Clinical and Radiographic Variables Around Implant With Simultaneous Graft Among Type 2 Diabetic Patients Treated With Different Hypoglycemic Medications: A Retrospective Study.

Clinical and Radiographic Variables Around Implant With Simultaneous Graft Among Type 2 Diabetic Patients Treated With Different Hypoglycemic Medications: A Retrospective Study. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical and Radiographic Variables Around Implant With Simultaneous Graft Among Type 2 Diabetic Patients Treated With Different Hypoglycemic Medications: A Retrospective Study. Shaojie Shi, Feng Ding, Xiangdong Liu, Lei Wang, Xingxing Wang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-134530/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background: The clinical and radiographic variables around dental implants in type 2 diabetes mellitus patients with different hypoglycemic agents still remained unclear. Methods: This retrospective cohort study collected the dental records and digital periapical radiographs of type 2 diabetes mellitus patients and implants. These patients were grouped according to their medication: insulin, metformin, and glucagon-like peptide-1 drugs. The radiographic marginal bone loss around implants and clinical parameters, including peri-implant bleeding on probing and probing depth, were compared among groups using the Kruskal-Wallis test. Results: A total of 150 patients with 308 implants (101 in insulin group, 121 in metformin group and 86 in glucagon-like peptide-1 drugs group) were assessed. The peri-implants marginal bone loss in insulin group ( P <0.05) and metformin group ( P <0.01) were significantly higher than glucagon-like peptide-1 drug group. The radiographic bone loss in metformin was higher than insulin group ( P 0.05). Conclusions: The radiographic variables were not exactly the same among type 2 diabetes mellitus patients with different hypoglycemic agents. glucagon-like peptide-1 drugs might be more beneficial to bone tissue around implants. More studies are needed to verify the direct effect of these drugs on peri-implant bone. Clinical trial registration number: ChiCTR2000034211 (retrospectively registered) Dentistry Head & Neck Surgery type 2 diabetic mellitus dental implant marginal bone loss hypoglycemic agents guided bone regeneration Figures Figure 1 Figure 2 Background The number of individuals with type 2 diabetes mellitus (T2DM) constitutes a large population, and a recent report in 2019 showed that, the prevalence of T2DM worldwide had reached 8% in 2018 1 . Due to the relationship between T2DM and periodontitis 2 , there is a large proportion of patients with missing teeth in the T2DM population. Implant-supported denture restoration has been an excellent treatment for the loss of teeth and T2DM individuals have a large requirement for dental implant treatment. However, T2DM patients often face the challenge of atrophic alveolar bone width at implant sites 3 . The minor and moderate atrophic ridge often need horizontal bone augmentation by guided bone regeneration (GBR)with the combination of bone graft materials and barrier membranes 4 . The uncontrolled hyperglycemia would impact the therapeutic effect of dental implants in T2DM 5 . And some studies have shown that early osseointegration around implants is compromised by T2DM even if glucose is strictly controlled 6 . It is crucial for clinicians to promote the efficacy of implant treatment in T2DM patients. Dental implant treatment success is related to the osseointegration and peri-implant bone around implants 7 – 8 . Previous research has shown that diabetes impacts bone remodeling around implants, especially at the early stage of osseointegration 9 . The changes of bone levels around implants is a biomechanical process that could be influenced by several factors in patients and implants 10 . The marginal bone loss (MBL) in diabetes patients is higher than that in nondiabetic individuals, despite being glycemic controlled 11 . The higher MBL in T2DM patients could reflect the impaired bone condition around implants. Therefore, MBL was considered an important radiographic parameter for bone tissue around implants in the present study. Recently, abundant evidence has revealed the role of hypoglycemic agents in bone metabolism 12 . There is growing concern about their direct bone target effect. For example, insulin and metformin could be beneficial to bone tissue 13 . This beneficial effect might improve the outcome of dental implants. It was reported that local application of insulin could promote osseointegration in T2DM rats 14 . Glucagon-like peptide-1 (GLP-1) drugs also have the potential to promote osseointegration around implants 15 . Currently, there is no clinical evidence of hypoglycemic drugs interfering with bone tissue around implants. Therefore, the present study aimed to obtain more detailed information about the clinical and radiographic variables around implants in T2DM patients using different hypoglycemic agents. Methods Ethical protocol The retrospective cohort study was approved by the Ethics Committee of School of Stomatology, the Fourth Military Medical University (Ethics Approval Number: IRB-REV-2020045) and in compliance with the Helsinki Declaration. All patients were given complete information about the treatment and signed informed consent forms before surgery. The implant treatment was performed by the same doctor and the trauma was minimized. This study is reported in agreement with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement. Study design and setting This retrospective cohort study was designed to compare the clinical and radiographic variables around implants with simultaneous GBR in T2DM patients using different hypoglycemic agents. The examiners collected dental records of T2DM patients who received implant surgery from January 2015 to November 2019. After information collection, one examiner divided them into three groups based on their major hypoglycemic agent species: insulin (group 1), metformin (group 2), and GLP-1 (group 3). The state immediately after surgery was recorded as baseline. The MBL from immediately after implant placement to before prosthetic installation and to the first-year follow-up after functional loading were measured to suggest the change of bone tissue around implants. The clinical inflammatory parameters at the first-year follow-up after functional loading, including bleeding on probing (BOP) and probing depth (PD), were collected. To ensure the principle of blinding, the groups were sealed and another independent examiner assessed the data among groups. Eligibility criteria The inclusion criteria were as follows: (a) medically diagnosed T2DM; (b) good blood glucose control before surgery (HbA1c%≤8% 16 ); (c) treatment with one of the hypoglycemic agents: metformin, insulin or GLP-1; (d) implant site with Seibert class I ridge deficiencies resulting in the implant thread exposure which treated only with GBR (graft mass≤0.25g); (e)good oral hygiene care with regular semidiurnal brushing and semiannual professional cleaning. The exclusion criteria were as follows: (a) poor glycemic control (HbA1c%>8%) or severe diabetic complications; (b) osteoporosis; (c) long-term use of bisphosphonates or steroids; (d) irregular use of hypoglycemic drugs; (e) excessive tobacco use and alcohol consumption; (f) progressive periodontitis. Information collection The dental records of participants were reviewed by examiners and the baseline information about patients and implants were obtained. Patient information included age, sex, HbA1c, medication, bone augmentation and oral hygiene care. The implant information included the size, location, arch, position of fixture and major surface treatment of implants. The surgical complications after implant placement were recorded, including wound bleeding, swelling and membrane exposure. And the infection around implant was obtained. Radiographic analysis A standardized digital dental periapical radiographic evaluation performed immediately after implant placement was recorded as the baseline. The radiographic evaluation was carried out before prosthetic installation and at 1-year follow-up after function loading (Figure 1). All radiographs were viewed on a computer screen using Digimizer v5.4.5 (MedCalc Inc., Mariakerke, Belgium) software. The examiner measured the crestal bone levels as the vertical distance from the tip of the implant body to the coronal edge of the first bone-to-implant contact (Figure 2). The image error of magnification was calibrated by the reference value of the actual implant length. Clinical parameters at the first year after functional loading The clinical parameters recordings at the first year after functional loading were collected and analyzed, including BOP and PD. These clinical parameters were measured at six sites around implants and reported as the mean value. Statistical analysis Statistical analysis was performed using specialized software (SPSS v25.0, IBM, Chicago, Illinois). The baseline information was analyzed by the chi-square test and analysis of variance. Dependent variables were evaluated for a normal distribution by the Shapiro-Wilk test. The data are expressed as the means and SDs. Peri-implant MBL and clinical parameters was compared