The Efficacy of Pharmacotherapy in the Treatment of Obesity in Patients With Type 2 Diabetes: A Systematic Review

Obesity is a global public health challenge that poses a significant threat to the effective control and management of type 2 diabetes mellitus (T2DM). Being overweight/obese with T2DM is associated with a wide range of comorbidities, including cardiovascular, cerebrovascular, and renal diseases. This systematic review aimed to investigate the drug therapy used globally among this type of patients in the period between 2014 and 2024. Four databases (PubMed, Web of Science, Scopus, and Cochrane) were searched using the keywords “(Drug Therapy OR Pharmaceutical Preparations OR Pharmacotherapy) AND (Diabetes Mellitus, Type 2) AND (Obesity OR Overweight OR Weight Loss OR Weight reduction) in the title and abstract. All papers assessing the efficacy of any drug class on blood sugar and body weight (BW) were included in the systematic review. Out of 5,206 papers extracted through the database search, 25 randomized clinical trials (RCTs) were considered suitable for the systematic review. The articles included 8,208 participants who tested different drug classes, e.g., glucagon-like peptide-1 (GLP-1) and sodium-glucose co-transporter-2 (SGLT2), with or without metformin. All the reviewed drugs showed significant weight loss over 12-52 weeks. However, the magnitude of weight loss was modest, and the long-term health benefits and safety remain unclear. Interventions that combine pharmacologic therapy with lifestyle modifications may be more effective but need additional research. Continued development of new treatment options for obesity in T2DM is crucial to reduce morbidity and mortality among these patients.


Introduction And Background
Strong evidence shows that greater weight loss often leads to more significant improvements in glycemic control and cardiovascular risk markers [1].Numerous studies have stated that a 5% weight loss from baseline improves A1C by 0.5%, and a 15% weight loss from baseline improves A1C by ~1% [2][3][4].
Unfortunately, achieving both weight and glycemic control is challenging.Lifestyle modifications alone might lead to initial weight loss, but weight regain is common [5].In addition, some anti-hyperglycemic agents (AHAs), e.g., thiazolidinedione, sulfonylurea, and glinide, are also associated with weight gain [6][7][8].Therefore, there has been an increased need for newer modalities that address these unmet clinical needs.
Metformin has been used as the first line of treatment for type 2 diabetes mellitus (T2DM) since it was approved by the Food and Drug Administration (FDA) in 1994 [9].Despite its efficacy and safety, recent clinical trials have been investigating the potency of newer AHAs such as dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists on weight loss and glycemic control alone or in combination with behavioral therapy and metformin when treatment escalation is indicated [10,11].The effects of other drug classes such as pegbelfermin (a polyglycated analog of human fibroblast growth factor 21 (FGF21)), montelukast (leukotriene receptor antagonist), phentermine and topiramate (anorectics and anticonvulsants), bimagrumab (human monoclonal antibody inhibitor of activin type II receptors (ActRII)), and lorcaserin (serotonin receptor antagonist) have also been studied.
Because of the rising necessity of finding suitable treatment options to prevent the complications and comorbidities of overweight/obese patients with T2DM, we conducted a comprehensive overview of all the pharmacotherapy used in the management of patients with coexisting obesity and T2DM in the last 10 years.This systematic review of the available literature will provide better guidance for physicians in making personalized treatment plans and improving the lives of these patients.

Review
This systematic review complied with established criteria (Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)) [12,13].

Screening and data extraction
Endnote software (Clarivate Analytics, PA, USA) [14] removed duplicates.The retrieved references were screened in two steps: the first consisted of screening the titles/abstracts independently by two authors to determine their relevance, and the second consisted of screening the full-text papers and evaluating them for inclusion criteria.Independent authors independently extracted data in a Microsoft Excel spreadsheet (Microsoft Corp., Redmond, WA).The data included authors, year of publication, study design and period, objective, methodology, population characteristics, and results of different drug classes used for the treatment of obesity with T2DM.Any discrepancies identified were thoroughly elaborated among the authors until a consensus was reached.The Rayyan website was used in the selection process [15].

Risk of bias assessment
For data synthesis, a summary table was created using data from relevant studies to provide a qualitative interpretation of the findings and study components.The Cochrane risk of bias assessment tool 2 (RoB2) was utilized to evaluate the quality of RCTs [16].The RoB2 tool assesses the risk of bias (ROB) based on the following domains: randomization process, deviation from intended interventions, outcome measurement, missing outcome data, selection of reported results, and the potential sources of bias.The outcome assessed was weight loss in overweight/obese patients with T2DM during 2014-2024.The judgment options were low, moderate, and high, and the overall ROB was reached using signaling questions.Two independent authors conducted the ROB, and disagreements were resolved by discussing them with a third author.

Results
A total of 5,206 papers were extracted from four databases (PubMed, Web of Science, Scopus, and Cochrane).Of these, 592 were omitted as duplicates via EndNote (Clarivate Analytics, Philadelphia, PA).After a thorough full-text screening, we identified 26 RCTs that met our inclusion criteria for this systematic review, as shown in Figure 1.

