and disturbances in gut microbiota also play important roles.(11) Genetic variants that influence body fat distribution and the production of pro-inflammatory cytokines in response to expansion of adipose stores also likely contribute to interindividual variation in the degree of metabolic disturbance associated with a given level of adiposity.

Implications of Postprandial Dysmetabolism

Testing for postprandial hyperglycemia is well standardized.(12) However, measuring postprandial lipids is not. In their original article, O’Keefe and Bell reported using a standard glucose load (75-g) mixed with 700-kcal/m2 whipping cream as a mixed glucose-fat tolerance test.(3) Other protocols have been used for research, but not in the clinical setting due to lack of normative data and practical challenges associated with administration of tests that take several hours to complete.

The conventional methods for the detection of postprandial hyperglycemia are the 75-g oral glucose tolerance test and self-monitoring of glucose through finger sticks or continuous glucose monitoring. Glycated hemoglobin provides an integrated measure of the average blood glucose level over a period of several weeks, thus it incorporates fasting and postprandial exposure. (12) An emerging technology for the evaluation of postprandial glucose levels is the measurement of plasma 1,5-anhydroglucitol (1,5-AG). Glycemic control has long been known to be important for maintaining health of the microvasculature. Evidence also exists for a role of TG management in prevention of microvascular complications. Results from the Fenofibrate and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Type 2 Diabetes (ACCORD) studies showed reduced microvascular complications in T2D patients treated with fenofibrate, which lowers fasting and postprandial TG concentrations.(13)

Although limited data are available to assess the independent predictive value of postprandial lipemia, the results to date suggest that it is likely that some individuals show discordance, i.e., higher levels of postprandial lipemia than would be suggested by fasting levels of TG and TG-rich lipoproteins. (14,15) Surrogate measures now available include apolipoprotein (apo)B-48 levels and remnant-like lipoprotein (RLP) cholesterol and TG concentrations. A study in 10 male, normolipidemic subjects showed that postprandial levels of apoB-48, TG, RLP-C and RLP-TG significantly increased after the intake of a high-fat meal; however, there was no postprandial increase in apoB-100 or LDL-C levels.(16)

In human carotid and femoral endarterectomy samples, the quantity of apoB-48 proteins was similar to that of apoB-100 proteins, and the apoB-48/apoB-100 ratio was much higher than predicted based on the relative plasma concentration (< 1% of the apoB in fasting samples is apB-48).(17) These results support the Zilversmit hypothesis, first proposed in the 1970s, emphasizing the roles of chylomicron particles and postprandial lipemia in the promotion of atherosclerosis.(18) Fasting apoB-48 levels correlate significantly with the incremental area under the curve of TG after the intake of a high-fat meal.(19) Additional data are needed to determine whether such information can be used clinically to identify those with increased cardiometabolic risk due to postprandial dysmetabolism, and, further, whether interventions to address postprandial dysmetabolism will enhance risk reduction.

Excessive postprandial lipemia and glycemia are both known to induce oxidative stress, thus lowering nitric oxide availability and triggering transient endothelial dysfunction.(20,21) The degree of endothelial dysfunction after a high-fat meal correlates strongly with postprandial elevations in TG, apoB-48 (reflecting the number of chylomicron particles) and glucose.(19) Postprandial endothelial dysfunction is associated with increases in release of pro-inflammatory cytokines and expression of adhesion molecules (intercellular adhesion molecule-1 and vascular adhesion molecule-1). These processes stimulate infiltration of monocytes into the subendothelial space, where they can differentiate into macrophages.

Thus, there is a strong theoretical basis for the view that normalizing postprandial levels of TG-rich lipoproteins and glycemia might reduce risk for atherothrombosis. Recently published results from studies of interventions that have these effects provide indirect support for this hypothesis, including studies showing reduced major adverse cardiac event (MACE) risk with glucagon-like peptide 1 receptor agonists, sodium-glucose co-transporter 2 inhibitors and icosapent ethyl.(22,23) The Reduction
of Cardiovascular Events with Icosapent Ethyl—Intervention Trial (REDUCE-IT) showed a 25% reduction in MACE risk with 4 g/d of icosapent ethyl compared with placebo in statin-treated patients at high- and very-high ASCVD risk. Changes in LDL-C and non-high-density lipoprotein cholesterol with icosapent ethyl appear unlikely to explain more than approximately one-third of the risk reduction.(23) Icosapent ethyl has been shown to reduce fasting and postprandial levels of TG as well as biomarkers of inflammation and indicators of monocyte activation.(24,25) Additional research appears warranted to further investigate the potential contribution of improved postprandial metabolism as a partial explanation for the benefits associated with icosapent ethyl, as well as other therapies.

Treating Postprandial Dysmetabolism

The current primary treatment approach for postprandial dysmetabolism is lifestyle therapies, including weight loss (5-10% of body weight) if overweight or obese, smoking cessation and physical activity, incorporating both aerobic (≥ 150 min of moderate intensity activity) and resistance exercise.(7,26) In addition to weight loss, dietary intervention should include a diet low in saturated fat, cholesterol and added sugars, as well as moderation or abstinence from alcohol consumption.(7)

Antiglycemic and lipid-lowering medications generally improve both fasting and postprandial levels of glucose and TG-rich lipoproteins.  Additional research is needed to determine whether emerging biomarkers of postprandial dysmetabolism can be utilized clinically to identify subsets with greater likelihood of improved cardiometabolic outcomes with specific types of interventions. For example, those with well-controlled LDL-C and fasting TG in the normal or slightly elevated range, but with an elevated level of apoB-48 (suggesting postprandial lipemia) might experience greater risk reduction with omega-3 fatty acid or fibrate therapy compared with intensification of LDL-C reduction. Like metabolic syndrome, levels of apoB-48, RLP-C, RLP-TG, and 1,5-AG may also be useful for identifying individuals to target for intensification of lifestyle intervention through referral to behavioral programs and/or prescription of weight loss medications. At present, these remain hypotheses that will need to be tested in clinical trials.

Conclusions

Postprandial dysmetabolism is characterized by elevated levels of plasma glucose and TG after meals. A strong theoretical basis exists for the view that postprandial dysmetabolism may contribute to risks for atherothrombosis and microvascular damage, affecting numerous tissues. Overweight, obesity and insulin resistance appear to be key factors driving the development of postprandial dysmetabolism. The primary goal of preventive efforts is to avoid overweight and obesity and to treat these early to prevent downstream consequences. Lifestyle therapies are critically important and drug therapies for control of lipids and glycemia will generally improve both fasting and postprandial levels. Additional research is needed to establish normative data for biomarkers of postprandial dysmetabolism and assess their clinical utility. Individuals with discordance between fasting and postprandial levels of glucose and TG, i.e., normal or
mildly elevated fasting levels, but with exaggerated postprandial responses, may represent a group with increased and modifiable risk for adverse micro- and macrovascular outcomes. Further validation of biomarkers for postprandial dysmetabolism may provide useful clinical tools to guide risk stratification and treatment selection.

Disclosure statement: Dr. Maki received honoraria from Acasti, Akcea, Amgen, AstraZeneca, Corvidia, Matinas Biopharma, Pharmavite, LLC, Sanofi/Regeneron, Kellog, and General Mills.  Dr. Dicklin received honoraria from Acasti, Akcea, Amgen, AstraZeneca, Corvidia, Matinas Biopharma, Pharmavite, LLC, Sanofi/Regeneron, Kellog, and General Mills.  Dr. Balakrishnan received honoraria from Intercept, Gilead, and Ebix Reviews.
Dr. Neff has no financial disclosures to report.

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