Emerging role of GLP-1 agonists in cardio-metabolic therapy - Focus on Semaglutide

Abstract

Semaglutide, a GLP-1 receptor agonist, has emerged as a promising agent in cardiovascular disease management, particularly for patients with obesity and diabetes. Recent studies have demonstrated significant benefits of Semaglutide beyond glycemic control, including reduced major adverse cardiovascular events (MACE), improvements in heart failure symptoms, and weight reduction. Notably, the STEP-HFpEF trial highlighted improved exercise capacity and a reduction in NT-proBNP levels, offering a novel therapeutic pathway for heart failure management. Additionally, Semaglutide has shown anti-inflammatory effects, reducing C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α), thereby mitigating atherosclerotic risks. Moreover, the SELECT trial demonstrated Semaglutide's cardiovascular benefits in non-diabetic, obese patients, suggesting that its effects extend beyond weight loss. These findings represent a potential paradigm shift in cardiovascular risk management, although access and affordability remain key challenges.

Highlights

• •Semaglutide reduces major adverse cardiovascular events (MACE) in patients with or without diabetes.
• •The STEP-HFpEF trial shows Semaglutide improves exercise capacity and NT-proBNP levels in heart failure patients with preserved EF.
• •Semaglutide lowers CRP and TNF-α which may reduce atherosclerotic risk.
• •The SELECT trial demonstrates cardiovascular benefits in non-diabetic, obese patients, beyond weight loss.

1. Introduction

Semaglutide is an incretin hormone produced in the upper gastrointestinal tract. The cardiovascular (CV) community has generated significant enthusiasm for its potential cardiovascular benefits. In this article, we present an in-depth review of the literature on the newly discovered role of this class of drugs in mitigating CV risk and treatment of CV disease.

2. History of GLP-1

The term incretin hormone was coined by Jean La Barre in 1932, describing endogenous factors produced by the intestine to influence pancreatic secretions [1]. In the later part of the 20th century, Nauck et al. [2] described GLP-1 and its biology in humans. GLP-1 is a 30-peptide residue hormone that is secreted by L-cells in the ileum and colon in response to overall nutrient intake, primarily carbohydrates and amino acids. GLP-1 is quickly metabolized by dipeptidyl peptidase 4 (DPP-4), limiting its half-life to about 2 mins. In addition to the pancreas and hypothalamus, GLP-1 receptors are also found on vascular endothelium and cardiac myocytes at lower concentrations [3,4]. The physiologic effects of GLP-1 are well studied. Their primary biological impact on the pancreas is to secrete insulin, reduce glucagon, and induce early satiety by delaying gastric emptying and acting on hypothalamic receptors.

On the other hand, GLP-1 effects on vascular endothelium result in vasodilation and modulation of atherosclerosis via anti-inflammatory pathways [5,6]. Since cardiovascular complications are the most common cause of morbidity and mortality in diabetics, it became essential to study the impact of GLP-1 agonists on CV outcome in these patients.

Exenatide, a synthetic GLP-1 analog, was the first GLP-1 analog approved by the FDA in 2005 for clinical use in diabetics, as a once-daily subcutaneous injection [7,8]. Since then, there have been gradual but significant improvements in our understanding and availability of pharmacologic alternatives that primarily work by stimulating GLP-1 receptors with a longer duration of action of up to 7 days following a single subcutaneous injection [8]. Liraglutide, Dulaglutide, and Semaglutide are the 3 GLP-1 agonists approved for once-weekly use. Semaglutide appears to be the most studied with now proven positive outcomes in patients with or without diabetes and cardiovascular disease [[9], [10], [11]].

3. Pharmacokinetics and pharmacodynamics of Semaglutide

Semaglutide is a long-acting GLP-1 analog with a half-life of 165 h [12]. It has 94 % sequence homology with native GLP-1 [13]. Structural differences include amino acid substitution at position 8 (alanine to α-aminoisobutyric acid) and position 34 (lysine to arginine), and acylation of the lysine in position 26 with a spacer and C-18 fatty acid chain [14]. The substitution at position 8 makes Semaglutide less susceptible to degradation by DPP-4 in the gut, and the lysine acylation increases affinity to albumin in the plasma, significantly increasing its half-life [14]. Semaglutide is >99 % bound to albumin in the plasma. It is metabolized by proteolytic cleavage of the peptide backbone with beta-oxidation of the fatty acid sidechain. It is excreted in urine and feces; no dosage adjustment is required for renal or hepatic impairment. Oral Semaglutide has a bioavailability of ~0.4 %, while subcutaneous preparation has a bioavailability reaching 89 %.

