Tirzepatide: a dual approach to combat obesity and obstructive sleep apnea

INTRODUCTION

Obesity

Obesity is defined by an excessive buildup of body fat, which frequently happens when the body consumes more calories than it can use. The surplus calories are stored as fat, orose tissue.¹ Among the most dangerous medical conditions in existence today, this condition is categorized as a chronic disease and represents a growing global concern.² Numerous health and psychological issues are associated with it, which raises mortality and disability rates.^3,4 Obesity and a sedentary lifestyle are strongly and directly related, especially in Western countries; a recent meta-analysis found that among obese people, the prevalence rates of sedentary behavior and physical inactivity were 31% and 43%, respectively.⁵ Consequently, a comprehensive lifestyle intervention is typically regarded as the primary approach for managing obesity, encompassing calorie reduction, regular physical exercise, and regular check-ins with healthcare providers.⁶ Behavioral treatment methods play a vital role for these individuals, having proven effective in enhancing adherence to lifestyle modification programs.⁷

Obstructive sleep apnea

In OSA, the airway collapses during sleep, causing recurrent episodes of obstruction. This leads to recurring instances of low oxygen levels and reoxygenation, resulting in nighttime awakenings, fragmented sleep, and heightened sympathetic activity. Ultimately, these factors contribute to unrefreshing sleep, which is linked to daytime drowsiness, diminished quality of life, and increased risk of metabolic and cardiovascular diseases.⁸ OSA is notably prevalent among middle-aged adults, with studies indicating that 34% of males and 17% of females in this demographic fulfils the diagnostic criteria for the disorder.⁹ Given the close relationship between obesity and OSA, coupled with the rising obesity rates in developed countries, it is likely that more individuals will begin to experience this condition.¹⁰

The connection between obstructive sleep apnea and obesity

There exists a direct correlation between OSA and obesity. Obesity peoples may have fat deposits in their upper respiratory tracts, which can narrow their airways and reduce their muscle activity. Sleep apnea is the result of hypoxic and apneic episodes brought on by this condition. Such episodes result in a reduced oxygen supply to body tissues and blood vessels, which can cause tissue hypoxia— a significant contributor to atherosclerosis and a primary risk factor for cardiovascular diseases.¹¹

HOW OBESITY CONTRIBUTES TO OSA PATHOPHYSIOLOGY

Obesity significantly increases the risk of developing OSA through various interconnected mechanisms. One of the primary factors is the accumulation of fat around the upper airway; this excess fat around the neck and pharyngeal area narrows the airway, raising the chances of airway collapse during sleep.¹² This issue worsens when there is fat buildup in the parapharyngeal region, which mechanically compresses the airway. Additionally, obesity diminishes the muscle tone that helps keep the airway open, particularly during REM sleep when muscle tone is naturally reduced, making the airway more susceptible to collapse. People with obesity may also experience impaired neuromuscular responses, which further hinder the airway's ability to stay open, leading to apneic events.¹³

Furthermore, increased abdominal fat elevates intra-abdominal pressure, pushing the diaphragm upwards and lowering lung volumes, which heightens the risk of airway collapse. This additional abdominal fat can also hinder effective diaphragm movement, affecting respiratory function and making it more difficult to breathe during sleep. Chronic low-grade systemic inflammation associated with obesity can influence the muscles and tissues of the upper respiratory tract, leads to collapse. Inflammatory substances released from excess adipose tissue can exacerbate the severity of OSA.¹⁴ Obesity is also closely linked to metabolic disorders like insulin resistance and metabolic syndrome, which can disrupt respiratory function, leading to further complications. Hormonal imbalances, particularly fluctuating leptin levels, may interfere with breathing regulation, increasing the likelihood of apneic episodes.¹⁵

Fat infiltration in respiratory muscles weakens their function, raising the chances of airway collapse.¹⁶ In some instances, OSA may occur alongside obesity hypoventilation syndrome (OHS) characterized by chronic carbon dioxide retention from impaired ventilation, which worsens hypoxemia and hypercapnia. Leptin resistance, commonly seen in obesity, complicates appetite and respiration regulation, contributing to ventilatory instability and more severe apneas. Lastly, excess fat around the thoracic region can reduce chest wall compliance, making lung expansion more challenging and resulting in shallow, ineffective breathing. Together, these mechanisms reveal how obesity crucially impacts the onset and worsening of obstructive sleep apnea.¹⁷

