Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Intima-Media Thickness: Systematic Review and Meta-Analysis

Background Beyond glycemic control, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been proposed to reduce the risk of cardiovascular events. The aim of the present systematic review and meta-analysis is to demonstrate the effects of GLP-1 RA and SGLT2is on intima-media thickness (IMT). Methods PubMed, EMBASE, Web of Science, SCOPUS, and Google Scholar databases were searched from inception to September 9, 2023. All interventional and observational studies that provided data on the effects of GLP-1 RAs or SGLT2is on IMT were included. Critical appraisal was performed using the Joanna Briggs Institute checklists. IMT changes (preintervention and postintervention) were pooled and meta-analyzed using a random-effects model. Subgroup analyses were based on type of medication (GLP-1 RA: liraglutide and exenatide; SGLT2i: empagliflozin, ipragliflozin, tofogliflozin, and dapagliflozin), randomized clinical trials (RCTs), and diabetic patients. Results The literature search yielded 708 related articles after duplicates were removed. Eighteen studies examined the effects of GLP-1 RA, and eleven examined the effects of SGLT2i. GLP-1 RA and SGLT2i significantly decreased IMT (MD = −0.123, 95% CI (-0.170, -0.076), P < 0.0001, I2 = 98% and MD = −0.048, 95% CI (-0.092, -0.004), P = 0.031, I2 = 95%, respectively). Metaregression showed that IMT change correlated with baseline IMT, whereas it did not correlate with gender, duration of diabetes, and duration of treatment. Conclusions Treatment with GLP-1 RA and SGLT2i can lower IMT in diabetic patients, and GLP-1 RA may be more effective than SGLT2i.


Introduction
Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and sodium/glucose cotransporter 2 inhibitors (SGLT2is) have been introduced for the treatment of type 2 diabetes mellitus (T2DM).Their promising results in glycemic control and weight loss, as well as their low risk of hypoglycemia, less adverse events, and favourable renocardiovascular effects have made them desirable therapies for the treatment of T2DM and its concomitant diseases and complications [1].In addition to their putative target, numerous molecular targets for GLP-1s have been identified, justifying their potential for broader medical applications, including autophagy, oxidative stress, platelet function, lipid metabolism, and inflammation [2][3][4][5][6][7][8][9].GLP-1 RA causes an increase in insulin secretion and a decrease in glucagon levels in response to glucose and delays gastric emptying, thereby suppressing postprandial hyperglycemia and appetite, resulting in a decrease in total energy intake and body weight [10].SGLT2is act independently of insulin; they block renal glucose reabsorption mediated by SGLT2 expressed along proximal tubules and cause glucosuria [7].
Carotid intima-media thickness (IMT) is a quick and noninvasive ultrasound marker that indicates the thickness of the two innermost layers of the carotid artery.It is a risk stratification tool used as a surrogate marker for atherosclerosis in numerous studies to assess the risk of cardiovascular events [11][12][13].We are interested in comparing the effects of GLP-1 RA and SGLT2i therapies on IMT, which may reflect the cardioprotective effects of these drugs.A direct comparison of the cardioprotective benefits of two second-line therapies in T2DM could help us find a better strategy for glycemic control.However, no systematic comparison has been performed for GLP-1 RA or SGLT2i therapies in terms of their effect on IMT.Therefore, we performed a comprehensive systematic review and meta-analyses to determine the effects of GLP-1 RA and SGLT2i drugs on IMT.

Methods
This systematic review is in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [14].The study protocol was registered with the International Prospective Registry of Systematic Reviews (PROSPERO).

Data Sources and Searching Strategy.
To identify potentially relevant studies, searches were conducted in the following four databases (since inception to September 9, 2023): PubMed, EMBASE, Web of Science, and SCOPUS, with two reviewers (A.A. and S.H.) working independently and in parallel.Citations of all included studies and relevant published papers were reviewed by hand search."Google Scholar" was also searched to find potentially relevant articles.Studies were found by searching for three main terms and their synonyms, including "IM," "SGLT2i," and "GLP-1 RA."The complete search strategy for each term is shown in Table S1.The search was not limited by time, type of article, or language.We used reference management software (EndNote X8) to import references, remove duplicates, and review the literature.