Semaglutide has gained significant traction in the medical community due to its potent blood glucose-neutralizing and weight-lowering effects and its once-weekly dosing. It may also promote anti-inflammation, cardio-protection, and blood pressure regulation [15,16]. Several mechanisms have been proposed to account for these effects, including reduction of reactive oxygen species in endothelial cells and monocytes/macrophages [16], proliferation of human endothelial cells in ex vivo studies, suggesting a possible effect on new vessel formation, and increased nitric oxide synthetase activity in human endothelial cells [17].

4. Role of GLP-1 agonists and Semaglutide in heart failure

Longitudinal studies strongly suggest an association of obesity with heart failure with preserved ejection fraction, increasing the relative risk by up to 56 % compared to normal weight, even after correcting for other risk factors [6]. Weight control strategies like bariatric surgeries have significantly reduced heart failure prevalence per registry studies [18].

Early studies suggested that intravenous GLP-1 agonists may improve left ventricular function, myocardial oxygen uptake, and physical performance in congestive heart failure [19]. In a small pilot study in both diabetic and non-diabetic patients, 72 h of intravenous GLP-1 infusion administered to patients with acute myocardial ischemia undergoing percutaneous revascularization improved left ventricular ejection fraction and regional wall motion [20]. Liraglutide was the first GLP-1 agonist studied in the LIVE trial (Effect of Liraglutide on Left ventricular Function in Stable Chronic Heart Failure Patients) a randomized control trial in patients with chronic stable HFrEF with or without type II DM, but it failed to show improvement in systolic function or clinical outcomes [5]. The National Institute of Health-sponsored FIGHT trial (Functional Impact of GLP-1 for HF Treatment) randomly assigned 300 patients with HFrEF and recent decompensation regardless of diabetes status to liraglutide or placebo for 6 months [21]. The trial was neutral overall with no differences in HF-related outcomes or functional capacity. Albiglutide was also tested in 82 patients with type II DM with HF and LVEF < 40 % [22]. No significant difference was seen in LVEF, BNP or 6-minute walk test. A similar outcome was observed in patients with EF < 40 % in the EXSCEL trial (Exenatide Study of Cardiovascular Event Lowering) [23].