using the Kruskal-Wallis test. The Bonferroni post hoc test was applied for multiple comparisons. Multiple regression analysis was performed to control the baseline variables as covariates. The direction and strength of association between outcome variable and covariates were assessed by regression coefficients, and the precision of which was measured by 95% confidence intervals. Statistical significance threshold was set at P < 0.05. Results The general condition of population A total of 150 patients with 308 implants with GBR were eligible for this study. The system of implant included Straumann, Basel, Switzerland and Nobel Biocare, Gothenburg, Sweden. The condition of implant was analyzed by position of fixture and the major surface treatment to avoid the conflicts of interest. Sixty-one implants in groups with GBR experiences surgical complication and no implant suffered infection. And 54 patients with 101 implants were followed up for a year after the prosthesis installation, and other patients lost to follow-up. No further complications were reported during the follow-up period. The Information Analysis Of Patients And Implants With Gbr The basic information about patients and implants with GBR is shown in Table 1 . There were 54 patients and 101 implants in insulin group, 54 patients and 121 implants in metformin group, 42 patients and 86 implants in GLP-1 group. These groups were comparable with respect to age, HbA1c, sex, implant location and the major surface treatment of implants (P > 0.05). However, the position of fixture was significantly different among the groups (P < 0.01). A total of 71 patients with 129 implants completed one-year follow-up after functional loading (30 patients and 53 implants in insulin group, 24 patients and 44 implants in metformin group, 17 patients and 32 implants in GLP-1 group). The basic confounding factors of patients and implants among groups were comparable (P > 0.05). Table 1 Information on patients and implants with GBR variable Group 1 Group 2 Group 3 Total patients (n) 54 54 42 Age (y) 56.50 ± 9.44 55.46 ± 8.20 56.81 ± 8.69 HbA1c (%) 6.99 ± 0.49 6.93 ± 0.51 6.99 ± 0.45 Sex Male/Female 40/14 46/8 33/9 Total implants (n) 101 121 86 Length (mm) 10.54 ± 1.45 10.84 ± 1.67 10.79 ± 1.88 Arch Maxillary/mandibular 61/40 72/49 44/42 Location Anterior/Posterior 22/79 34/87 25/61 Position of fixture Submerged /Non-submerged 54/47 55/66 61/25 a** Major surface treatment SLA/Anodic oxidation Restoration Single/Multiple ceramic restoration 54/47 39/62 73/48 38/83 39/47 35/51 Notes; Group 1: insulin. Group 2: metformin. Group 3: GLP − 1. GBR, guided bone regeneration. a: the position of fixture among groups is significantly different ( P < 0.01). ** p < 0.01. The comparison of radiographic and clinical parameters of implants with GBR At 12 months of follow-up, the mean MBL around implants with GBR is shown in Table 2 . The MBL was not the same among these medication groups. The mesial and distal MBL parameters in group 1 (mesial: 0.43 ± 0.14 mm, distal: 0.42 ± 0.13 mm) ( P < 0.05) and group 2 (mesial: 0.45 ± 0.14 mm, distal: 0.47 ± 0.13 mm) ( P < 0.01) were higher than those in group 3 (mesial: 0.38 ± 0.12 mm, distal: 0.36 ± 0.12 mm). The distal MBL was significantly higher in group 2 (0.47 ± 0.13 mm) than in group 1 (0.42 ± 0.13 mm) ( P < 0.05). Similarly, the distal MBL in the percentage of implant length was significantly higher in group 1 (P < 0.01) and group 2 (P < 0.01) than in group 3. While at 24 months of follow-up, the mesial and distal MBL parameters in group 1 (mesial: 0.63 ± 0.15 mm, distal: 0.61 ± 0.17 mm) (P < 0.05) and group 3 (mesial: 0.58 ± 0.13 mm, distal: 0.61 ± 0.19 mm) (P < 0.05) were smaller than those in group 2 (mesial: 0.72 ± 0.14 mm, distal: 0.68 ± 0.13 mm). Table 2 The comparison of MBL among groups with GBR MBL Group 1 Group 2 Group 3 12months 24months 12months 24months 12months 24months Mesial MBL in millimeters 0.43 ± 0.14 a* 0.63 ± 0.15 c* 0.45 ± 0.14 b** 0.72 ± 0.14 0.38 ± 0.12 0.58 ± 0.13 d** Distal MBL in millimeters 0.42 ± 0.13 a**c* 0.61 ± 0.17 c* 0.47 ± 0.13 b** 0.68 ± 0.13 0.36 ± 0.12 0.61 ± 0.19 c* Mesial MBL in percentage 4.08 ± 1.37 6.05 ± 1.47 4.30 ± 1.58 b** 6.83 ± 1.73 3.67 ± 1.50 5.48 ± 1.48 d** Distal MBL in percentage 4.04 ± 1.25 b** 5.87 ± 1.78 4.45 ± 1.56 b** 6.48 ± 1.75 3.42 ± 1.38 5.69 ± 1.97 Notes; Group 1: insulin. Group 2: metformin. Group 3: GLP − 1. MBL: marginal bone loss. GBR, guided bone regeneration. a: compared with group 3 ( P < 0.05), b: compared with group 3 ( P < 0.01); c: compared with group 2 ( P < 0.05); d: compared with group 2 ( P < 0.01). * p < 0.05, ** p 0.05) and the PD in group 1 (1.72 ± 0.17 mm) was comparable with group 2 (1.78 ± 0.15 mm) and group 3 (1.69 ± 0.26 mm) at 24 months of follow-up (P > 0.05) (Table 3 ). Table 3 The comparison of clinical parameters among groups with GBR variables Group 1 Group 2 Group 3 P BOP(+) 44(83.02%) 36(81.82%) 27(84.38%) 0.958 PD(mm) 1.72 ± 0.17 1.78 ± 0.15 1.69 ± 0.26 0.071 Notes: Group 1: insulin. Group 2: metformin. Group 3: GLP − 1. BOP: bleeding on probing. PD: probing depth. Regression analysis to control the position of fixture at the 12months of follow-up The position of fixture among groups should be controlled as confounders by multiple regression analysis (Table 4 ). The mesial and distal MBL at 12 months of follow-up still showed statistically significant differences among the groups even after controlling for the position of fixture ( P < 0.05). The table IV showed that the mesial MBL at 12 months of follow-up in group 1 ( P < 0.05) and group 2 ( P < 0.01) were higher than group 3 and the distal MBL in group 1 ( P < 0.01) and group 3 ( P < 0.01) were smaller than group 2 after controlling the position of fixture consistent among groups. Table 4 MBL in patients with GBR at 12 months of follow-up after controlling the position of fixture Variable β (95% CI) P Mesial MBL in millimeters Group 1(compared with group 3) 0.042 (0.003,0.080) 0.034 * Group 2(compared with group 3) 0.066 (0.028,0.104) 0.001 ** Distal MBL in millimeters Group 1(compared with group 3) 0.060 (0.023,0.097) 0.002 ** Group 2(compared with group 3) 0.103 (0.067,0.139) < 0.001 *** Distal MBL in millimeters Group 1(compared with group 2) -0.043 (-0.077, -0.010) 0.011 * Group 3(compared with group 2) -0.103 (-0.139, -0.067) < 0.001 *** Mesial MBL in percentage Group 1(compared with group 3) 0.274 (-0.147,0.695) 0.201 Group 2(compared with group 3) 0.436 (0.027,0.846) 0.037 * Distal MBL in percentage Group 1(compared with group 3) 0.485 (0.087,0.883) 0.017 * Group 2(compared with group 3) 0.841 (0.454,1.229) < 0.001 *** Notes: Group 1: insulin. Group 2: metformin. Group 3: GLP − 1. MBL, marginal bone loss. GBR, guided bone regeneration. (95% CI): 95% confidence interval. P value in bold indicates that the statistical results are consistent with the results of the Kruskal-Wallis test after accounting for the influence of covariates on the outcome variable, and the difference among groups is statistically significant. * p < 0.05, ** p < 0.01, *** p < 0.001 Discussion The influence of diabetes on the properties of a patient’s bone would impact the outcomes of dental implants. In cases where diabetes cannot be completely cured, clinicians generally use hypoglycemic drugs to reduce the adverse effects of diabetes. Numerous studies have reported the direct effect of hypoglycemic drugs on systemic bone metabolism. However, little attention has been paid to the effect of hypoglycemic drugs on peri-implant bone. In the present study, the peri-implant radiographic parameters showed different characteristics among patients using different hypoglycemic agents. The results could serve as a reference for the direct effect of drugs on systemic bone. This study showed that MBL among groups was not exactly the same. The MBL parameters in insulin group and metformin group were higher than those in GLP-1 group at 12 months of follow-up. The MBL in metformin group was higher than insulin group and GLP-1 drugs group at 24 months of follow-up. Similarly, the MBL in the percentage of original implant length in insulin group and metformin group was higher than that in GLP-1 drugs group. During these periods, the bone and bone substitution material had experienced the bone healing and remodeling process and this process could be influenced by the bone condition around implants. The difference of MBL among groups showed the possibility of these drugs interfering with bone tissue around the implant in T2DM patients. After controlling for the baseline information variable, the difference in MBL among groups still existed. This means that these confounding variables, including position of fixture and major surface treatment, did not influence the comparative results of MBL among groups. The change of bone levels around implants could show the bone healing and remodeling process and the higher MBL might suffer higher risk of failure. From these results, the medication type might be related to the bone healing and remodeling around implant at the early stage and the potential among medication might be different. However, the present result showed there was no statistically significant difference in clinical parameters, including BOP (+) and PD, among groups. Although the diabetes could be related to