Selection Criteria.
Inclusive criteria for this systematic review were studies that investigated IMT in groups of patients treated with GLP-1 RA or SGLT2i.Eligible studies that met the following criteria were included in the metaanalysis: (1) the studies reported mean IMT at baseline and final or mean change in IMT after GLP-1 RA or SGLT2i therapy, and (2) the follow-up period was at least 2 weeks.Two authors (A.A. and S.H.), working independently and in parallel, reviewed the abstract and included the paper reporting the effects of GLP-1 RA or SGLT2i on IMT.Subsequently, A.A. and S.H. independently assessed the full text of the papers and made the final decision.Disagreements in study selection were adjudicated by a third reviewer.
2.3.Quality Assessment.Two authors (L.H. and S.H.) independently assessed the quality of studies using the JBI checklists [15].The JBI checklist assessed bias in selection, measurement, and analysis.If there were disagreements, they were resolved by discussion or referral to another investigator to achieve consensus.The checklist questions were answered "yes," "no," "unclear," or "not applicable."For each "yes" answer, 1 point is awarded, and after adding the points, the final score is calculated.
2.4.Data Extraction.The two investigators (A.A. and S.H.) independently extracted the following data: first name, year in which studies were conducted (if no data were provided, the year of study publication was considered), groups, dosage, population, size, gender, age, location, study design, follow-up, IMT at baseline, IMT at end, and disease duration.
2.5.Publication Bias and Statistical Analysis.Publication bias was examined using funnel plots, Egger's test, and Duval and Tweedie's trim and fill test.Pre-and postintervention IMT values were recorded to calculate the mean difference (MD) and 95% confidence interval (CI).Subgroup analyses were performed based on drug classes, and sensitivity analyses were performed based on effect models (random to fixed or vice versa), RTCs, T2DM patients, and R values (0.3, 0.5, and 0.8).The Cochrane Q statistic was used to assess heterogeneity, and if it was less than 0.05, a randomeffects model was used for analysis.Metaregression was performed to determine the correlation between IMT changes and disease duration, gender, follow-up period, and baseline IMT.A P value of less than 0.05 was considered statistically significant for the outcome and heterogeneity analyses.Data analysis was performed using Comprehensive Meta-Analysis software (CMA) V.3.
All comparisons were repeated by changing the R value to 0.3, 0.5, or 0.8, but no differences were found.A sensitivity analysis in which the random-effects analysis was replaced by a fixed-effects analysis also confirmed the results, except as noted in the manuscript.S2.All funnel plots of all analyses are shown in the figures.Figure 9 shows the funnel plot of the pre-post comparison of GLP-1 RA and SGLT2i treatment, and Figure S4 shows the funnel plots of the sensitivity analysis.In addition, the results of the Egger test and the trim-and-fill method of Duval and Tweedie, which indicate no significant publication bias, are shown in Table 2 (Table 2).