The pathophysiology of OSAS involves mechanisms that impact upper airway collapse and the interaction of many variables (Figure 1). One major contributing reason to upper airway collapse is the decrease in upper airway volume brought on by obesity or anomalies of the craniofacial structure and soft tissue. The degree of damage to the upper airway's anatomical structure varies across OSAS patients. An increase in peripheral pressure is known as a nocturnal rostral fluid shift, which occurs when fluid that has accumulated in the legs during the day re-distributes to the upper body when the person is lying down at night. Furthermore, the mechanism is unclear, and the majority of patients have mucosal edema. Additionally, OSAS may be involved in a number of processes linked to low respiratory arousal threshold, poor pharyngeal neuromuscular muscle response, excessive loop gain, and high passive Pcrit. When awake, the dilated throat's muscles are kept active by neural activity, which keeps the throat from collapsing. The airway may collapse if this muscle (chemosensitivity, central respiratory neurons, and ventilatory drive) stops being activated during rapid eye movement (REM) sleep. Multiple pathogenic mechanisms interacting to induce cyclical OSAS development are shown schematically in Figure 1b. Furthermore, these pathways may serve as targets for treatment.

TIRZEPATIDE

The US FDA has endorsed tirzepatide, a novel drug, to treat type 2 diabetic mellitus (T2DM). This drug also shows effectiveness in promoting weight loss, which has led to its alternative use for treating obesity. Tirzepatide is a long-acting stimulating agent that efficiently activates both the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. Its amino acid structure features a C20 fatty acid moiety that allows for binding to albumin, extending its half-life.¹⁸ Treatment of obstructive sleep apnea with tirzepatide has resulted in notable reductions in excessive weight, improvements in cardiovascular health, and reductions in indicators of vascular endothelial dysfunction and inflammation.^19,20

Adults who are overweight (BMI of 27 kg/m² or higher) or obese (BMI of 30 kg/m² or higher) and who suffer from obesity-related medical conditions such as cardiovascular disease, type 2 diabetes mellitus, hypertension, dyslipidemia, or obstructive sleep apnea are prescribed Zepbound (Tirzepatide) to aid in weight loss and maintenance. It should be taken alongside increased activity and a low-calorie diet. Patients with a history of severe gastrointestinal disorders, such as severe gastroparesis, or pancreatitis have not had the safety of Zepbound examined. It is not recommended to be used with any GLP-1 receptor agonists or tirzepatide preparations.²¹

MECHANISM OF ACTION OF TIRZEPATIDE

Dual GLP-1 and GIP receptor agonist activity

All around the body, but especially in the gastrointestinal tract and pancreatic beta cells, are GLP-1 receptors (GLP-1R). Because GLP-1R signalling is involved in controlling glucose levels by increasing insulin secretion in response to glucose, slowing stomach emptying, lowering plasma glucagon levels, and lowering body weight by activating appetite-suppressing brain pathways, they contribute to the pathophysiology of type II diabetes. The peptide hormones GIP and GLP-1 are essential for preserving glucose homeostasis and inducing the release of insulin from beta cells in the pancreas. However, when food is consumed, the main incretin hormone that has insulinotropic effects is GIP.^22,23

Although tirzepatide's exact mode of action is yet unknown, the drug's benefits on weight management and glycemic control may be due to the combined activation of GIP and GLP-1R.²⁴ Studies have demonstrated that when GIP and a GLP-1R agonist are administered together, the insulin response is markedly increased and glucagon release is decreased in comparison to when either hormone is administered alone.²⁴ Tirzepatide has a high affinity for both GIP and GLP-1R; it is five times less effective at binding GLP-1R than native GLP-1, but it is comparable to native GIP in binding GIP receptors.²⁴ In vitro, tirzepatide strongly stimulates the GLP-1R signaling pathway to promote glucose-dependent insulin secretion, whether through GIPR or GLP-1R activation. More research is necessary to clarify the part that GIPR activation plays in the drug's overall mechanism, as preclinical and clinical studies have produced contradictory findings about the impact of GIPR agonism on glycemic and obesity management.²⁴

Role in appetite regulation and weight loss

Tirzepatide activates hormone receptors from the intestine, namely GLP-1 and GIP, which helps to reduce hunger and lower food intake. This action prompts the pancreas to release insulin while suppressing agon— a hormone that increases blood sugar levels. As a result, sugar management improves after meals.²⁵ Moreover, tirzepatide affects certain brain chemicals, leading to a reduced appetite, heightened energy expenditure, and the limitation of unusual fat buildup in areas typically low in fat, which significantly aids in weight loss (Figure 3).²⁶

THE IMPACT OF WEIGHT LOSS CAUSED BY TIRZEPATIDE ON OSA MANAGEMENT

The most modifiable causes for OSA is obesity, and the AHA scientific statement on OSA and heart health emphasizes that OSA is associated with BMI.²⁸ This claim is supported by a population-based study that found that even modest weight control can successfully prevent the onset of new OSA cases or lessen the severity of AHI, while a 10% increase in body mass is related with a 32% increase in AHI.²⁹ Reduces of 10%, 20%, and 30% in body mass or BMI were linked to decreases in AHI of 36%, 57%, and 69%, respectively, according to a recent meta-analysis.³⁰ Therefore, for all OSA patients, weight loss and lifestyle modifications should be given first priority.³⁰