the periodontal inflammation, the peri-implant inflammation parameters seem to have nothing to do with the medication type of the T2DM patient. The results showed that GLP-1 drugs might have a more positive effect on the peri-implant bone than other agents. This is consistent with previous studies. Liang 17 indicated that compared with other hypoglycemic drugs, GLP-1 drugs could significantly reduce the risk of fracture. A meta-analysis also supports that exenatide, a GLP-1 receptor agonist (RA), might have advantages in preventing fracture risk over other hypoglycemic drugs 18 . Preclinical studies have reported the superior osteogenic properties of GLP-1 drugs. GLP-1 receptors are widely distributed, and knockout of the GLP-1 receptor gene leads to severe bone changes related to the abnormality of osteoclasts 19 , which supports the direct effect of GLP-1 on bone. GLP-1RA might also enhance early osseointegration. GLP-1RA improved factors beneficial to osseointegration around implants in a T2DM animal model 20 . The injection of GLP-1RA could improve serum osteogenesis factors after dental implant surgery 21 . However, some researchers believe that the effect of GLP-1RA on bone is neutral 22 , which may be due to the different eligibility conditions of the study participants. Li 23 indicated that there was no difference in the effects of exenatide and insulin on bone turnover markers and bone mineral density, but the observation time was short. More studies are needed to clarify the specific effects of GLP-1RA on bone tissue. Metformin and insulin are both classic hypoglycemic medications and there are many studies about their positive influence on bone tissue. The results showed that the distal MBL in the metformin group was higher than that in the insulin group ( P < 0.05). The most previous comparison of the bone metabolism effect between these two drugs focused on the systematic body. Raj 24 pointed out that compared with metformin, insulin could significantly protect bone through osteocalcin and other pathways. However, some fracture risk studies presented different views. Losada 25 and Hidayat 26 determined that metformin could reduce the fracture risk and protect bone metabolism compared with the effects of insulin. The underlying mechanism of this contradiction is unclear. The explanation may be that diabetes is generally more severe in insulin users than oral medicine users. Patients using insulin could suffer more fall fractures caused by illness complications and hypoglycemic reactions, while metformin users had a lower incidence of fractures due to fewer complications 27 . Therefore, the fracture risk cannot accurately reflect the influence of drugs on bone metabolism. This study selected patients with good blood glucose control and no severe complications. The interference of different conditions was removed as far as possible to increase the reliability of the results. There are also many studies on the beneficial bone target mechanism of metformin and insulin. A large number of studies have proven the positive effect of insulin on bone tissue. Insulin has been shown to promote bone formation by upregulating the serum osteogenesis factor 28 . Some studies have shown that a local injection of insulin can promote early fracture healing in diabetic animals 29 . Moreover, local or systematic use of insulin could improve implant osseointegration 30 – 31 . Another study has shown that insulin could promote angiogenesis 32 , which is also a conducive factor to early osseointegration. Metformin is a first-line drug for the treatment of diabetes. Its positive mechanism on bone has been confirmed by a large number of preclinical studies. It is reported that metformin could promote osteogenesis and inhibit bone resorption 33 . However, metformin would reduce the level of bone turnover factors and hinder the bone remodeling 34 . This effect might compromise the self-repair of minor bone tissue damage. In this study, the MBL in the insulin group was smaller than that in the metformin group, which might be related to their effect on bone metabolism. At present, the major controversy about the bone target effect of some hypoglycemic drugs entails their indirect effect on bone by controlling blood glucose 35 . Firstly, it is noteworthy that all T2DM patients included in this study had good controlled blood glucose, with HbA1c less than 8%. And the results showed that MBL was different among groups, even though the patients in each group reported good controlled blood glucose. This meant that these drugs might have different influences on peri-implant bone. The process of bone remodeling around implants requires an environment conducive to bone formation. Therefore, T2DM patients undergoing implant surgery should choose hypoglycemic drugs more conductive to bone formation, such as insulin and GLP-1RA. However, this adjustment in the medication plan should not violate the clinical principle of diabetes treatment. Hence, the results of this study are more useful for patients who have flexibility regarding agent use. One limitation of this study is that blood glucose could not be monitored in real time. Therefore, further laboratory-based investigations should be executed to guarantee blood glucose control more strictly and eliminate bias in this type of research in the future. Another contribution of the present study is that it provides feedback on clinical systemic bone research. Previous research on the systematic bone target effect of hypoglycemic drugs focused more on the changes in fracture risk, bone mineral density and bone-related biochemical indexes 36 . However, these indexes could not accurately reflect the influence of drugs on bone. The bone mineral density in patients with T2DM might be higher than that in normal individuals, and the fracture risk in T2DM patients could be high 37 . The fracture risk reason might be related to damaged bone quality, higher incidence of falls and severe complications of diabetes. While the MBL around the implant is an important criterion for the efficacy of implant treatment and could be affected by bone metabolism 38 . Therefore, MBL could serve as an indicator of the bone target effect and could be used to supplement relevant research results about systematic bone. Considering the cost and radiation risk, conventional standard periapical radiography is still the most preferable clinical method to assess MBL around implants. This study focused on the MBL around implants with GBR in different hypoglycemic agent groups. However, it is beyond the scope of this study to examine the horizontal change of the alveolar ridge at the implant site as this study was based on two-dimensional images. Follow-up studies on the horizontal change in the ridge would be executed by cone beam computed tomography. Conclusion Though some studies have shown the different effects of medication on bone metabolism in T2DM patients, there is still a lack of clinical investigation for peri-implant parameters in T2DM patients with different hypoglycemic agents. This study could offer new reference regarding medication for T2DM patients undergoing implant surgery. The findings of this study suggest different MBL around implants in T2DM patients using different hypoglycemic agents. GLP-1RA seems be beneficial to bone tissue around the implants compared with insulin and metformin. However, the present study could not provide a high level of evidence for the influence of these drugs on bone condition around implants. Because the skeletal effects of hypoglycemic drugs are very complex, and much clinical evidence is still needed through future research. Abbreviations T2DM: type 2 diabetic mellitus GLP-1: glucagon-like peptide-1 MBL: marginal bone loss GBR: guided bone regeneration BOP: bleeding on probing PD: probing depth Declarations Acknowledgements: Firstly, the authors would like to take this opportunity to show sincere gratitude to Kejian Wu, who has provided so much useful advices on statistical process. Secondly, the authors thank the staff in the Department of Oral Implants, School of Stomatology, The Fourth Military Medical University for their help in this project. Funding: This work was supported by National Natural Science Foundation of China(grant number 81771107) Competing interests: The authors claim to have no financial interest, either directly or indirectly, in the products or information listed in the article. Authors’ contributions: Shaojie Shi and Yingliang Song conceived the ideas and conception; Feng Ding, Lei Wang and Xingxing Wang collected the data; Shaojie Shi and Feng Ding mearsured the data; Shaojie Shi, Xiangdong Liu and Sijia Zhang analyzed the data; and Shaojie Shi and Lei Wang led the writing. All authors read and approved the final manuscript Ethics approval and consent to participate: The retrospective cohort study was approved by the Ethics Committee of School of Stomatology, the Fourth Military Medical University (Ethics Approval Number: IRB-REV-2020045) and in compliance with the Helsinki Declaration. All patients were given complete information about the treatment and signed informed consent forms before surgery. Consent for publication: Not applicable. Availability of data and materials: The data generated and analyzed during this study are available from corresponding author on reasonable request. Author details: State key Laboratory of military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Shaanxi Xi’an, 710032, China References IDF Diabetes Atlas TEC, IDF DIABETES ATLAS Ninth edition 2019, 2019 Glurich I and Acharya A. Updates from the Evidence Base Examining Association between Periodontal Disease and Type 2 Diabetes Mellitus: Current Status and Clinical Relevance. Curr Diabetes Rep 2019; 19. Zhang S, Song S and Wang S, et al. Type 2 diabetes affects postextraction socket healing and influences first-stage implant surgery: A study based on clinical and animal evidence. Clin Implant Dent Relat Res 2019; 21: 436–445. Naenni N, Bienz SP and Muñoz F, et al. 