The seminal STEP program evaluated the impact of Semaglutide in patients with HFpEF. The STEP-1 trial (Semaglutide Treatment in people with obesity), a phase 3 study with Semaglutide 2.4 mg weekly, given subcutaneously, showed a mean weight reduction of 14.9 % by week 68 compared to 2.4 % in the placebo arm, leading to the FDA approval for Semaglutide for weight loss [24]. Given this potent effect on weight reduction, Semaglutide was studied in 2 randomized control trials for clinical outcomes in both diabetics and nondiabetics with obesity and HFpEF [[25], [26], [27]]. STEP-HFpEF trial studied 529 patients with HFpEF, NYHA II-IV symptoms, and BMI of 30 or higher who were randomized to once weekly Semaglutide vs placebo for 52 weeks [24]. The study showed an increased 6 min walking distance (21.5 m with Semaglutide compared to 1.2 m with placebo), improved KCCQ CSS Score [24] and a consistent reduction in NT-proBNP in the Semaglutide arm compared to placebo regardless of weight loss [28], and there was a reduction of the loop diuretic dose by 17 % compared to an increase of 2.4 % in the placebo group, regardless of baseline diuretic dose despite similar weight loss among both arms in the STEP-HFpEF program [29]. The effect of improved KCCQ CSS Scores with Semaglutide was observed irrespective of left ventricular ejection fractions (45–49 %, 50–59 %, >/ 60 %) at baseline. The effect of Semaglutide on the symptomatology of heart failure among male and females was similar despite females having more weight loss (9.6 % compared to males with 7.2 %) [30]. This finding may indicate that the effect of Semaglutide on heart failure goes beyond weight. Interestingly, in a subgroup analysis of the STEP-HFpEF program, patients with atrial fibrillation (Afib) showed improvement in heart failure related symptoms compared to patients without Afib [31]. Semaglutide also reduced COVID-19 related deaths in patients enrolled in the STEP program [32]. A large, pooled analysis of the STEP HFpEF, STEP HFpEF-DM, plus the SELECT (Semaglutide Effect on Cardiovascular Outcomes in People with Overweight ABD Obesity) and FLOW trials (Research Study to see How Semaglutide Works Compared to Placebo in People with Type-2 Diabetes and Chronic Kidney Disease) showed that Semaglutide was associated with reduced composite of cardiovascular death and worsening of heart failure events [33]. Interestingly, in the SELECT trial 24 % of patients (4286 patients) had an investigator reported diagnosis of HF at baseline (31 % HFrEF, 53 % HFpEF, and 16 % were unclassified) [11]. In a prespecified analysis, the effects of Semaglutide to reduce cardiovascular death was seen both in patients with investigator-identified HFpEF and HFrEF [11]. However, heart failure hospitalizations were seen only in patients with HFpEF despite reduced all-cause and cardiovascular mortality in both types of heart failure [11].Of note, the HFrEF events reported in the SELECT trial were lower than historical numbers which casts doubt on whether these patients from the SELECT trial have had true HFrEF. Therefore, based on available data, Semaglutide seems to be effective in reducing events related to HFpEF in obese patients with or without diabetes (Table 2). The event reduction may not be related to weight reduction as explained previously. However, available data do not support use of Semaglutide or any other GLP-1 agonist in HFrEF. More studies are needed especially in obese patients with HFrEF.

Table 2.

Impact of GLP-1 Analogs and Semaglutide on Outcomes in Patients with Heart Failure.

Trial	HF subtype	Diabetic	Non-diabetic patients	(BMI > 30)	(BMI < 30)	Outcome in diabetic patients	Outcome in non-diabetic patients	Outcome in patients with BMI > 30	Outcome in patients with BMI < 30
STEP-HFpEF	HFpEF	Yes	Yes	Yes (Median BMI ~37)	Not explicitly analyzed	Improvement in symptoms and exercise capacity	Improvement in exercise capacity and weight loss	Significant weight loss and functional improvement	Not analyzed separately
SUSTAIN-6	Mixed (not heart failure specific)	Yes	No	Mixed	Mixed	Reduced CV events, including heart failure hospitalizations	Not applicable (only diabetic population studied)	Not clearly reported	Not analyzed separately
FIGHT	HFrEF	Yes	Yes	Not reported	Not reported	No significant improvement in outcomes or LV function	No significant improvement in outcomes	Not reported	Not reported
LIVE	HFrEF	Yes	Yes	Not reported	Not reported	No significant improvement in outcomes or LV function	No significant improvement in outcomes	Not reported	Not reported

5. Effect of GLP-1 agonists and Semaglutide on atherosclerotic risk and events

5.1. Effects on inflammatory markers

Clinical conditions like insulin resistance, dyslipidemia, and hypertension have been shown to have associated elevated inflammatory markers, and these conditions elevate the risk of cardiovascular disease (CVD) [[34], [35], [36]].

Early animal studies suggested that Liraglutide and Semaglutide reduce the development of atherosclerotic plaques in mice models, even at doses that did not lead to weight loss or substantial cholesterol lowering [37]. Semaglutide decreased plasma markers of systemic inflammation, such as TNF-α, and altered gene expression related to leukocyte recruitment, adhesion, and extracellular matrix turnover in aortic tissue [37].

Subsequently, clinical studies with Semaglutide showed substantial reduction in CRP levels compared to placebo in multiple trials [[38], [39], [40]]. These reductions were consistent across various baseline characteristics, including body weight, body mass index (BMI), and glycemic status. Notably, more participants in the Semaglutide groups transitioned from higher to lower CRP-defined cardiovascular risk categories compared to those in the placebo groups, suggesting a meaningful reduction in inflammation-driven cardiovascular risk [38].