The estimated treatment difference in weight in SURMOUNT trial 1 was -16.1% (95% CI -18.0, -14.2), whereas the AHI change was -47.7% (-65.8, -29.6). Trial 2 also showed a treatment difference in weight of -17.3% (-19.3, -15.3) and a change in AHI of -56.2% (-73.7, -38.7), which is similar to what would be anticipated from a 20% weight loss.³⁰ AHI alterations and weight loss have not yet been thoroughly examined, indicating the need for more research on this topic. AHI and BMI were found to have a non-linear relationship in a cross-sectional research, with steady AHI levels up to 35 kg/m² as BMI increased.³¹ The need for weight loss in obese people with OSA was reinforced by Malhotra et al.'s meta-analysis, which comprised weight reduction research in persons with a baseline BMI of 35 kg/m². Consistent reductions in AHI were found.³²

TIRZEPATIDE’S EFFECT ON DIABETES MANAGEMENT

Tirzepatide is an artificial double agonist targeting glucagon like peptide-1 and gastric inhibitory peptide. Known as "twincretin," it has unique features that differentiate it from standard GLP-1 receptor agonists.³³ With a composition of 39 amino acids, it serves as an analog of GIP.³⁴ Functionally, tirzepatide drives insulin production from the pancreas and alleviates hyperglycemia. Additionally, it raises levels of adiponectin.³⁵

Tirzepatide’s dual agonism substantially lowers hyperglycemia when compared to standalone GLP-1 agonist medications and also curbs appetite.^36,37 In non-diabetic patients, weekly doses of tirzepatide between 5 to 15 mg for obesity management resulted in significant weight reductions, between 16.5% and 22.4%, over 72 weeks. Post hoc studies revealed that tirzepatide led to marked improvements in insulin sensitivity and β-cell function.^38,39

CLINICAL RESEARCH ADVANCEMENTS

Under the supervision of Malhotra et al, two phase 3, double-blind, randomized controlled trials were carried out. Trial 2's mean AHI was 49.5 occurrences per hour, compared to trial 1's initial mean of 51.5 incidents per hour. The average BMI for each experiment was 39.1 and 38.7. Study 1's mean reduction in AHI after 52 weeks was -25.3 events per hour (95% CI, -29.3 to -21.2) for tirzepatide and -5.3 events per hour (95% CI, -9.4 to -1.1) for placebo, with an estimated treatment difference of - 20.0 events per hour (95% CI, -25.8 to -14.2) (p<0.001). The results of trial 2 indicated that tirzepatide caused a mean reduction in AHI after 52 weeks of -29.3 events per hour (95% CI, -33.2 to -25.4) and the control group caused -5.5 occurrences per hour (95% CI, -9.9 to -1.2). The estimated treatment difference was -23.8 occurrences per hour (95% CI, -29.6 to -17.9) (p<0.001). Tirzepatide significantly improved all pre-specified critical secondary endpoint metrics when compared to a placebo. Gastrointestinal side effects were most frequently recorded, and they were usually mild to moderate in intensity.⁴⁰

Another large multinational RCT, headed by Jastreboff et al, involved 2,539 obese people who were given TZP at doses of 5, 10, or 15 mg per week for 72 weeks, or a placebo. Participants were examined for waist circumference (WC), and results indicated greater reductions in WC for all TZP doses compared to placebo at week 72: -14.0 cm, -17.7 cm, -18.5 cm for 5, 10, and 15 mg TZP, respectively, versus -4.0 cm in the placebo group. A subset of 255 participants underwent DXA scans to evaluate body composition, but data was only available at the 72-week mark for 160 participants. In the TZP groups, the change in total fat mass from baseline to week 72 was -33.9%, while in the placebo group, it was -8.2%, representing a 25.7% treatment difference. Additionally, the TZP groups experienced a greater decrease in total fat-free mass, with values of -10.9% for TZP and -2.6% for the placebo. In the TZP group, the ratio of fat mass to fat-free mass increased from 0.93 to 0.70, whereas in the placebo group, it changed from 0.95 to 0.88.⁴¹

In an 84-week multicenter experiment, Wadden et al evaluated the effectiveness of TZP in helping overweight or obese adults lose 5% of their initial weight over the course of a 12-week behavior modification phase. Following that, at random, 579 subjects were given either a control group or the highest tolerable dose of TZP (10 or 15 mg) once a week. 86.4% of the TZP cohort received the maximal dose of 15 mg. The TZP group experienced a more substantial decrease in WC at week 72 (-14.6±0.7 cm) than the placebo group (+0.2±1.0 cm).⁴²

