Impact of Cotadutide Drug on Obese Individuals with Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis


 Background: The food and drug administration approved many drugs to treat diabetes mellitus, but those drugs do not have a noticeable effect on weight management. Recently, glucagon-like peptide 1 agonist known as Cotadutide was estimated to serve as a potent drug in treating type 2 diabetes by reducing blood glucose levels and body weight indices. This study aimed to explore the safety and efficacy of Cotadutide as a treatment for type 2 diabetes individuals.Methods: A comprehensive literature search was done on different databases, including PubMed, Scopus, Web of Science, and Cochrane Library to capture all relevant articles using an established search strategy. The inclusion criteria were randomized controlled trials that assessed the safety and efficacy of Cotadutide versus placebo or any anti-diabetes drugs in obese and overweight people with type 2 diabetes mellitus. Data analysis was accomplished using Revman 5.4 software.Results: We found 663 relevant articles. From which nine studies were included and subjected to qualitative analysis and eight for quantitative analysis. The pooled effect showed that Cotadutide was better than placebo in reducing body weight (Mean difference (MD) = 3.31, p > 0.00001), glycated hemoglobin (HbA1c ) (MD = -0.68, p > 0.00001), glucose area under the plasma concentration curve (AUC [0-4h]) (MD = 30.15, p > 0.00001), and fasting plasma glucose over time (mg/dl) (MD = 31.31, p > 0.00001).Conclusion: Cotadutide is safe and effective in reducing blood glucose levels and body weight in individuals with type 2 diabetes.Study protocol registration: The study protocol was registered on PROSPERO (CRD: CRD42021257670).


Background
Type 2 diabetes mellitus is one of the most common endocrine disorders worldwide, according to the International Diabetes Federation (IDF) its prevalence has surged rapidly to include more than 400 million individuals over the past three decades (1). Type 2 diabetes mellitus is a long-term disease characterized by chronic insulin resistance and hyperglycemia that increases over time, resulting in increasing of insulin resistance leading to weight gain (2,3). Therefore, reducing body weight will prevent more insulin resistance and better control of the body weight condition.
Many medications with different mechanisms are available to control type 2 diabetes mellitus as (a) metformin which acts through various trajectories to inhibit gluconeogenesis and reduce the level of lipopolysaccharide, (b) insulin secretagogues, (c) alpha-glucosidase inhibitors, (d) dipeptidyl peptidase 4 inhibitors, and (e) sodium-glucose co-transporter-2 inhibitor (4). However, none of them is signi cant in reducing body weight at doses approved for blood glucose reduction. Therefore, weight loss remains an unmet medical need for these people (5).
Glucagon-like peptide-1 (GLP-1) receptor agonist's therapy known as Cotadutide seems to be effective in glycemic control and weight loss. The impact of GLP-1 drugs varies depending on the pharmacokinetic pro le (6). Lorenz M et al 2013 showed that short-acting GLP-1 receptor agonists (lixisenatide) at a dose of 20 μg daily lowers postprandial hyperglycemia excursions in individuals with type 2 diabetes mellitus, probably caused by the continuous slowing of stomach emptying (7). In the same way, J van Can et al 2014 investigated the effects of long-acting GLP-1 receptor agonists (liraglutide) on gastric emptying and the result indicated that liraglutide at 3 mg signi cantly delays the gastric emptying (8). In addition, Daniel R et al reported in 2020 that lixisenatide reduced the gastric emptying rate more than liraglutide (9).
Based on the above-mentioned data, GLP-1 receptor agonists are useful in treating individuals with type 2 diabetes and obesity by controlling hyperglycemia and delaying stomach emptying. They also help people lose weight by reducing the appetite and increasing energy expenditure by optimizing metabolic reactions such as amino acid catabolism, and fatty acid oxidation (10).
Many studies have investigated the effect of Cotadutide (GLP-1 receptor agonist) on type 2 diabetes mellitus. In this study, we aim to summarize, review, and analyze those studies to understand the safety and e cacy pro les of this new medication in controlling type 2 diabetes mellitus and its effect on weight reduction.