5.2. Effects on major adverse cardiovascular events

As mentioned before, early studies suggested Semaglutide can modulate vascular function. Therefore, it was logical to study the impact of GLP-1 agonists in patients with known or at risk for atherosclerotic coronary artery disease. The LEADER trial [41] was designed to assess if liraglutide, in addition to standard care, could reduce the risk of cardiovascular events in patients with type 2 diabetes who were at high risk for cardiovascular disease. The primary goal was to determine if liraglutide could lower the incidence of cardiovascular events, defined as the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, compared to a placebo. There was a significantly lower risk of death from cardiovascular causes in the Liraglutide arm (4.7 % when compared to placebo 6.0 % with a hazard ratio of 0.78, p = 0.007) [41]. There was also a trend towards fewer nonfatal myocardial infarctions and strokes in the Liraglutide group although the difference was not statistically significant [41,42]. This was a pivotal point, as it was the first trial showing a significant reduction in cardiovascular events with GLP-1 agonists. Subsequently, The HARMONY (Albiglutide and Cardiovascular Outcomes in Patients with Type 2 diabetes and Cardiovascular Disease) trial [22] showed that Albiglutide significantly reduced the incidence of the primary composite outcome (cardiovascular death, myocardial infarction, or stroke) by 22 % compared to placebo, The risk of non-fatal myocardial infarction was also reduced by 25 % in the albiglutide group [22]. The REWIND trial (Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes) [43], found that dulaglutide significantly reduced the composite outcome of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke by 12 % compared to placebo [43]. The risk of non-fatal stroke was also reduced by 24 % in the dulaglutide group [43,44]. A meta-analysis of these trials suggested that GLP-1 agonists reduce the risk of major adverse cardiovascular events (MACEs) in diabetic persons with or without established ASCVD [45,46].

Semaglutide was first studied in the SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) [9]. Patients who received Semaglutide had a 26 % risk reduction in death from cardiovascular cause, non-fatal Myocardial infarction or nonfatal stroke compared with placebo [9]. There was also a reduction in coronary revascularization events. Some of the more systemic observations noted in the SUSTAIN-6 trial was an average decrease in systolic blood pressure of 1.3 mmHg to 2.6 mmHg with 0.5 mg and 1 mg weekly of Semaglutide respectively compared to placebo [9].

Given these positive results with the SUSTAIN-6 trial, the SELECT trial evaluated the impact of Semaglutide on Cardiovascular outcomes in Obese non-diabetic patients [11]. This was a large-scale, multicenter, double-blind, randomized, placebo-controlled study. 17,604 patients with preexisting cardiovascular disease (CVD) but no history of diabetes were enrolled and randomized to receive either 2.4 mg of Semaglutide or a placebo weekly. The primary endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. A 20 % relative risk reduction in major cardiovascular events was seen with Semaglutide compared to placebo, highlighting its potential role in secondary cardiovascular prevention for obese patients without diabetes [11]. The cardiovascular benefits observed in the SELECT trial were concomitant with its known metabolic effects, including significant reductions in body weight and waist circumference [11]. The trial's findings suggest that Semaglutide's effect on cardiovascular outcome may extend beyond weight loss as the degree of reduction in CV risk is more profound than what is observed with strict weight loss strategies like bariatric surgery [18].

The findings of the SELECT trial have several important implications for clinical practice. First, the demonstrated reduction in MACE with Semaglutide suggests that this GLP-1 receptor agonists could be a valuable addition to the therapeutic arsenal for patients with obesity and preexisting cardiovascular disease, even in the absence of diabetes. This could lead to a paradigm shift where cardiovascular risk management in obese patients might increasingly include pharmacological strategies aimed at weight reduction and metabolic regulation rather than focusing solely on traditional risk factors such as dyslipidemia and hypertension.

Historically, weight management has been underutilized in cardiovascular prevention, partly due to the limited efficacy of lifestyle interventions and pharmacotherapy in producing sustained weight loss. The substantial weight reduction achieved with Semaglutide in the SELECT trial (mean decrease of 9.39 %) demonstrates that effective pharmacological interventions can lead to meaningful cardiovascular benefits, potentially setting a new standard for obesity management in at-risk populations (Table 1).

Table 1.

Impact of Semaglutide on Ischemic Cardiovascular Outcomes.