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Res. 2013; 31: 783–791. Malekzadeh BÖ, Erlandsson MC and Tengvall P, et al. Effects of implant-delivered insulin on bone formation in osteoporotic rats. J. Biomed. Mater. Res. A 2018; 106: 2472–2480. Jia T, Wang Y and Zhang J, et al. Cinaciguat in combination with insulin induces a favorable effect on implant osseointegration in type 2 diabetic rats. Biomed. Pharmacother. 2019; 118: 109216. Wang D, Du S and Xu M, et al. Effects of insulin therapy on fracture healing and expression of VEGF in diabetic rats. J. Appl Biomed 2013; 11: 33–40. Serrão CR, Bastos MF and Cruz DF, et al. Role of Metformin in Reversing the Negative Impact of Hyperglycemia on Bone Healing Around Implants Inserted in Type 2 Diabetic Rats. The International journal of oral & maxillofacial implants 2017; 32: 547–554. Stage TB, Christensen MH and Jørgensen NR, et al. Effects of metformin, rosiglitazone and insulin on bone metabolism in patients with type 2 diabetes. Bone 2018; 112: 35–41. Mabilleau G, Pereira M and Chenu C. Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists. J. Endocrinol. 2018; 236: R29-R42. Miyake H, Kanazawa I and Sugimoto T. Association of Bone Mineral Density, Bone Turnover Markers, and Vertebral Fractures with All-Cause Mortality in Type 2 Diabetes Mellitus. Calcified Tissue Int. 2018; 102: 1–13. Wang H, Ba Y and Xing Q, et al. Diabetes mellitus and the risk of fractures at specific sites: a meta-analysis. Bmj Open 2019; 9: e24067. Kang M, Jung U and Cho K, et al. Retrospective radiographic observational study of 1692 Straumann tissue-level dental implants over 10 years. II. Marginal bone stability. Clin Implant Dent R. 2018; 20: 875–881. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 25 Jan, 2021 Reviews received at journal 04 Jan, 2021 Reviewers agreed at journal 30 Dec, 2020 Reviewers invited by journal 30 Dec, 2020 Editor assigned by journal 30 Dec, 2020 Editor invited by journal 24 Dec, 2020 Submission checks completed at journal 24 Dec, 2020 First submitted to journal 22 Dec, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-134530","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":7052362,"identity":"5e7070ee-2f15-463a-84e4-164bd146a3ea","order_by":0,"name":"Shaojie Shi","email":"","orcid":"","institution":"Air Force Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shaojie","middleName":"","lastName":"Shi","suffix":""},{"id":7052363,"identity":"13f1d5a1-daf9-4141-88fb-684c4f9635ef","order_by":1,"name":"Feng Ding","email":"","orcid":"","institution":"Air Force Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Feng","middleName":"","lastName":"Ding","suffix":""},{"id":7052364,"identity":"6b7d7bfc-8887-4205-a402-e168642111f0","order_by":2,"name":"Xiangdong Liu","email":"","orcid":"","institution":"Air Force Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiangdong","middleName":"","lastName":"Liu","suffix":""},{"id":7052365,"identity":"04b6f8dd-44eb-4f96-9f4a-303ad6157871","order_by":3,"name":"Lei Wang","email":"","orcid":"","institution":"Air Force Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Wang","suffix":""},{"id":7052366,"identity":"2319e299-80dd-40ac-916d-4f368724b994","order_by":4,"name":"Xingxing Wang","email":"","orcid":"","institution":"Air Force Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xingxing","middleName":"","lastName":"Wang","suffix":""},{"id":7052367,"identity":"2f68347d-d95a-4f19-9252-90acb35d2a01","order_by":5,"name":"Sijia Zhang","email":"","orcid":"","institution":"Air Force Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sijia","middleName":"","lastName":"Zhang","suffix":""},{"id":7052368,"identity":"e7443ea7-4e09-465d-aaec-80f455fcde1b","order_by":6,"name":"Guoqiang Zhao","email":"","orcid":"","institution":"Air Force Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Guoqiang","middleName":"","lastName":"Zhao","suffix":""},{"id":7052369,"identity":"330307db-c574-4dbb-93e6-ae5fba780c18","order_by":7,"name":"Yingliang Song","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYNACAwYGPmYQo0JCTp5oLWxgLWcsjA0biLWIDUQwtlUkMhwgoFK+vffwa56CO3Zt7MzPHn6dJ5HA2MD88NENfE46cy7NmsfgWXIbM5u5sew2iTx2BjZj4xx8WiRyzIx5DA4nA/1iJi25TaKYsYGHTRqfFvkZcC3s36Ql50gkNhwgoIXhRo7xY6AWOzZmHjPJjw1EaDE4c8aMcY7B4QSgljJphmMSxobNBPwi395j/OHNn8P2/PzHt0n+qKmTk2dvfvgYr8OAMSLFw8CQ2ABkMfOA+Mz4lYOVfPzBwGAPYjH+IKx6FIyCUTAKRiAAAGvEQ+C5SPNzAAAAAElFTkSuQmCC","orcid":"","institution":"Air Force Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yingliang","middleName":"","lastName":"Song","suffix":""}],"badges":[],"createdAt":"2020-12-23 03:14:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-134530/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-134530/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":4632186,"identity":"43d593e2-4970-412c-8072-4217c3e6c0b0","added_by":"auto","created_at":"2020-12-31 16:01:18","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46031,"visible":true,"origin":"","legend":"Periapical radiographs taken. A. Immediately after the first-stage surgery, B. Before the second-stage surgery, C. Immediately after prosthetic installation, D. The first year after functional loading","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-134530/v1/ceb5ec8db5c3bd246c84aac2.jpg"},{"id":4631944,"identity":"4b2fb9a5-a660-46c7-bce3-a6c4047f3120","added_by":"auto","created_at":"2020-12-31 15:58:17","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":54940,"visible":true,"origin":"","legend":"The method of measuring the crestal bone levels.","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-134530/v1/d09d0277519bd21048a883ae.jpg"},{"id":13642565,"identity":"219b402e-4197-48fb-a56b-9a6168283af2","added_by":"auto","created_at":"2021-09-17 09:07:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":509212,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-134530/v1/81e14891-d722-48c2-b338-b6ecb60dea81.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eClinical and Radiographic Variables Around Implant With Simultaneous Graft Among Type 2 Diabetic Patients Treated With Different Hypoglycemic Medications: A Retrospective Study.\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eThe number of individuals with type 2 diabetes mellitus (T2DM) constitutes a large population, and a recent report in 2019 showed that, the prevalence of T2DM worldwide had reached 8% in 2018\u003csup\u003e1\u003c/sup\u003e. Due to the relationship between T2DM and periodontitis\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, there is a large proportion of patients with missing teeth in the T2DM population. Implant-supported denture restoration has been an excellent treatment for the loss of teeth and T2DM individuals have a large requirement for dental implant treatment. However, T2DM patients often face the challenge of atrophic alveolar bone width at implant sites\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. The minor and moderate atrophic ridge often need horizontal bone augmentation by guided bone regeneration (GBR)with the combination of bone graft materials and barrier membranes\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The uncontrolled hyperglycemia would impact the therapeutic effect of dental implants in T2DM\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. And some studies have shown that early osseointegration around implants is compromised by T2DM even if glucose is strictly controlled\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. It is crucial for clinicians to promote the efficacy of implant treatment in T2DM patients.\u003c/p\u003e \u003cp\u003eDental implant treatment success is related to the osseointegration and peri-implant bone around implants\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Previous research has shown that diabetes impacts bone remodeling around implants, especially at the early stage of osseointegration\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The changes of bone levels around implants is a biomechanical process that could be influenced by several factors in patients and implants\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The marginal bone loss (MBL) in diabetes patients is higher than that in nondiabetic individuals, despite being glycemic controlled\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. The higher MBL in T2DM patients could reflect the impaired bone condition around implants. Therefore, MBL was considered an important radiographic parameter for bone tissue around implants in the present study.