Study design and registration:
This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline and Cochrane Handbook of Systematic Reviews of Intervention (11,12). The study protocol was registered on PROSPERO (CRD: CRD42021257670). treatment period of the study NCT03444584, participants were on metformin and dapagli ozin as well. Table 1 elucidates the full summary of the included studies. The baseline characteristics of the participants are illustrated in Table 2.
Quality assessment results: The risk of bias summary is illustrated in gures 2 and 3. Regarding the Randomization process bias, all the studies were of low risk in terms of the randomization process except for NCT03550378, which was judged as some concerns because there was inadequate information about the allocation concealment, randomization, and baseline balance.
Regarding the intended interventions bias, most of the included trials had a low risk of bias in terms of deviations from the intended interventions except for NCT03645421 and NCT03745937, which were judged as some concerns. This is because there was no information about the statistical analysis used to estimate the effect of assignments in both of them despite blinding the personnel.
Regarding the missing outcome data bias, most of the included trials had a low risk of bias in terms of the missing outcome data due to applying the intention to treat analysis. We judged NCT03645421 and P.D. Ambery et al. as high risk of bias because the authors applied astreated analysis (14).
Regarding the measurement outcome bias, we judged the risk of bias in the measurement of the outcome as low risk of bias in most of the studies due to blinding of all outcome assessors and using appropriate methods in measuring the outcomes. We judged NCT03645421 and NCT03550378 as some concerns due to the lack of information about blinding the outcome assessor.
For the selection of the reported results bias, the risk of bias due to the selection of the reported results ranged between low and some concerns. We judged all the registered protocols as some concerns because there is no published data yet to compare it with the protocols. The published studies (6,14-16) were of low risk as all outcomes mentioned in the results were present in the protocols.
For other sourced of bias, we judged almost all the studies as high risk in terms of other potential sources of bias as most of them are registered protocols without any published papers yet. Parker et al (15) stated the lack of statistical power to draw inferences between cohorts and the absence of validated questionnaires as a limitation in their study and so we judged it as having a high risk of bias. Accordingly, Ambery et al (6) had a relatively small population size which we considered as high-risk potential. Only (14,16) showed no other potential sources of bias.     Treatment-emergent serious adverse events (TESAEs): We didn't do a meta-analysis for this outcome because none of the participants suffered any TESAEs in three out of six studies in both the Cotadutide and the placebo group. Only three studies reported some participants having TESAEs and they are relatively very low. In terms of TESAEs, NCT03550378 reported two out of 21 persons in the Cotadutide group and two out of 20 in the placebo group. On the other hand, NCT03596177 reported two persons out of 18 and zero out of seven in the Cotadutide group and the placebo group, respectively. In the MAD portion of the study by P. Ambery et al, they reported one out of seven participants having TESAEs in the Cotadutide 200 mcg group and none out of 19 participants in the placebo group (6).

Discussion
This meta-analysis on 1258 participants with type 2 diabetes revealed that e cacy outcomes, including body weight, fasting blood glucose, HbA 1c , and AUC [0-4h], were signi cantly better in people receiving Cotadutide treatment than placebo. The number of participants with positive ADA to Cotadutide was high but without a signi cant difference compared to placebo. Furthermore, no signi cant difference was observed between the Cotadutide group and placebo in TESAEs. Hence, Cotadutide is safe and effective as a hypoglycemic drug in people with controlled type 2 diabetes.
In ten years, more than half of individuals with type 2 diabetes mellitus switch from oral monotherapy (usually Metformin) to insulin therapy to control their blood glucose levels (17). Multiple combination therapies are routinely used before insulin is initiated. Insulin use causes weight gain, which can exceed 6 kg 20 in the rst year after starting insulin medication (18). The overall gain in weight can cause an increase in insulin resistance which is associated with high blood pressure, dyslipidemia, and a high risk of cardiovascular mortalities and morbidities such as non-fatal myocardial infarction or stroke, both before and after diagnosis of diabetes (19,20). Pre-clinical ndings further suggest that the balance of activities at GLP-1 receptors and glucagon receptors was appropriate for both weight reduction and glycemic management (21). These activities are supposed to be balanced by stimulating insulin release mediated by glucose, delayed gastric emptying, and enhanced oxidation of fatty acids (22,23). GLP-1, including Cotadutide (MEDI0382) and glucagon receptor dual agonists, may have central impacts on appetite as glucagon receptor agonist has been found in animal and human studies to increase energy expenditure (24).
Cotadutide (5-300 µg) corrected the glucose levels to the normal range in phase one of the rst human trial which was conducted on healthy volunteers, with a pharmacokinetic pro le that included once-daily treatment (6). Similar to these previous ndings (6, 14), in phase 2a, Cotadutide (100-300 μg) signi cantly lowered blood glucose levels and body weight indices in overweight or obese Japanese people with type 2 diabetes throughout a 48-day treatment period compared to placebo. Parker et al. found a substantial decline in glucose AUC (0-4h) by −21.52% with up titrated Cotadutide (50-300 μg) in comparison to +6.32% with placebo. Similarly, a decline in body weight was reported by −3.41% versus −0.08% for Cotadutide versus placebo, respectively (15). Nevertheless, in different study (25), with a lower BMI (26.3-28.8 kg/m2) than Parker et al (31.5 kg/m2) (15), blood glucose and weight reduction with Cotadutide 300 μg remained signi cant compared to placebo at −37.86% versus +2.45% and −3.34% versus −0.82%, respectively.
Cotadutide therapy reduced body weight in a dose-dependent approach, and the highest reductions occurred at 300 μg. Moreover, Cotadutide improved fasting plasma glucose, fructosamine, HbA 1c , percentage of time in hyperglycemia, insulin secretion, and resistance. After 6 weeks of Cotadutide medication, signi cant decreases in HbA 1c were found, with e cacy remaining constant (25).
Cotadutide has also been known to signi cantly reduce hepatic glycogen and steatosis, as well as having a bene cial effect on hepatic in ammation and brosis markers (25,26). The decrease in hepatic glycogen contrasts with what would be expected from a GLP-1 monoagonist, which would cause glycogen accumulation and exhibit glucagon receptor interaction (27). Furthermore, the degree of liver fat loss with Cotadutide (39% reduction) was comparable to that shown in a small study of women three months following bariatric surgery (42% reduction) (28). This decrease in liver fat found with Cotadutide was larger than would be expected from weight loss alone-for example, in individuals with documented non-alcoholic fatty liver disease, a 5% decrease in BMI results in a 25.5 percent relative decline in liver fat (29).
MEDI0382 had a linear pharmacokinetic pro le in the rst human study on healthy volunteers (phase 1), and no participants tested positive for ADA (14). In a previous study, participants were given Cotadutide for a year and had a signi cant ADA incidence. Only 16% of participants acquired ADAs over a titer of 80, at which point the in uence on pharmacokinetics was around two times higher than the population average (16) (ClinicalTrials.gov identi er NCT04019561).
In the Harmony Outcomes study, albiglutide outperformed placebo in terms of serious adverse cardiovascular problems in people with type 2 diabetes and cardiovascular morbidities with a hazard ratio of 0.78, which implies that GLP-1 agonists can improve cardiovascular outcomes according to these data (30). Due to GLP-1 and glucagon receptor agonism on the heart and vascular system, an increase in heart rate was expected. The rise in heart rate by 6.8 beats per minute observed with Cotadutide was not signi cantly greater than that seen with the GLP-1 receptor agonist liraglutide which increased by 6 to 9 beats from baseline. Furthermore, the drop in blood pressure was comparable to that seen with GLP-1 receptor agonists (22,31).
Cotadutide plasma concentrations increased in agreement with the anticipated dose titration at all dose levels, with no TEAEs linked to immunogenicity observed (6). In this study, Cotadutide had a higher rate of gastrointestinal co-morbidities such as nausea and vomiting compared to placebo. This outcome is also seen with the GLP-1 receptor mono-agonists (32,33). In addition, Cotadutide's safety pro le was equivalent to that of previous global trials (6,14), with a greater incidence of gastrointestinal adverse events.
To lower the gastrointestinal adverse events associated with Cotadutide 300 μg, dose escalation was required upon which a phase 2 study in obese type 2 diabetes participants reported that Cotadutide was effective and well-tolerated with starting doses of 50 μg for 7 days, then gradual dose escalation up to 300 μg (15,34). Despite causing more gastrointestinal upset than placebo, escalated dosages of Cotadutide of up to 300 μg which were given once daily were generally tolerated because the symptoms were mild or moderate in severity (14).
This study comprehensively evaluated the e cacy and safety of Cotadutide for people with type 2 diabetes. Nine RCTs were included in the study, resulting in a valuable evidence level. The included trials varied from low to high quality. The majority of the identi ed heterogeneity was resolved. Our analysis also has certain limitations, including the small sample size and the small number of included studies. Publication bias could not be detected due to the small number of included studies. The short follow-up period and lack of placebo were the major drawbacks of the study. Most of the included studies were protocols with published results, not articles. Cotadutide medication should also be evaluated for its effects on stomach emptying, energy intake, and energy expenditure in larger studies.