	Primary endpoint: composite cardiovascular death			Secondary endpoint: nonfatal myocardial infarction
	Semaglutide	Placebo	Hazard ratio (95 % CI)	Semaglutide	Placebo	Hazard ratio (95 % CI)
SUSTAIN-6	6.6 %	8.9 %	0.74	2.9 %	3.9 %	0.74a
SELECT	6.5 %	8.0 %	0.80	2.7 %	3.7 %	0.72

Note: Primary cardiovascular endpoint is defined as a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

^aHazard ratio (0.51–1.08); all other Hazard ratios did not cross 1.0, indicating a protective mechanism.

6. Effect on chronic kidney disease and renoprotection

GLP-1 has been studied in chronic kidney disease to slow the disease progression. In one cohort of 27,000 patients with DM2 and advanced CKD, GLP-1 has been shown to decrease all causes of mortality [47]. The effects of GLP-1 in CKD patients, irrespective of the presence of diabetes, remain controversial. There is an assumed CV benefit in CKD due to its mechanistic effect on lowering blood pressure, better blood glucose control, and weight management [11,24]. In a meta-analysis, there was a decrease in major CV events in patients with DM2, and it was in patients with CKD with eGFR<60 ml/min/1.73 m2 primarily due to the reduction of albuminuria [48].

In the SUSTAIN 6 [9], PIONEER 6 [49], and the LEADER [41] clinical trials, studying the effects of GLP-1 in patients with DM2, there has been evidence of slowing of CKD progression by lower rates of eGFR reduction in the subgroup and the post hoc analyses. Liraglutide has been found to downregulate the receptors for advanced glycation-endproducts-induced inflammation in diabetic mice [50]. In another study, GLP-1R was expressed less in CKD mice and correlated with the disease severity [51]. Multiple ongoing studies have analyzed the effect of GLP-1 on renal inflammation and fibrosis.

More specifically for Semaglutide, the Flow (Evaluate Renal Function with Semaglutide Once Weekly) international multicenter clinical trial, Semaglutide 1 mg once weekly dose has been shown to reduce primary renal outcomes, primarily reduction in the decline of eGFR over time, and renal and CV related deaths in patients with Diabetes Mellitus and chronic kidney disease [52].

7. Effect on NAFLD

A key pathogenic driver of NASH is insulin resistance which is a shared characteristic with type 2 diabetes and obesity. Adipose tissue dysfunction, insulin resistance and increased adiposity contribute to increased levels of free fatty acids and carbohydrates resulting in excess lipotoxic and metabolic loads on the liver leading to hepatic lipid accumulation, cell injury, inflammation, and fibrosis.

Liraglutide which is a glucagon-like peptide-1 receptor agonist has been shown to improve liver enzyme levels, reduce liver fat and also has a beneficial effect on histologic resolution of NASH in the LEAN trial [53], which was a multicenter, double-blinded, randomized, placebo controlled phase 2 trial conducted in four UK medical centers. The ESSENCE trial [54] which is an ongoing trial has shown that Semaglutide reduces the levels of alanine aminotransferase and inflammatory markers. The ESSENCE trial is a randomized, double blind, placebo controlled, parallel group trial, phase 2 trial conducted at 143 sites in 16 countries over a 72-week treatment period and 7 week follow up period showed that treatment with Semaglutide resulted in significantly higher resolution of NASH compared to placebo however there was no significant improvement in the percentage of patients in the fibrosis stage.

The ESSENCE is a two-part, phase 3 study that is ongoing to evaluate the effect of subcutaneous Semaglutide 2.4 mg in participants with biopsy proven NASH and fibrosis stages 2 or 3 with primary objective of part 1 is to demonstrate improvement in liver histology with Semaglutide compared to placebo. The primary endpoints are resolution of steatohepatitis and no worsening of liver fibrosis.

8. Current guidelines

Semaglutide recently gained FDA approval for treatment of Type II diabetes mellitus and chronic weight management [55,56]. Subsequently, it was approved for reduction of major cardiovascular events in adults with known heart disease and either obesity or overweight and in patients with diabetes and known heart disease. The dose used is 2.4 mg, once weekly subcutaneous injection [57].

