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Global Translational Medicine Incretins and cardiorenal disease

effects, including glucose-lowering effects, delayed gastric Diabetes Statistics Report from the Centers for Disease
emptying, decreased glucagon secretion, and weight loss. 26- Control and Prevention, an estimated 97.6 million adults
29 These culminating effects make GLP-1 receptor agonists aged 18 years or older had pre-diabetes (38.0% of the adult
powerful tools for controlling blood glucose and improving U.S. population) in 2021. Moreover, 27.2 million people
CKM syndrome. aged 65 years or older (48.8%) had pre-diabetes. These
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Notably, endogenous levels of gut incretin hormones data demonstrate the significant public health impact of
shift as prediabetes progresses to diabetes or regresses the potential progression of those with pre-diabetes to
to normoglycemia. This dynamic nature of incretin overt diabetes.
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hormone levels underscores the potential benefits of early A new American Heart Association (AHA)
intervention with incretin-based therapies. Recently, multi- presidential advisory identified the strong connections
agonist approaches have been developed, particularly the between cardiovascular disease (CVD), kidney disease,
combination of GLP-1, glucose-dependent insulinotropic type 2 diabetes mellitus (T2DM), and obesity, defining
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polypeptide (GIP), and glucagon receptor activation. cardiovascular-kidney-metabolic (CKM) syndrome.
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This tri-agonist approach, exemplified by investigational As the pre-cursor to diabetes, pre-diabetes is the earlier
medications like retatrutide, aims to provide enhanced phase of the toxic CKM cascade of diabetes. Pre-
therapeutic benefits compared to GLP-1 receptor agonists diabetes is clinically diagnosed with glycated hemoglobin
alone. Early clinical data suggest that these tri-agonists may (hemoglobin A1C) or dysglycemia levels. According to
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offer superior efficacy in weight reduction and glycemic the American Diabetes Association, pre-diabetes can be
control compared to selective GLP-1 receptor agonists. 35 defined by the following: 5
Contemporary research indicates that early intervention (i) Hemoglobin A1C: 5.7 – 6.4%
with incretin-based therapies may be crucial in hindering (ii) Fasting blood glucose: 100 – 125 mg/dL
the progression of T2DM and CKM syndrome. Targeting (iii) Oral glucose tolerance test 2-h blood glucose: 140 –
not only the GLP-1 receptor but also the GIP and glucagon 199 mg/dL
receptors in earlier phases of the disease could potentially
lead to better outcomes. The pathophysiology of pre-diabetes involves
dysglycemia with increased insulin production and
As the development of incretin-based therapies continue overstimulation of pancreatic β-cells, with diminished
to evolve, additional research has been focused upon insulin receptor response over time. Consequently, if
optimizing the balance between GLP-1, GIP, and pre-diabetes is unabated, insulin resistance, insulin
glucagon receptor activation, developing long-acting hypersecretion, and progression of pancreatic β-cell
formulations for improved patient compliance, and function decline will occur, resulting in T2DM. Ultimately,
investigating potential applications beyond T2DM, such if left untreated, inflammatory responses stimulate both
as in neurodegenerative optic disease and metabolic micro- (i.e., retina, kidney, and nerves) and macrovascular
dysfunction-associated steatohepatitis. 21,41 Thus, incretin- complications (i.e., cardiovascular [CV] system). The
based therapies offer a promising approach to targeting the AHA recently developed an inclusive equation, Predicting
progression of diabetes and CKM syndrome, with potential Risk of Cardiovascular Disease Events (PREVENT), with
benefits extending beyond glycemic control to address the clinical variables of obesity, diabetes, kidney disease, and
broader spectrum of metabolic disorders. social risk, thereby supporting a multicomponent concept

2. Impact of pre-diabetes and diabetes in for effectively and equitably enhancing CKM population
health. The PREVENT equation facilitates both 10- and
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the United States 30-year risk estimates among adults at 30 – 79 years of
In 2021, diabetes was the eighth leading cause of mortality age for total CVD and includes the estimated glomerular
in the United States (U.S.), with 103,294 death certificates filtration rate as a predictor while adjusting for competing
documenting diabetes as the underlying cause of death risk of non-CVD death. Ndumele et al. provided a synopsis
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(crude rate: 31.1/100,000 people). Among the U.S. of new strategies and research aimed at improving CKM
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population in 2021, the crude estimate for diabetes was syndrome, focusing on CKM variables and their relation to
38.4 million people across all ages (11.6% of the U.S. where, when, and how to implement and disseminate the
population). Furthermore, in 2022, the total direct and vast array of cardioprotective therapies for CKM. Recently,
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indirect estimated costs of diagnosed diabetes in the U.S. meta-analyses demonstrated that pre-diabetes is associated
was $413 billion. Besides diabetes being a leading cause with the risk of mortality, diabetes-related complications,
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of mortality globally, it is also a leading cause of disability and CV comorbidities, representing a continuum of risk
worldwide, accounting for 26.8%. Based upon the National for diabetes and eventual CKM. 5,8
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Volume 4 Issue 1 (2025) 48 doi: 10.36922/gtm.4405