TZT improves ED and associated inflammatory changes through the modulation of glucose homeostasis, insulin sensitivity, and release of pro-inflammatory biomarkers. A clinical trial of once-weekly TZT in T2DM patients illustrated that at 26 weeks of treatment, TZT led to the significant reduction of intercellular adhesion molecule 1 (ICAM-1), growth differentiation factor 15 (GDF-15), chitosan-3 like protein 1 (YKL-40), leptin and CRP compared to the baseline values. Remarkably, CRP, YKL-40, and ICAM-1 were rapidly reduced within the first 4th
weeks of treatment, while leptin was gradually reduced till the time of trial. Of note, IL-6 serum level was not significantly affected by TZT treatment in this trial (Wilson et al. 2020
). A study conducted by Hartman et al. to evaluate the potential effect of TZT on the biomarkers of non-alcoholic steatohepatitis in T2DM patients showed that TZT treatment increases adiponectin and reduces related inflammation in T2DM patients. Remarkably, procollagen III is keratin-18 reduced following TZT treatment in T2DM patients with non-alcoholic steatohepatitis (Hartman et al. 2020
). These findings proposed the anti-inflammatory effects of TZT against the development of ED and liver inflammation.
These verdicts suggest that TZT could effectively manage Covid-19 by modulation of inflammatory pathways and regulating adiponectin and IGF.
Tirzepatide and GLP-1 in Covid-19
Regardless of its cause, glucose variability triggers the development of oxidative stress and the release of pro-inflammatory cytokines (Nusca et al. 2018
). Of interest, poor glycemic control alters the interaction between innate and adaptive immune response with the subsequent promotion of infectious/inflammatory processes and viral replication, as in SARS-CoV-2 infection (Villarreal-Calderón et al. 2019
; Marfella et al. 2022
). Therefore, many studies reported that T2DM patients were associated with developing serious complications during SARS-CoV-2 infection (Batista et al. 2021
). Thus, good glycemic control is correlated with low mortality in T2DM Covid-19 patients compared to Covid-19 patients with poor glycemic control. A retrospective study illustrated that T2DM Covid-19 patients with blood glucose 3.9–10.0 mml/l were associated with low mortality (Zhu et al. 2020
). It has been shown that Covid-19 patient mortality related to T2DM is linked with higher HbA1c
above 7.65% (Holman et al. 2020
). Notably, strict glucose control may increase the risk of hypoglycemia and augment Covid-19 mortality in T2DM patients (Son et al. 2022
). Thomas et al. observed that TZT strictly improves glucose homeostasis and prevents glucose variability via modulation of insulin sensitivity and pancreatic β cell function. A multicenter, retrospective study revealed that TZT was more effective than dulaglutide in improving glucose homeostasis in T2DM patients (Thomas et al. 2021
). Therefore, TZT could effectively control blood glucose in T2DM patients with Covid-19 through modulation of insulin sensitivity and pancreatic β cell function, which are highly deranged in severe Covid-19 (Ilias et al. 2021
On the other hand, TZT, through activation of the GLP-1 receptor, may produce beneficial effects against Covid-19 severity. Since GLP-1 receptor agonists (GLP-1RAs) have anti-inflammatory and pulmoprotective effects, they may effectively manage ALI/ARDS and hyperinflammation in Covid-19 (Belančić et al. 2021
). Therefore, GLP-1RAs could effectively treat severely affected Covid-19 diabetic and non-diabetic patients. GLP-1RAs are classified as short-acting, like exenatide, and long-acting, like liraglutide. They are used subcutaneously weekly (Nauck et al. 2021
). However, orally active GLP-1RA is semaglutide which was recently approved for the treatment of T2DM patients (Thethi et al. 2020
). Of note, using GLP-1RAs in T2DM patients prevents glucose variability, a common finding in Covid-19 patients (Nauck et al. 2021
). Thus, GLP-1RAs like TZT could be a therapeutic strategy in T2DM patients with Covid-19 to prevent glucose variability-induced complications.
Of note, GLP-1RAs reduce inflammatory biomarkers like IL-6, CRP, and ferritin in Covid-19 patients. Therefore, GLP-1RAs like TZ may be effective in Covid-19 patients by reducing the inflammatory burden (Katsiki and Ferrannini 2020
). Remarkably, GLP-1Rs are highly expressed in various tissues, including pancreatic β cells, brain, endothelium, lung, GIT, kidneys, and immune cells (Baggio and Drucker 2021
). Activation of GLP-1Rs on the immune cells results in reduced expression of various inflammatory signaling pathways like nod-like receptor pyrin 3 (NLRP3) inflammasome and nuclear factor kappa B (NF-κB) with subsequent inhibition release of pro-inflammatory cytokines like IL-6 and tumor necrosis factor-alpha (TNF-α) (Wan and Sun 2019
; Tsukahara et al. 2015
). In addition, activation of GLP-1Rs has anti-inflammatory effects via stimulation of AMPK, cAMP, endothelial nitric oxide synthase (eNOS), and suppression of chemokine expression (Jin and Liu 2020
). Besides, in Covid-19, inflammatory signaling pathways like NLRP3 inflammasome and NF-κB are highly activated, leading to hyperinflammation and the development of cytokine storms (Al-kuraishy et al. 2022a
, b). In this state, TZT may effectively reduce the risk of cytokine storm development through the activation of GLP-1RAs.
