Page 59 - GTM-4-1

Global Translational Medicine Incretins and cardiorenal disease

in both fasting and post-prandial states, the development 48 weeks, the average weight loss was 24.2% with a weight
of selective GLP-1 receptor agonists and co-agonists reduction of up to 30% from the baseline weight among
(i.e., stimulation of GIP and GLP-1 receptors) are the 25% of participants. Notably, the weight reductions were
imminent therapeutic focus for early intervention of accompanied by several encouraging CKM outcomes,
diabetes. Furthermore, in June 2024, a 1.8 mg liraglutide including improved glycemic control among both fasting
injection became the first generic GLP-1 approved in the glucose and Hemoglobin A1C (HbA1c), decreased waist
U.S. for the treatment of T2DM. 28 circumference, lower systolic and diastolic blood pressures,
and lower lipid levels. The side effects and safety profile
An example of the synergistic effects of GIP and
GLP-1 includes the medication tirzepatide, which is were similar to GIP/GLP-1 receptor co-agonists, with
mild-to-moderate GI effects, which mostly occurred during
an innovative treatment for T2DM classified as a dual dose escalations. Importantly, the documented weight loss
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agonist. Tirzepatide increases post-prandial insulin is the most significant through a pharmacological agent,
secretion, while concurrently inhibiting glucagon
secretion. Moreover, tirzepatide enhances satiety through and the mechanism of action is secondary to the GIP/
GLP-1 receptor co-agonism complemented by the glucagon
central (hypothalamus) and peripheral (slowing of gastric receptor activation and augmentation of energy intake. 35
emptying) action, resulting in substantially improved
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glycemic control and weight reduction in T2DM. 5. Potential side effects of incretin agonists
Notably, tirzepatide has demonstrated a greater degree of in overweight and obesity
engagement for the GIP receptor than the GLP-1 receptor,
corroborating an imbalanced mechanism of action. This Although incretin agonists provide multiple beneficial
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supports its classification as an imbalanced dual GIP and impacts on CKM, including significant weight reduction
GLP-1 receptor agonist. Post hoc analysis from the “Study of ∼15 – 24% in adults with overweight and obesity,
of Tirzepatide in Participants with Type 2 Diabetes Not there is a concern for potential sarcopenia. Several trials
Controlled with Diet and Exercise Alone” (SURPASS) have reported that about 25 – 40% of the weight loss
program indicated beneficial effects of tirzepatide with was composed of fat-free mass (FFM)/lean body mass;
improvement in A1c, body weight, and cardiometabolic however, obese people have greater amounts of FFM and
markers. These benefits were observed in participants with skeletal muscle mass (SMM) than the lean population. The
early-onset T2DM (<40 years of age), who, despite their SMM is higher in obese people than in lean individuals,
younger age, demonstrated higher glycemic levels and but the percentage of the SMM (compared to total body
lower metabolic health at baseline. Recently, Malhotra mass) is lower.
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et al. completed a 52-week phase 3, double-blind RCT Intentional weight loss leads to a greater decrease
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to evaluate the efficacy and safety of tirzepatide for the in body fat than FFM or SMM, thus improving the
treatment of moderate to severe obstructive sleep apnea ratio of FFM/SMM to fat mass and the quality of the
(OSA) in obese people. Of the 469 participants that remaining muscle. 31,36 Recent reports have demonstrated
were randomized 1:1 to receive tirzepatide or placebo, that appropriate counseling to mitigate this potential
tirzepatide reduced moderate-to-severe OSA severity by side effect includes maintaining a balanced diet rich in
up to 62.8%, which translates to 30 fewer events restricting protein, ensuring adequate hydration, and engaging in
or blocking a person’s airflow per hour of sleep. In regular physical activity with resistance training. 37,38 While
addition to reducing the hypoxic burden, tirzepatide also achieving fat loss, Locatelli et al. further proposed that
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reduced body weight, high-sensitivity C-reactive protein resistance training should be integrated as an adjunct to
concentration, and systolic blood pressure and enhanced incretin therapy to optimize changes in body composition,
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sleep-related patient-reported outcomes. Currently, leading to the preservation of lean body mass. Although
tirzepatide is being investigated with dulaglutide to evaluate there is concern that significant weight loss induced by
the CV protective outcomes in the “Effect of Tirzepatide incretin mimetics can cause physical frailty or sarcopenia,
Versus Dulaglutide on Major Adverse Cardiovascular there is currently no data to support this claim. 39
Events” (SURPASS-CVOT) study in patients with T2DM In regards to the adverse effects of GLP-1 receptor
(ClinicalTrials.gov: NCT04255433). 33 agonists, GI effects are the most prevalent; however, these
In addition, a novel incretin mimetic under investigation effects are dependent on agent potency and dose. The side
is retatrutide, a GLP-1/GIP/glucagon receptor tri-agonist. effects include various upper GI (i.e., nausea, vomiting)
Jastreboff et al. completed a phase 2 RCT in 338 obese and lower GI (i.e., diarrhea, constipation) symptoms.
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adults with retatrutide versus placebo over 48 weeks. At However, slower dose titration reduced these effects, and
the maximum dosage of retatrutide (12 mg) and after thus, the overall safety profile remains strong. According
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Volume 4 Issue 1 (2025) 51 doi: 10.36922/gtm.4405