\u003c/p\u003e \u003cp\u003eRecently, abundant evidence has revealed the role of hypoglycemic agents in bone metabolism\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. There is growing concern about their direct bone target effect. For example, insulin and metformin could be beneficial to bone tissue\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. This beneficial effect might improve the outcome of dental implants. It was reported that local application of insulin could promote osseointegration in T2DM rats\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Glucagon-like peptide-1 (GLP-1) drugs also have the potential to promote osseointegration around implants\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Currently, there is no clinical evidence of hypoglycemic drugs interfering with bone tissue around implants. Therefore, the present study aimed to obtain more detailed information about the clinical and radiographic variables around implants in T2DM patients using different hypoglycemic agents.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eEthical protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe retrospective cohort study was approved by the Ethics Committee of School of Stomatology, the Fourth Military Medical University (Ethics Approval Number: IRB-REV-2020045) and in compliance with the Helsinki Declaration. All patients were given complete information about the treatment and signed informed consent forms before surgery. The implant treatment was performed by the same doctor and the trauma was minimized. This study is reported in agreement with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003cstrong\u003eand setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective cohort study was designed to compare the clinical and radiographic variables around implants with simultaneous GBR in T2DM patients using different hypoglycemic agents. The examiners collected dental records of T2DM patients who received implant surgery from January 2015 to November 2019. After information collection, one examiner divided them into three groups based on their major hypoglycemic agent species: insulin (group 1), metformin (group 2), and GLP-1 (group 3). The state immediately after surgery was recorded as baseline. The MBL from immediately after implant placement to before prosthetic installation and to the first-year follow-up after functional loading were measured to suggest the change of bone tissue around implants. The clinical inflammatory parameters at the first-year follow-up after functional loading, including bleeding on probing (BOP) and probing depth (PD), were collected. To ensure the principle of blinding, the groups were sealed and another independent examiner assessed the data among groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria were as follows: (a) medically diagnosed T2DM; (b) good blood glucose control before surgery (HbA1c%\u0026le;8%\u003csup\u003e16\u003c/sup\u003e ); (c) treatment with one of the hypoglycemic agents: metformin, insulin or GLP-1; (d) implant site with Seibert class I ridge deficiencies resulting in the implant thread exposure which treated only with GBR (graft mass\u0026le;0.25g); (e)good oral hygiene care with regular semidiurnal brushing and semiannual professional cleaning.\u003c/p\u003e\n\u003cp\u003eThe exclusion criteria were as follows: (a) poor glycemic control (HbA1c%\u0026gt;8%) or severe diabetic complications; (b) osteoporosis; (c) long-term use of bisphosphonates or steroids; (d) irregular use of hypoglycemic drugs; (e) excessive tobacco use and alcohol consumption; (f) progressive periodontitis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformation collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dental records of participants were reviewed by examiners and the baseline information about patients and implants were obtained. Patient information included age, sex, HbA1c, medication, bone augmentation and oral hygiene care. The implant information included the size, location, arch, position of fixture and major surface treatment of implants. The surgical complications after implant placement were recorded, including wound bleeding, swelling and membrane exposure. And the infection around implant was obtained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRadiographic analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA standardized digital dental periapical radiographic evaluation performed immediately after implant placement was recorded as the baseline. The radiographic evaluation was carried out before prosthetic installation and at 1-year follow-up after function loading (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll radiographs were viewed on a computer screen using Digimizer v5.4.5 (MedCalc Inc., Mariakerke, Belgium) software. The examiner measured the crestal bone levels as the vertical distance from the tip of the implant body to the coronal edge of the first bone-to-implant contact (Figure 2). The image error of magnification was calibrated by the reference value of the actual implant length.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical parameters at the first year after functional loading\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe clinical parameters recordings at the first year after functional loading were collected and analyzed, including BOP and PD. These clinical parameters were measured at six sites around implants and reported as the mean value.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis was performed using specialized software (SPSS v25.0, IBM, Chicago, Illinois). The baseline information was analyzed by the chi-square test and analysis of variance. Dependent variables were evaluated for a normal distribution by the Shapiro-Wilk test. The data are expressed as the means and SDs. Peri-implant MBL and clinical parameters was compared using the Kruskal-Wallis test. The Bonferroni post hoc test was applied for multiple comparisons. Multiple regression analysis was performed to control the baseline variables as covariates. The direction and strength of association between outcome variable and covariates were assessed by regression coefficients, and the precision of which was measured by 95% confidence intervals. Statistical significance threshold was set at \u003cem\u003eP\u003c/em\u003e\u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":" \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eThe general condition of population\u003c/h2\u003e \u003cp\u003eA total of 150 patients with 308 implants with GBR were eligible for this study. The system of implant included Straumann, Basel, Switzerland and Nobel Biocare, Gothenburg, Sweden. The condition of implant was analyzed by position of fixture and the major surface treatment to avoid the conflicts of interest. Sixty-one implants in groups with GBR experiences surgical complication and no implant suffered infection. And 54 patients with 101 implants were followed up for a year after the prosthesis installation, and other patients lost to follow-up. No further complications were reported during the follow-up period.\u003c/p\u003e \u003c/div\u003e \n\u003ch2\u003eThe Information Analysis Of Patients And Implants With Gbr\u003c/h2\u003e\n \u003cp\u003eThe basic information about patients and implants with GBR is shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. There were 54 patients and 101 implants in insulin group, 54 patients and 121 implants in metformin group, 42 patients and 86 implants in GLP-1 group. These groups were comparable with respect to age, HbA1c, sex, implant location and the major surface treatment of implants (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, the position of fixture was significantly different among the groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). A total of 71 patients with 129 implants completed one-year follow-up after functional loading (30 patients and 53 implants in insulin group, 24 patients and 44 implants in metformin group, 17 patients and 32 implants in GLP-1 group). The basic confounding factors of patients and implants among groups were comparable (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eInformation on patients and implants with GBR\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003evariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup 3\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal patients (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56.50\u0026thinsp;\u0026plusmn;\u0026thinsp;9.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55.46\u0026thinsp;\u0026plusmn;\u0026thinsp;8.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56.81\u0026thinsp;\u0026plusmn;\u0026thinsp;8.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHbA1c (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.93\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003cp\u003eMale/Female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40/14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46/8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33/9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal implants (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.54\u0026thinsp;\u0026plusmn;\u0026thinsp;1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.84\u0026thinsp;\u0026plusmn;\u0026thinsp;1.