Overview of the included studies
The included papers were published between 2014 and 2024 in different countries across the world.The studies' duration range was six to 56 weeks (Table 1).The study design was limited to RCTs.The articles included 8,208 individuals, mostly males, with an age average of 54.5±8.7,BMI ranging from 27 to 40 kg/m 2 , diagnosed with T2DM inadequately controlled with diet and exercise (hemoglobin A1C (HbA1C): 6.5%-8.5%).Most patients were already taking at least one hypoglycemic agent, e.g., metformin and sulfonylurea, at the beginning of the study but were not controlled.Most RCTs excluded patients with type 1 diabetes, a history or presence of a condition that could interfere with the assessment of the study drug (as judged by investigators), fasting blood glucose (FBG) concentration of 11.1 mmol/L or more, concurrent or previous use of a GLP-1 agonist within three months prior to screening, ongoing hypocaloric diet, or use of weightloss agents or insulin for glycemic control within 12 months prior to screening and women who were lactating or of childbearing potential.All patients included in the RCTs were advised to follow a restricted diet and exercise program along with the tested drugs.Moreover, all patients were measured for BW, BMI, waist circumference (WC), HbA1C, FBG, and lipid profile at the beginning of RCTs and at one or more points during the study.The major drug class studied in the included RCTs was glucagon-like peptide-1 receptor agonists (GLP-1RAs), e.g., semaglutide, taspoglutide, cotadutide, survodutide, polyethylene glycol loxenatide (PEG-Loxe), liraglutide, and efinopegdutide, followed by SGLT-1 inhibitors, e.g., canagliflozin, ertugliflozin, dapagliflozin, and licogliflozin.Among the tested drugs were pegbelfermin, montelukast, phentermine (PHEN) and topiramate (TPM), bimagrumab, alpha-lipoic acid (a caprylic acid-derived antioxidant), and lorcaserin.
These drugs were assessed according to their potency in lowering blood glucose levels by measuring the change in the HbA1C and FBG, as well as their efficacy in inducing weight loss, evidenced by the reduction in BW, BMI, WC, and body fat percent.The adverse effects of each drug were also reported.The results showed the superiority of these drugs (whether used alone or in combination with metformin) in controlling blood glucose and BW over lifestyle modifications.The most reported side effects were gastrointestinal disorders, including nausea and vomiting.

Risk of bias assessment
Using the Cochrane RoB2 tool, 25 RCTs were assessed as having a low ROB, including nine RCTs with unclear risk in the domain of randomization method, allocation, and blinding of participants.However, the overall ROB is low.All details regarding the ROB assessment are illustrated in Figure 2 and Figure 3.

FIGURE 2: Risk of bias graph
Review authors' judgments about each risk of bias item presented as percentages across all included studies

FIGURE 3: Risk of bias summary
Review authors' judgments about each risk of bias item for each included study [10, In this systematic review, we summarized and synthesized the most up-to-date data from RCTs that evaluate the efficacy of recent drugs used to treat obesity associated with T2DM.To the best of our knowledge, there was no updated systematic review of the pharmacotherapy used in the last decade for the treatment of overweight/obese patients with T2DM.According to older studies, drugs such as fluoxetine, orlistat, and sibutramine were investigated.However, they only caused modest weight loss.In addition, their long-term health benefits and safety remained unclear [41].Based on recent RCTs, the most promising two drug classes were GLP-1RAs and SGLT2 inhibitors [42].Other drugs, classes, FGF21 analogs, leukotriene receptor antagonists, anorectics and anticonvulsants, serotonin receptor antagonists, and antioxidants were explored.
GLP-1RAs achieve glycemic control through mechanisms such as boosting insulin secretion induced by hyperglycemia, decreasing glucagon secretion during hyperglycemia, slowing gastric emptying, and preventing significant increases in postprandial glucose [43,44].SGLT inhibitors work by blocking SGLT2 cotransporters in the proximal tubules in the kidney, leading to the inhibition of glucose re-absorption and promotion of the renal excretion of glucose, thereby modestly lowering elevated blood glucose levels [45].Despite their efficacy in controlling blood glucose levels, their effect on reduction in BW and BMI was still uncertain.There are a wide variety of GLP-1RAs and SGLT2 inhibitors, including short-acting and longacting drugs.Because of these differences in pharmacokinetics, efficacy, adverse reaction rates, and dosing requirements of each GLP-1RA and SGLT2 inhibitor, most RCTs focused on evaluating each drug independently.

GLP-1 drugs
Cotadutide Three RCTs were carried out by Asano et al. ( 2023) [18], Nahra et al. (2021) [34], and Ambery et al. ( 2018) [17] to investigate the effects of cotadutide on BW and blood glucose versus placebo.The results showed that the drug significantly reduced the HbA1C and BW at the end of the treatment.In the study by Asano et al. ( 2023) [18], the mean respective changes in HbA1C were 1.13% versus 0.17% in placebo, and the mean percentage changes in BW were 6.93% versus 1.23% in placebo.Also, cotadutide was tolerated up to 600 μg.According to Nahra et al. ( 2021) [34], the most common adverse events with cotadutide (nausea: 35%, vomiting: 17%) decreased over time.