Discussion
T2DM is associated with a high prevalence of cardiovascular risk, and pharmacotherapies have been introduced to reduce the risk of atherosclerosis in various ways, including glycemic control, lipid balance, uric acid lowering, and blood pressure control [61].Our meta-analysis showed a significant reduction in IMT, a surrogate atherosclerosis marker, after GLP-1 RA or SGLT2i therapy; however, it appears that GLP-1 RA is more effective in reducing IMT.Similarly, a recent meta-analysis of RCTs showed that GLP-1 RAs were effective in preventing serious adverse cardiovascular events in T2DM patients with obesity (relative risk = 0 88, 95% CI (0.81, 0.96)), whereas SGLT2i marginally prevented serious adverse cardiovascular events (relative risk = 0 91, 95% CI (0.83, 1.00)) [62].In contrast to a recent review showing cardiovascular benefits for liraglutide and semaglutide but not for exenatide, we demonstrated that exenatide can also reduce IMT [63].It appears that the effects of GLP-1 RA are not class-dependent, whereas the effects of SGLT2i are.Consistent with our findings, previous studies reported that GLP-1 RA was effective in reducing major adverse events associated with cardiac events regardless of gender.In contrast, in terms of reducing major adverse events associated with cardiac events, SGLT2i was effective in men but not in women [64].This inconsistency may be due to different outcome measures.Metaregression analysis showed that the effects of GLP-1 RA and SGLT2i persisted with longterm treatment, suggesting that these drugs do not induce tolerance.In contrast to a previous study claiming that the duration of T2DM might influence efficacy, the metaregression showed no significant correlation between the duration of diabetes and change in IMT [65].However, the metaregression showed that higher baseline IMT leads to greater IMT reduction.A study by Kahal et al. showed that GLP-1 RA was not significantly effective in patients with polycystic ovary syndrome whose baseline IMT was lower than that of T2DM patients [18].In these cases, confounding factors and heterogeneity may affect the results, so well-designed RCTs are warranted.A meta-analysis by Song et al. evaluated the efficacy of GLP-1-based therapies and concluded that IMT was not significantly reduced.Insufficient studies, heterogeneity, and pooling other GLP-1-based therapy other than GLP-1 RA including dipeptidyl peptidase-4 inhibitors may lead to different results compared with our findings [66].They also showed that brain natriuretic peptide, a marker of atherosclerosis, decreased significantly with GLP-1-based therapies.Furthermore, in a prospective study of elderly people in Sweden, it was observed that higher serum GLP-1 levels correlated with lower IMT [67].
Prior studies suggest that liraglutide can regulate the NLRP3 inflammasome and NF-κB signaling pathway, which causes the inflammatory state [28,68,69].It has also been shown that GLP-1 RA protects cardiomyocytes from IL 1β-induced metabolic dysfunction and mitochondrial dysfunction [70].Previous studies have shown that GLP-1 RA therapy lowers both systolic and diastolic blood pressure [71], improves endothelial dysfunction [72,73], and reduces macrophage foam cell formation and atherosclerosis [74].Qu and Qu reviewed evidence from epidemiological and human studies that low-density lipoprotein cholesterol (LDL-C) is an important regulator in the development of atherosclerosis [75].A previous meta-analysis by Zhao et al. showed a significant reduction in LDL-C following GLP-1 RA therapy [76], whereas Sánchez-García et al. did   9 Journal of Diabetes Research not achieve a significant reduction after SGLT2is [77].Another mechanism described for GLP-1 RA agonists is that these drugs increase antioxidant enzymes (superoxide dismutase and glutathione reductase) and decrease reactive oxygen species and malondialdehyde levels [78].In vivo studies have shown that GLP-1 RA reduces atherosclerosis by suppressing endoplasmic reticulum stress, macrophage apoptosis, and microvesicle production [79].Hyperglycemia has also been shown to lead to a decrease in endothelial nitric oxide function via a decrease in synthesis and an increase in degradation and to play a role in endothelial dysfunction, with liraglutide effectively restoring endothelial nitric oxide synthase activity in the diabetic mouse model [80,81].The same mechanism involving amelioration of inflammation, insulin resistance, endothelial dysfunction, dislipidemia, hyperglycemia, and oxidative state has been proposed for SGLT2is [82][83][84][85][86]. Previous studies have demonstrated the importance of AT1R/NADPH oxidase/SGLT1 and 2 signaling pathways in promoting atherosclerosis [87][88][89].They showed that atherosclerotic plaques have higher SGLT2 expression [87][88][89].A recent meta-analysis summarizing data from 9 RCTs and 2 cohorts concluded that SGLT2i improves flow-mediated dilation but not pulse wave velocity [90].
The paucity of high-quality randomized clinical trials in this systematic review is one of the major limitations of the current study.Lacking sufficient studies, we could not evaluate the effects of different classes, different doses, or patient characteristics of GLP-1 RA or SGLT2i on IMT.Also, there were insufficient studies to compare SGLT2i with control groups.There was too much heterogeneity, which could be due to different inclusion criteria, different types and dosages of GLP-1 RA or SGLT2i, follow-up time, and study design.Despite these aforementioned biases, sensitivity analyses yielded nearly consistent results.
In conclusion, GLP-1 RA and SGLT2i may reduce IMT.Among the different GLP-1 RAs, liraglutide was the most studied and had a significant effect on IMT reduction.In

Figure 2 :
Figure 2: Forest plot displaying pre-post difference and 95% confidence interval for the impact of GLP-1 RA on IMT.

Figure 3 :Figure 4 :
Figure 3: Forest plot displaying pre-post difference and 95% confidence interval for the impact of GLP-1 RA on IMT based on randomized clinical trials.

Figure 6 :
Figure 6: Forest plot displaying pre-post difference and 95% confidence interval for the impact of SGLT2i on IMT.

Figure 7 :
Figure 7: Forest plot displaying pre-post difference and 95% confidence interval for the impact of SGLT2i on IMT based on randomized clinical trials.

Figure 8 :
Figure 8: Metaregression plots of the association between IMT with gender, follow-up, duration of diabetes, and baseline IMT for SGLT2i studies.

Figure 9 :
Figure 9: Funnel plot displaying the impact of GLP-1 RA and SGLT2i on IMT.

Table 1 :
Characteristics of included studies.
6Conference papers.†Chineselanguage.‡MaxMIT.Abbreviations: HfpEF: heart failure with preserved ejection fraction; T2DM: type 2 diabetes mellitus; PCOS: polycystic ovary syndrome; NAFLD: nonalcoholic fatty liver disease; IGT: impaired glucose tolerance; ND: not determined.6Journal of Diabetes Research studies, cross-sectional studies, RCTs, and nonrandomized clinical trials are described in detail in Table Figure 5: Forest plot displaying mean difference and 95% confidence interval for the impact of GLP-1 RA compared to control groups on IMT.

Table 2 :
Publication bias evaluation by Egger's regression test and Duval and Tweedie trim and fill test.Finding/distribution pattern Egger's test Trim and fill method Egger's intercept P value Number of trimmed studies Point estimate after trim Change after trim RAs might be more effective than SGLT2is in lowering IMT.