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.79\u0026thinsp;\u0026plusmn;\u0026thinsp;1.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArch\u003c/p\u003e \u003cp\u003eMaxillary/mandibular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61/40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72/49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44/42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation\u003c/p\u003e \u003cp\u003eAnterior/Posterior\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22/79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34/87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25/61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePosition of fixture\u003c/p\u003e \u003cp\u003eSubmerged /Non-submerged\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54/47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55/66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61/25 \u003csup\u003e\u003cb\u003ea**\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMajor surface treatment\u003c/p\u003e \u003cp\u003eSLA/Anodic oxidation\u003c/p\u003e \u003cp\u003eRestoration\u003c/p\u003e \u003cp\u003eSingle/Multiple ceramic restoration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54/47\u003c/p\u003e \u003cp\u003e39/62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73/48\u003c/p\u003e \u003cp\u003e38/83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39/47\u003c/p\u003e \u003cp\u003e35/51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eNotes; Group 1: insulin. Group 2: metformin. Group 3: GLP \u0026minus;\u0026thinsp;1. GBR, guided bone regeneration. a: the position of fixture among groups is significantly different (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). **\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eThe comparison of radiographic and clinical parameters of implants with GBR\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAt 12 months of follow-up, the mean MBL around implants with GBR is shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The MBL was not the same among these medication groups. The mesial and distal MBL parameters in group 1 (mesial: 0.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u0026nbsp;mm, distal: 0.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u0026nbsp;mm) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and group 2 (mesial: 0.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u0026nbsp;mm, distal: 0.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u0026nbsp;mm) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) were higher than those in group 3 (mesial: 0.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u0026nbsp;mm, distal: 0.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u0026nbsp;mm). The distal MBL was significantly higher in group 2 (0.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u0026nbsp;mm) than in group 1 (0.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u0026nbsp;mm) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Similarly, the distal MBL in the percentage of implant length was significantly higher in group 1 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and group 2 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) than in group 3. While at 24 months of follow-up, the mesial and distal MBL parameters in group 1 (mesial: 0.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u0026nbsp;mm, distal: 0.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17\u0026nbsp;mm) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and group 3 (mesial: 0.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u0026nbsp;mm, distal: 0.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u0026nbsp;mm) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) were smaller than those in group 2 (mesial: 0.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u0026nbsp;mm, distal: 0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u0026nbsp;mm).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe comparison of MBL among groups with GBR\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMBL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGroup 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eGroup 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eGroup 3\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMesial MBL in millimeters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14 \u003csup\u003ea*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15 \u003csup\u003ec*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14 \u003csup\u003eb**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003csup\u003ed**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistal MBL in millimeters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13 \u003csup\u003ea**c*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17\u003csup\u003ec*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13 \u003csup\u003eb**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003csup\u003ec*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMesial MBL in percentage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.08\u0026thinsp;\u0026plusmn;\u0026thinsp;1.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.05\u0026thinsp;\u0026plusmn;\u0026thinsp;1.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.30\u0026thinsp;\u0026plusmn;\u0026thinsp;1.58 \u003csup\u003eb**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.83\u0026thinsp;\u0026plusmn;\u0026thinsp;1.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.67\u0026thinsp;\u0026plusmn;\u0026thinsp;1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.48\u0026thinsp;\u0026plusmn;\u0026thinsp;1.48\u003csup\u003ed**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistal MBL in percentage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.04\u0026thinsp;\u0026plusmn;\u0026thinsp;1.25 \u003csup\u003eb**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.87\u0026thinsp;\u0026plusmn;\u0026thinsp;1.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.45\u0026thinsp;\u0026plusmn;\u0026thinsp;1.56 \u003csup\u003eb**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.48\u0026thinsp;\u0026plusmn;\u0026thinsp;1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.42\u0026thinsp;\u0026plusmn;\u0026thinsp;1.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.69\u0026thinsp;\u0026plusmn;\u0026thinsp;1.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eNotes; Group 1: insulin. Group 2: metformin. Group 3: GLP \u0026minus;\u0026thinsp;1. MBL: marginal bone loss. GBR, guided bone regeneration. a: compared with group 3 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), b: compared with group 3 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01); c: compared with group 2 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05); d: compared with group 2 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). *\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAfter the first year after functional loading, there was no statistical difference in the BOP (+) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05) and the PD in group 1 (1.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17\u0026nbsp;mm) was comparable with group 2 (1.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u0026nbsp;mm) and group 3 (1.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26\u0026nbsp;mm) at 24\u0026nbsp;months of follow-up (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe comparison of clinical parameters among groups with GBR\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003evariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBOP(+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44(83.02%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36(81.82%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27(84.38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.958\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD(mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.071\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eNotes: Group 1: insulin. Group 2: metformin. Group 3: GLP \u0026minus;\u0026thinsp;1. BOP: bleeding on probing. PD: probing depth.