Conclusion
Over a short dosage period, Cotadutide provided considerable metabolic bene ts to overweight and obese participants with type 2 diabetes.
Cotadutide's safety and pharmacokinetics allow once-daily administration of dosages less than 150 μg, which can be followed by dose escalation. Cotadutide's promising impacts on glycemic control, body weight, and liver fat suggest that it might be a helpful agent for type 2 diabetes individuals with longer-term treatment. All data generated or analyzed during this study are included in this published article or in the data repositories listed in References.

Abbreviations
Con icts of interest: Dr. Abd-ElGawad has nothing to disclose. All the authors also declare no con ict of interest.
Funding: not applicable Ethics approval: not applicable Consent to participate: not applicable Consent for publication: not applicable Availability of data and material: All data generated or analyzed during this study are included in this published article or in the data repositories listed in References.
Code availability: not applicable Authors contributions: Mahmoud M Ali leads the team, performed the search strategy and data collection step, solved any con ict in the screening phase, performed the meta-analysis part, and solved any con ict in the quality assessment part, took part in the data extraction phase.
Ahmed Hafez took part in the screening process, data extraction, and meta-analysis in addition to writing the results section and edited the whole manuscript.
Mahmoud Shaban took part in the screening process, data extraction, quality assessment, and drafting the tables.

Mohammed
Tarek Hasan took part in data extraction, and meta-analysis.
Mohammed Magdy El-Ghannam took part in quality assessment and writing the introduction section.
Osama M Ghogar tokk part in study selection and writing the methods section.
Asmaa Ahmed Elrashedy wrote the discussion section and edited the manuscript.      Risk of bias graph for randomized controlled trials using Excel tool to implement Rob2.

Figure 3
Risk of bias summary for randomized controlled trials using Excel tool to implement Rob2.

Figure 4
Percentage decrease in body weight plot.

Supplementary Files
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