9. Side effects and safety

Semaglutide received marketing approval in 2017. Adverse events investigated and reported ranged from gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), gallbladder events, acute renal injury, diabetic retinopathy, and thyroid cancer [19,[58], [59], [60]]. The safety profile for Semaglutide is like that of other GLP-1 receptor agonists [61]. Although the association with thyroid and pancreatic cancer is not fully established, both formulations of Semaglutide have received an official black box warning for thyroid C-cell tumors in the United States based on data from rodent studies [60]. However, this warning is not unique to Semaglutide among the drug class [61]. Additionally, the Food and Drug Administration (FDA) urges caution regarding compounding (i.e. mixing of several medications to create a customized drug) of Semaglutide formulations since they are not assessed for efficacy, safety, or quality [62,63]. Semaglutide is currently contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia [64]. GLP-1 agonists are primarily renally eliminated. There is no dose adjustment necessary for mild renal or hepatic impairment. Dose adjustments are recommended given delayed clearance in moderate renal dysfunction (especially in patients over 70 years of age). Patients with severe renal disease should avoid taking GLP-1 agonists altogether [64]. Semaglutide may alter the absorption of medications by delaying gastric emptying [64]. Consequently, patients prescribed a GLP-1 agonist while on warfarin although no dose adjustment is required, warfarin levels via an international normalized ratio (INR) should be obtained routinely [65]. There have been limited studies investigating GLP-1 overdosing. Treatment in most cases of toxic ingestion involves supportive care. Regarding suspension of semaglutide in the perioperative setting, the decision on whether to withhold should be based on minimizing the risk of complications. GLP-1 agonists can affect gastric emptying, which may increase the risk of pulmonary aspiration in patients undergoing monitored anesthesia care or general anesthesia as part of procedures performed in a catheterization laboratory. Patients with an increased risk are those tolerating a high GLP-1 dosing, experiencing gastrointestinal symptoms, in the escalation phase of therapy, or with gastric dysmotility. In these patients, it may be prudent to withhold. The timeframe to withhold can also depend on the formulation. It is recommended to withhold it on the day of the procedure if prescribed daily and one week prior to the procedure if prescribed on a weekly basis. If, after clinical assessment, the patient is deemed low risk according to the above-mentioned factors, then the decision to withhold should be individualized [66,67].

10. Conclusion and future directions

In conclusion, though GLP-1 analogs were primarily considered as anti-diabetic medications, recent evidence suggests their beneficial role in patients at high risk for cardiovascular events, including for primary prevention. Their benefit might be more pronounced in obese compared to non-obese patients. At present, affordability remains a significant barrier to access and widespread use. It remains to be seen if patients would develop tolerance to the medications and if a lifelong use is needed for continued benefits. Availability of preparations that require less frequent administration might improve compliance. Studies looking into medications with dual biologic pathways like Tirzepatide, which have co-agonist action on (GLP1 and GIP glucagon insulinotropic polypeptide) receptors have been shown to be more effective in diabetic, weight loss and lipid control (SURPASS-2 Trial) [68], the effect on weight loss. The SUMMIT trial also showed similar outcomes by reducing the risk of cardiovascular death, heart failure exacerbation and improving functional capacity of patients [69]. The effects of Tirzepatide on weight loss and by extension on moderate to severe sleep apnea was seen in the SURMOUNT-OSA trial with a reduction in apnea-hypopnea index by −29.3 events per hour compared to placebo leading to its FDA approval as the first drug for the treatment of sleep [70] (Table 1, Table 2).

Funding support and author disclosures

All the authors have no disclosures or relationships relevant to this paper.

CRediT authorship contribution statement

Celestine Odigwe: Writing – original draft, Formal analysis, Conceptualization. Rajasekhar Mulyala: Investigation, Data curation. Haijra Malik: Writing – original draft. Brent Ruiz: Validation, Methodology. Mariam Riad: Writing – original draft. Mohammad As Sayiadeh: Resources, Methodology. Sanchitha Honganur: Conceptualization. Alexis Parks: Data curation. Mustafeez Ur Rahman: Writing – review & editing. Nasser Lakkis: Writing – review & editing, Writing – original draft, Validation, Supervision, Investigation, Formal analysis, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.