Furthermore, stimulation of GLP-1RAs by specific agonists may improve airway inflammation by inhibiting mucus production and cytokine production. Preclinical studies demonstrated that GLP-1RAs attenuate experimental ALI in mice (Zhu et al. 2015
). Likewise, GLP-1RAs improve respiratory function in T2DM patients regardless of blood glucose. A prospective cohort study involving 32 T2DM patients on metformin monotherapy or metformin plus GLP-1RA illustrated that metformin plus GLP-1RA over 24 months of therapy was superior to metformin monotherapy (Rogliani et al. 2019
). These findings suggest the pulmoprotective effect of GLP-1RAs. Thus, TZT use in Covid-19 patients with T2DM may reduce the risk of ALI/ARDS through modulation of airway inflammation.
Moreover, GLP-1RAs reduce bodyweight and decrease the burden of obesity on Covid-19 pathogenesis. The anti-obesogenic effect of GLP-1RAs is mediated by direct inhibition of the feeding center and indirectly through modulation of energy expenditure (Jepsen and Christensen 2021
). Long-term use of GLP-1RAs can modulate obesity-mediated inflammation, immune dysfunction, and chronic low-grade inflammation in obese subjects developing Covid-19 (De Lorenzo et al. 2021
). A meta-analysis involving 50 relevant published articles showed that obesity is regarded as an independent risk factor for Covid-19 severity (Aghili et al. 2021
). Thus, the anti-obesogenic effect of TZT may reduce Covid-19 severity by ameliorating body weight and adiposity (Samms et al. 2021
). The experimental study demonstrated that TZT effectively reduced the body weight in mice (Aghili et al. 2021
; Samms et al. 2021
). In this state, TZT in obese subjects with or without T2DM could be a prophylactic measure against the development of Covid-19 in obesity.
Furthermore, Covid-19 may induce substantial alterations of gut microbiota due to the direct invasion of enterocytes with the progression of intestinal inflammation. Systemic hyperinflammation, hypercytokinemia, and the development of cytokine storms may affect intestinal microbiota (Jung and Jung 2022
). In addition, the development of ALI/ARDS with lung inflammation affects the intestinal integrity through the lung-gut axis (Al-Kuraishy et al. 2022a
, b). Alteration of gut microbiota induces systemic inflammation with augmentation of ALI/ARDS in severely affected Covid-19 (Sencio et al. 2021
). Therefore, modulation of gut microbiota by administration of probiotics and prebiotics could be a new strategy to prevent intestinal inflammation and systemic complications through modulation of inflammatory signaling pathway (Venegas-Borsellino et al. 2021
). Remarkably, T2DM and obese patients have altered gut microbiota toward pathogenic species compared to the healthy controls (Verma 2022
). Abnormal gut microbiota in patients with T2DM and obesity promote abnormal intestinal permeability with the development of endotoxemia and systemic complications (Venegas-Borsellino et al. 2021
). Therefore, abnormal gut microbiota in patients with T2DM and obesity could be an independent risk factor for developing Covid-19 severity. In this bargain, it has been shown that GLP-1RA liraglutide positively modulates gut microbiota in patients with T2DM and obesity (Verma 2022
). In addition, GLP-1RA preserves gut microbiota and prevents intestinal dysbiosis (Megur et al. 2022
; Shang et al. 2021
). Herein, TZT, like other GLP-1RA, may attenuate Covid-19-induced gut microbiota alterations and, by this mechanism, may mitigate intestinal inflammation and systemic complications in Covid-19 patients with either T2DM or obesity.
Moreover, the binding of SARS-CoV-2 with ACE2 is regarded as the basic point in the pathogenesis of Covid-19 (Mutter et al. 2020
). It has been suggested in the early Covid-19 pandemic that overexpression may increase the risk of SARS-CoV-2 infection (Peron and Nakaya 2020
). This suggestion was wrong since drugs that increase ACE2 expressions, like ibuprofen and angiotensin receptor blockers (ARBs), are protective rather than harmful when used in Covid-19 (Kelleni 2020
; Poutoglidou et al. 2021
). However, the potential effects of GLP-1RA on the ACE2 expression was revealed by preclinical studies that were not confirmed in human. For example, GLP-1RA liraglutide increases ACE2 expression in rats (Romaní-Pérez et al. 2015
). At the same time, liraglutide induces the expression of anti-inflammatory Ang1-7 (Fandiño et al. 2018
). Interestingly, ACE2 overexpression by GLP-1RA promotes the generation of anti-inflammatory Ang1-7 and reduces pro-inflammatory AngII (Romaní-Pérez et al. 2015
; Fandiño et al. 2018
). Therefore, GLP-1RA TZT may reduce airway inflammation and systemic disorders through the upregulation of ACE2.
TZT, through modulation of the GLP-1 effect, may reduce Covid-19 associated glucose variability, inflammatory changes, and airway inflammation.