Semaglutide
A single-arm, open-label study by Volpe et al. (2022) [39] showed that the drug improved HbA1C (-11.16±2.99;p<0.01) and caused a significant decrease in BW (-9.89±0.99kg; p<0.01) at all observational points.[33] revealed that PEG-Loxe along with lifestyle interventions or oral antidiabetic drug therapy has significantly decreased BW, HbA1C, fasting plasma glucose (FPG), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) levels in the combined treatment group more than that in the control group in addition to an increase in the level of high-density lipoprotein cholesterol (HDL-C) (p<0.05)compared to metformin alone.

Liraglutide
Three RCTs, Davies et al. (2015) [22], Feng et al. (2015) [25], and Garvey et al. (2020) [28] showed that in addition to blood glucose control, there was a significant weight loss between the liraglutide group and the control group.

Taspoglutide
An RCT by Hollander et al. (2021) [31] noted a significant decrease in the mean HbA1C from baseline with taspoglutide compared to placebo (least square (LS) mean: 0.81% versus 0.09%; p<0.0001).In addition, the reduction in weight loss at week 24 was significantly greater than placebo (least square (LS) mean: 3.16 versus 1.85 kg; p<0.01).Nausea and vomiting were the most reported side effects.

Dapagliflozin
Results from Kato et al. (2017) [32] showed that dapagliflozin caused a meaningful reduction in the levels of HbA1C, BW, blood pressure, total fat mass, and visceral fat area (VFA).However, these effects were largely reversed by the cessation of the drug.Also, changes from baseline to the end of treatment were noted in HbA1C from 8.0±1.5% to 7.3±1.3%and in BW from 81.7±17 kg to 78.5±17.8kg (p<0.01)[32].

Other drug classes
Pegbelfermin (PEGylated FGF21) The drug was evaluated by Charles et al. (2019) [21], but the results revealed no significant difference between the drug and placebo in HbA1C level and BW loss.However, significant improvements were observed in whole-body insulin sensitivity, HDL, and TG (p<0.05).

Montelukast (Leukotriene Receptor Antagonist)
El-Khateeb et al. (2023) [24] investigated the effects of montelukast with metformin.The study showed that the drug significantly improved all the measured parameters, including HbA1C and BW loss.The percent change in BW and BMI from baseline was -7.82% and -8.28%, respectively (p<0.0001).The percent change in FBG and HbA1C from baseline was -37% and -16.44%, respectively (p<0.0001).

Phentermine/Topiramate (Anorectics and Anticonvulsants)
An RCT by Garvey et [36] revealed that alpha-lipoic acid significantly reduced BMI and improved HbA1C and TG levels as an additive therapy.The difference in BMI from baseline to the end of treatment was -1.47 in the study group versus -0.8 in the placebo.In addition, the reduction in glucose concentration (mmol/L) was -2.36 mmol/L (p<0.001 for each).

Limitations
Despite these promising results, there were still some limitations.We identified a few eligible studies with small sample sizes and inadequate power, leading to imprecise estimates.Nevertheless, this systematic review was conducted comprehensively, with an appropriate number of databases searched by more than one reviewer to screen and extract data.It is based on high-quality RCTs, as indicated by the ROB assessment, which made our evidence more credible due to the quality of the data involved.
Moreover, the importance of our study lies in the clinical application of these results in the treatment of overweight/obese patients with T2DM.The addition of at least one of these drugs to the usual management of dietary and lifestyle modifications in patients with obesity and T2DM may help prevent disease progression and the various complications that accompany the disease.This opens the door for these novel treatment options to find a definitive solution for these types of patients, giving hope to millions of individuals.
Given the above, the literature surrounding the pharmacotherapy of obesity in T2DM is sparse.Consequently, one avenue of inquiry is testing the long-term side effects of these drugs.Therefore, more RCTs should investigate the therapeutic value of these medications with (1) larger sample sizes to ensure preciseness, (2) a wide range of ethnic populations, (3) study objectives assessing superiority or efficacy over placebo or standard of care (not only equivalence trials), (4) evaluation of the advantages of these drugs in each BMI subgroup, and (5) usage of intention-to-treat analysis to create results to tackle bias due to deviations from intended interventions.Furthermore, future research should consider determining the best drug and the most suitable dose with the least side effects.

Conclusions
In conclusion, there is an urgent need for more efficacious intervention as the prevalence of T2DM and obesity are increasing in all age groups.Hence, the clinical complexity is diverse in etiology and individual response to therapies in both clinical conditions; therefore, the optimum direction is precision medicine approaches to attain the best outcome using genetic, clinical, and biochemical aspects.In addition, a combination of pharmacotherapy and lifestyle modifications is a potential intervention that could help in reducing the mortality and morbidity of diabetic obese patients.