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Global Translational Medicine Incretins and cardiorenal disease

30 min/day. Therefore, proper management of pre- aim to provide data that may support the development of
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diabetes with specific lifestyle modifications is effective effective pharmacotherapies for patients with MASH.
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in preventing diabetes, thereby reducing the risk of CVD. Accordingly, efocipegtrutide (HM15211), long-acting
Accordingly, the U.S. National Diabetes Prevention glucagon, Glucose-dependent insulinotropic polypeptide
Program (DPP) integrates moderate weight loss (5 – 7%) (GIP), and GLP-1 triple full agonist, is currently in
through a healthy diet and physical activity over the course the pipeline and undergoing a phase 2 randomized,
of a year for those with increased risk of diabetes or multicenter 52-week study among patients with biopsy-
diagnosed with pre-diabetes. The DPP is an evidence- confirmed non-alcoholic steatohepatitis. 22
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based program that demonstrated a significant reduction
in risk of developing T2DM by 58% (71% for people over 4. Targeting incretin response
60 years old) after losing 5 – 7% of their body weight with Among healthy individuals, oral glucose stimulates greater
healthier eating and 150 min of physical activity per week. insulin secretory responses than intravenous glucose,
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Moreover, surgical interventions (i.e., bariatric surgery) despite equivalent glucose levels. Food breakdown in the
demonstrated beneficial outcomes, including improved gut promotes the release of incretins (i.e., GIP and GLP-1),
glycemic control and weight reduction, in the treatment of which enhance insulin release. Notably, this physiologic
pre-diabetes and T2DM. 15 response (also known as the “incretin effect”) in T2DM
Although difficult to instill and maintain, lifestyle is markedly decreased or absent. The malfunction may
interventions, including diet and exercise, are considered be linked to the dysfunction of β-cells or a specific defect
first-line cornerstone treatments. As exemplified by the long- within the GIP signaling pathway. Thus, a depressed
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term follow-up of the original DPP study, the DPP outcomes incretin effect of GIP leads to an increase in post-prandial
study evaluates the effects of the interventions on diabetes glucose levels, potentially worsening glycemic control. In
complications, (i.e., retinopathy, microangiopathy, CVD). contrast, GLP-1 is much less impaired than GIP in the
Accordingly, although the lifestyle group participants started setting of T2DM. The CKM outcomes of GLP-1 secondary
off with the most weight loss (mean of 7 kg after 1 year), they to its glucose-lowering effects include a reduction in A1C
gradually regained most of the weight. Therefore, the need (∼0.8 – 1.6%), body weight (∼1 – 3 kg), blood pressure,
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for medical therapy, in addition to lifestyle interventions, and lipids. 24,25
should be instilled and maintained as part of a toolbox
of interventions. Pre-diabetes can be managed with two In 2024, the landmark “Evaluate Renal Function with
medications, metformin and acarbose; however, these are Semaglutide Once Weekly” trial reported findings of the
contraindicated among patients with renal disease. A first kidney outcomes trial evaluating the GLP-1 receptor
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compounding challenge of pre-diabetes is its predominantly agonist semaglutide. Compared to those who received
asymptomatic nature, which acts as a “silent incubator” for a placebo, participants with T2DM and chronic kidney
impending morbidity. As pre-diabetes develops into T2DM, disease who received semaglutide demonstrated a 24% risk
medications also contribute significantly to controlling the reduction of the composite primary endpoint, including
toxic effects of hyperglycemia. Despite these evidence- kidney outcomes and mortality secondary to CV and
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based treatment options, tackling pre-diabetes is not fully kidney causes. Secondary endpoints include significant
targeted as a method to prevent the negative impacts of enhancements with semaglutide, slower estimated
T2DM. Examining the mechanism of action and potential glomerular filtration rate slope, a decrease in major CV
early targets of the newer incretin mimetics may expose the events (18%), and a reduced risk of all-cause death (20%).
underutilization of these mechanisms to slow or potentially Notably, the reduction in kidney outcomes with semaglutide
halt the progression of overt diabetes (Table 1). Given the was consistent in participants with/without baseline
abundant data conferring pre-diabetes as an increased risk sodium-glucose cotransporter-2 inhibitor (SGLT2i) use. A
for progression to T2DM and CKM syndrome, treatment recent meta-analysis and systematic review of randomized
should focus on preventing the progression to T2DM. 19 controlled trials (RCTs) validated the long-term efficacy and
safety of semaglutide compared to placebo in overweight/
Encouragingly, Glucagon-like peptide-1 (GLP-1)
receptor agonists demonstrate a reduction in liver fat and obese adults without diabetes. The once-weekly semaglutide
dose was associated with decreased body weight and
consequently improve liver enzyme levels, thereby paving demonstrated beneficial effects on CV risk factors (i.e., body
a treatment avenue for metabolic dysfunction-associated mass index, waist circumference, blood pressure), with
steatotic liver disease or the more advanced form, limited mild-to-moderate gastrointestinal (GI) side effects. 27
metabolic dysfunction-associated steatohepatitis (MASH),
for which there is no Food and Drug Administration- Since exogenous GLP-1 stimulates insulin, suppresses
approved treatment at this time. Ongoing phase 3 trials glucagon, and decreases plasma glucose concentrations
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Volume 4 Issue 1 (2025) 50 doi: 10.36922/gtm.4405