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eRegression analysis to control the position of fixture at the 12months of follow-up\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe position of fixture among groups should be controlled as confounders by multiple regression analysis (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The mesial and distal MBL at 12 months of follow-up still showed statistically significant differences among the groups even after controlling for the position of fixture (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The table IV showed that the mesial MBL at 12 months of follow-up in group 1 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and group 2 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) were higher than group 3 and the distal MBL in group 1 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and group 3 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) were smaller than group 2 after controlling the position of fixture consistent among groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMBL in patients with GBR at 12 months of follow-up after controlling the position of fixture\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMesial MBL in millimeters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup 1(compared with group 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.003,0.080)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.034\u003c/b\u003e\u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup 2(compared with group 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.028,0.104)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003csup\u003e\u003cb\u003e**\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistal MBL in millimeters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup 1(compared with group 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.060\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.023,0.097)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003csup\u003e\u003cb\u003e**\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup 2(compared with group 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.067,0.139)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003csup\u003e\u003cb\u003e***\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistal MBL in millimeters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup 1(compared with group 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.043\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(-0.077, -0.010)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.011\u003c/b\u003e\u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup 3(compared with group 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(-0.139, -0.067)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003csup\u003e\u003cb\u003e***\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMesial MBL in percentage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup 1(compared with group 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.274\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(-0.147,0.695)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.201\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup 2(compared with group 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.436\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.027,0.846)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.037\u003c/b\u003e\u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistal MBL in percentage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup 1(compared with group 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.485\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.087,0.883)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.017\u003c/b\u003e\u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup 2(compared with group 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.841\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.454,1.229)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003csup\u003e\u003cb\u003e***\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eNotes: Group 1: insulin. Group 2: metformin. Group 3: GLP \u0026minus;\u0026thinsp;1. MBL, marginal bone loss. GBR, guided bone regeneration. (95% CI): 95% confidence interval. P value in bold indicates that the statistical results are consistent with the results of the Kruskal-Wallis test after accounting for the influence of covariates on the outcome variable, and the difference among groups is statistically significant. *\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01, ***\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eThe influence of diabetes on the properties of a patient\u0026rsquo;s bone would impact the outcomes of dental implants. In cases where diabetes cannot be completely cured, clinicians generally use hypoglycemic drugs to reduce the adverse effects of diabetes. Numerous studies have reported the direct effect of hypoglycemic drugs on systemic bone metabolism. However, little attention has been paid to the effect of hypoglycemic drugs on peri-implant bone. In the present study, the peri-implant radiographic parameters showed different characteristics among patients using different hypoglycemic agents. The results could serve as a reference for the direct effect of drugs on systemic bone.\u003c/p\u003e \u003cp\u003eThis study showed that MBL among groups was not exactly the same. The MBL parameters in insulin group and metformin group were higher than those in GLP-1 group at 12 months of follow-up. The MBL in metformin group was higher than insulin group and GLP-1 drugs group at 24 months of follow-up. Similarly, the MBL in the percentage of original implant length in insulin group and metformin group was higher than that in GLP-1 drugs group. During these periods, the bone and bone substitution material had experienced the bone healing and remodeling process and this process could be influenced by the bone condition around implants. The difference of MBL among groups showed the possibility of these drugs interfering with bone tissue around the implant in T2DM patients. After controlling for the baseline information variable, the difference in MBL among groups still existed. This means that these confounding variables, including position of fixture and major surface treatment, did not influence the comparative results of MBL among groups. The change of bone levels around implants could show the bone healing and remodeling process and the higher MBL might suffer higher risk of failure. From these results, the medication type might be related to the bone healing and remodeling around implant at the early stage and the potential among medication might be different. However, the present result showed there was no statistically significant difference in clinical parameters, including BOP (+) and PD, among groups. Although the diabetes could be related to the periodontal inflammation, the peri-implant inflammation parameters seem to have nothing to do with the medication type of the T2DM patient.\u003c/p\u003e \u003cp\u003eThe results showed that GLP-1 drugs might have a more positive effect on the peri-implant bone than other agents. This is consistent with previous studies. Liang\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e indicated that compared with other hypoglycemic drugs, GLP-1 drugs could significantly reduce the risk of fracture. A meta-analysis also supports that exenatide, a GLP-1 receptor agonist (RA), might have advantages in preventing fracture risk over other hypoglycemic drugs\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Preclinical studies have reported the superior osteogenic properties of GLP-1 drugs. GLP-1 receptors are widely distributed, and knockout of the GLP-1 receptor gene leads to severe bone changes related to the abnormality of osteoclasts\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, which supports the direct effect of GLP-1 on bone. GLP-1RA might also enhance early osseointegration. GLP-1RA improved factors beneficial to osseointegration around implants in a T2DM animal model\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. The injection of GLP-1RA could improve serum osteogenesis factors after dental implant surgery\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. However, some researchers believe that the effect of GLP-1RA on bone is neutral\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, which may be due to the different eligibility conditions of the study participants. Li\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e indicated that there was no difference in the effects of exenatide and insulin on bone turnover markers and bone mineral density, but the observation time was short. More studies are needed to clarify the specific effects of GLP-1RA on bone tissue.\u003c/p\u003e \u003cp\u003eMetformin and insulin are both classic hypoglycemic medications and there are many studies about their positive influence on bone tissue. The results showed that the distal MBL in the metformin group was higher than that in the insulin group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The most previous comparison of the bone metabolism effect between these two drugs focused on the systematic body. Raj\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e pointed out that compared with metformin, insulin could significantly protect bone through osteocalcin and other pathways. However, some fracture risk studies presented different views. Losada\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e and Hidayat\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e determined that metformin could reduce the fracture risk and protect bone metabolism compared with the effects of insulin. The underlying mechanism of this contradiction is unclear. The explanation may be that diabetes is generally more severe in insulin users than oral medicine users. Patients using insulin could suffer more fall fractures caused by illness complications and hypoglycemic reactions, while metformin users had a lower incidence of fractures due to fewer complications\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Therefore, the fracture risk cannot accurately reflect the influence of drugs on bone metabolism. This study selected patients with good blood glucose control and no severe complications. The interference of different conditions was removed as far as possible to increase the reliability of the results.