Zhao et al started the SURMOUNTCN study in 2024 with patients who were overweight or obese in China. A lifestyle modification and weekly subcutaneous doses of 10 mg or 15 mg TZP or a placebo were administered to 210 individuals over a 52-week period. When compared to the placebo group, those on TZP consistently lost weight, as evidenced by a dose-dependent drop in WC. Their mean age was 36.1 years, and their mean BMI was 32.3 kg/m².⁴³

The 52-week SURMOUNT-OSA study is a randomized, placebo-controlled experiment designed to assess tirzepatide's safety and effectiveness in treating moderate-to-severe OSA in obese patients.⁴⁴ The primary endpoint is the difference in AHI change as determined via polysomnography at the 52-week mark between the tirzepatide and placebo groups.⁴⁵ Secondary targets include functional outcomes, cardiometabolic markers, and sleep apnea-specific hypoxic load.⁴⁶ The trial incorporates acceleration measurements to evaluate daily activities and devices for at-home sleep testing to follow time till improvement.⁴⁷

Grunstein explored data from SURMOUNT-1, including 197 participants with OSA who met baseline criteria and were divided by tirzepatide dose (5 mg, 10 mg, and 15 mg) or placebo.⁴⁸ The average age ranged from 48 to 53 years, with body weights between 110-122 kg and BMIs from 39 to 43 kg/m². The mean weight change at week 72 between tirzepatide and placebo was calculated to be -11.2% for 5 mg, -18.2% for 10 mg, and -20.7% for 15 mg, all of which were statistically significant (p<0.001). An additional substantial percentage of those receiving tirzepatide achieved weight loss of 5% (83-98% versus 25% on placebo) and 10% (46-93% versus 15% on placebo). Notably, 27-62% of participants on tirzepatide reached a 20% weight loss milestone, opposed to 0% in the placebo group.⁴⁹

After propensity score matching, Rodriguez et al recruited 18,386 participants from a cohort study of more than 41,000 adults who met the criteria (semaglutide, 32,029; tirzepatide, 9,193). 52.0% of the population had a T2D diagnosis, while 70.5% of the population was female.^50,51 Their mean age was 52 years. The average starting weight was 110 kg. Discontinuation led to 5,140 (55.9%) of tirzepatide and 4,823 (52.5%) of semaglutide patients dropping out. Patients on tirzepatide had significantly higher chances of achieving specified weight loss percentages (5%; HR, 1.76; 10%; HR, 2.54; 15%; HR, 3.24). Weight changes after 3, 6, and 12 months were notably larger in those taking tirzepatide. Rates of gastrointestinal adverse events were comparable between both groups.^52,53

Yabe et al's SURPASS J-mono study in Japan involved 48 T2D individuals who were randomly assigned to receive either 0.75 mg of dulaglutide or 5, 10, or 15 mg of TZP for a 52-week period. The initial BMI and mean age were 27.5 kg/m² and 58.6, respectively. All TZP groups showed a reduction in total fat mass from baseline after 52 weeks, however the groups taking 10 and 15 mg of tirzepatide demonstrated a greater reduction in fat mass than the dulaglutide group.⁵⁴

In a 2023 study, Heise et al analyzed the impact of TZP on body composition in T2D patients.⁵⁵ For 28 weeks, 117 participants were given either 15 mg tirzepatide, 1 mg semaglutide, or a placebo once a week. Plethysmography was used to measure their body composition. Only those on TZP or semaglutide showed significant total fat mass and fat-free mass reductions. Furthermore, TZP users saw a significantly greater reduction of FM% than semaglutide users.⁵⁶

CONCLUSION

Clinical studies on tirzepatide show that it is a very effective treatment for OSA and obesity. The AHI and waist circumference (WC) consistently decrease with different dosages, according to several phase 3 randomized controlled trials. According to the results, tirzepatide not only lowers AHI but also significantly improves body composition, resulting in a favorable shift in the ratios of fat mass to fat-free mass (FFM) and a notable drop in fat mass (FM).

Notably, compared to placebo groups, those who received tirzepatide was more prevalent to reach weight loss goals, highlighting the medication's promise as a treatment for obesity and related disorders. Most adverse occurrences were mild to moderately severe, indicating a manageable side effect profile, even if gastrointestinal adverse events were the most frequent.

New research on tirzepatide's wider effects in treating OSA, like the SURMOUNT-OSA trial, highlights the need for more research on the drug's long-term effects and safety. All things considered, tirzepatide is a promising dual strategy for treating obesity and OSA, with the potential to enhance metabolic health and quality of life for those who are impacted.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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