Age-Related Changes in Glucose Metabolism, Hyperglycemia, and Cardiovascular Risk

Abstract

Aging and diabetes are two well known risk factors for cardiovascular disease (CVD). Over the past 50 years there has been an dramatic increase in life expectancy with a simultaneous increase in the prevalence of diabetes in the older population. This large number of older individuals with diabetes is problematic, given that CVD risk associated with aging and diabetes. In this review, we summarize epidemiological data relating to diabetes and CVD, with an emphasis on the aging population. We then present data on hyperglycemia as a risk factor for CVD and review the current knowledge of age-related changes in glucose metabolism. Next, we review the role of obesity in the pathogenesis of age-related glucose dysregulation, followed by a summary of the results from major randomized controlled trials that focus on cardiovascular risk reduction through glycemic control, with a special emphasis on older adults. We then conclude with our proposed model of aging, that body composition changes and insulin resistance link possible dysregulation of physiological pathways leading to obesity and diabetes—both forms of accelerated aging—and risks for CVD.

Incretins in obesity and diabetes

“…235,236,239,276 A recent review by Nauck and colleagues provided a comprehensive review of cardiovascular actions of GLP-1R agonists. With that understanding came the development of a whole new drug class-GLP-1R agonists-for managing type 2 diabetes and obesity.…”

“…Emerging data also showed the benefit of GLP-1R agonists, compared to placebo, in preventing diabetes progression as well as reducing heart attacks, nonfatal strokes, cardiovascular death, and all-cause mortality in type 2 diabetes, at least for liraglutide and semaglutide. 235,236,239,276 A recent review by Nauck and colleagues provided a comprehensive review of cardiovascular actions of GLP-1R agonists. 277 In addition, a new class of agents, dual incretin receptor agonists, is currently being developed.…”

High-Risk Atherosclerosis and Metabolic Phenotype: The Roles of Ectopic Adiposity, Atherogenic Dyslipidemia, and Inflammation

“…44 This chronic state of exaggerated postprandial dysmetabolism, including elevated plasma insulinglucose and free fatty acids, creates a milieu conducive to the development of high-risk atherosclerosis and type 2 diabetes mellitus (T2DM), one of the major risk factors for ASCVD. 45 As depicted in Figure 1, impaired insulin signaling affects processes in various tissues and organs relevant to ASCVD, including dysregulation of glucose and lipoprotein metabolism and ectopic fat accumulation 44 (Fig. 1A1-A3).…”

“…It represents a model for accelerated cardiovascular aging and leads to a substantial increase in risk for ASCVD, the leading cause of death in people with T2DM. 45 In this regard, it should, however, be noted that insulin resistance and compensatory hyperinsulinemia have been linked to the pathogenesis of CHD and cardiometabolic endpoints even in the absence of diabetes mellitus. 51,52 Lifestyle link.…”

“…13 Using waist circumference as a proxy, increased ectopic and hepatic fat 22 in particular, is an independent risk factor for high-risk atherosclerosis 9,10 and coronary artery disease and death in prospective studies. 45 Mendelian randomization analyses indicate that triglyceride-related risk is causal in ASCVD and considering triglyceride levels along with waist circumference improves risk prediction. 8,78 Hypertriglyceridemic waist, a visceral adiposity marker combining elevated waist circumference ( ‡90 cm) and elevated fasting plasma triglycerides ( ‡2 mmol/L), thus has good diagnostic accuracy for the identification of individuals at high risk of ASCVD.…”