\u003c/p\u003e \u003cp\u003eThere are also many studies on the beneficial bone target mechanism of metformin and insulin. A large number of studies have proven the positive effect of insulin on bone tissue. Insulin has been shown to promote bone formation by upregulating the serum osteogenesis factor\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Some studies have shown that a local injection of insulin can promote early fracture healing in diabetic animals\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Moreover, local or systematic use of insulin could improve implant osseointegration\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Another study has shown that insulin could promote angiogenesis\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e, which is also a conducive factor to early osseointegration. Metformin is a first-line drug for the treatment of diabetes. Its positive mechanism on bone has been confirmed by a large number of preclinical studies. It is reported that metformin could promote osteogenesis and inhibit bone resorption\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. However, metformin would reduce the level of bone turnover factors and hinder the bone remodeling\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. This effect might compromise the self-repair of minor bone tissue damage. In this study, the MBL in the insulin group was smaller than that in the metformin group, which might be related to their effect on bone metabolism.\u003c/p\u003e \u003cp\u003eAt present, the major controversy about the bone target effect of some hypoglycemic drugs entails their indirect effect on bone by controlling blood glucose\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Firstly, it is noteworthy that all T2DM patients included in this study had good controlled blood glucose, with HbA1c less than 8%. And the results showed that MBL was different among groups, even though the patients in each group reported good controlled blood glucose. This meant that these drugs might have different influences on peri-implant bone. The process of bone remodeling around implants requires an environment conducive to bone formation. Therefore, T2DM patients undergoing implant surgery should choose hypoglycemic drugs more conductive to bone formation, such as insulin and GLP-1RA. However, this adjustment in the medication plan should not violate the clinical principle of diabetes treatment. Hence, the results of this study are more useful for patients who have flexibility regarding agent use. One limitation of this study is that blood glucose could not be monitored in real time. Therefore, further laboratory-based investigations should be executed to guarantee blood glucose control more strictly and eliminate bias in this type of research in the future.\u003c/p\u003e \u003cp\u003eAnother contribution of the present study is that it provides feedback on clinical systemic bone research. Previous research on the systematic bone target effect of hypoglycemic drugs focused more on the changes in fracture risk, bone mineral density and bone-related biochemical indexes\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. However, these indexes could not accurately reflect the influence of drugs on bone. The bone mineral density in patients with T2DM might be higher than that in normal individuals, and the fracture risk in T2DM patients could be high\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. The fracture risk reason might be related to damaged bone quality, higher incidence of falls and severe complications of diabetes. While the MBL around the implant is an important criterion for the efficacy of implant treatment and could be affected by bone metabolism\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Therefore, MBL could serve as an indicator of the bone target effect and could be used to supplement relevant research results about systematic bone.\u003c/p\u003e \u003cp\u003eConsidering the cost and radiation risk, conventional standard periapical radiography is still the most preferable clinical method to assess MBL around implants. This study focused on the MBL around implants with GBR in different hypoglycemic agent groups. However, it is beyond the scope of this study to examine the horizontal change of the alveolar ridge at the implant site as this study was based on two-dimensional images. Follow-up studies on the horizontal change in the ridge would be executed by cone beam computed tomography.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eThough some studies have shown the different effects of medication on bone metabolism in T2DM patients, there is still a lack of clinical investigation for peri-implant parameters in T2DM patients with different hypoglycemic agents. This study could offer new reference regarding medication for T2DM patients undergoing implant surgery. The findings of this study suggest different MBL around implants in T2DM patients using different hypoglycemic agents. GLP-1RA seems be beneficial to bone tissue around the implants compared with insulin and metformin. However, the present study could not provide a high level of evidence for the influence of these drugs on bone condition around implants. Because the skeletal effects of hypoglycemic drugs are very complex, and much clinical evidence is still needed through future research.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eT2DM:\u003c/strong\u003e type 2 diabetic mellitus\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGLP-1:\u003c/strong\u003e glucagon-like peptide-1\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMBL:\u003c/strong\u003e marginal bone loss\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGBR:\u003c/strong\u003e guided bone regeneration\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBOP: \u003c/strong\u003ebleeding on probing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD:\u003c/strong\u003e probing depth\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements: \u003c/strong\u003eFirstly, the authors would like to take this opportunity to show sincere gratitude to Kejian Wu, who has provided so much useful advices on statistical process. Secondly, the authors thank the staff in the Department of Oral Implants, School of Stomatology, The Fourth Military Medical University for their help in this project.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This work was supported by National Natural Science Foundation of China(grant number 81771107)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests: \u003c/strong\u003eThe authors claim to have no financial interest, either directly or indirectly, in the products or information listed in the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions: \u003c/strong\u003eShaojie Shi and Yingliang Song conceived the ideas and conception; Feng Ding, Lei Wang and Xingxing Wang collected the data; Shaojie Shi and Feng Ding mearsured the data; Shaojie Shi, Xiangdong Liu and Sijia Zhang analyzed the data; and Shaojie Shi and Lei Wang led the writing. All authors read and approved the final manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate: \u003c/strong\u003eThe retrospective cohort study was approved by the Ethics Committee of School of Stomatology, the Fourth Military Medical University (Ethics Approval Number: IRB-REV-2020045) and in compliance with the Helsinki Declaration. All patients were given complete information about the treatment and signed informed consent forms before surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication: \u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e The data generated and analyzed during this study are available from corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details: \u003c/strong\u003eState key Laboratory of military Stomatology \u0026amp; National Clinical Research Center for Oral Diseases \u0026amp; Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Shaanxi Xi\u0026rsquo;an, 710032, China\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eIDF Diabetes Atlas TEC, IDF DIABETES ATLAS Ninth edition 2019, 2019\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlurich I and Acharya A. 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Role of Metformin in Reversing the Negative Impact of Hyperglycemia on Bone Healing Around Implants Inserted in Type 2 Diabetic Rats. \u003cem\u003eThe International journal of oral \u0026amp; maxillofacial implants\u003c/em\u003e 2017; 32: 547\u0026ndash;554.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStage TB, Christensen MH and J\u0026oslash;rgensen NR, et al. Effects of metformin, rosiglitazone and insulin on bone metabolism in patients with type 2 diabetes. \u003cem\u003eBone\u003c/em\u003e 2018; 112: 35\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMabilleau G, Pereira M and Chenu C. Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists. \u003cem\u003eJ. Endocrinol.\u003c/em\u003e 2018; 236: R29-R42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiyake H, Kanazawa I and Sugimoto T. Association of Bone Mineral Density, Bone Turnover Markers, and Vertebral Fractures with All-Cause Mortality in Type 2 Diabetes Mellitus. \u003cem\u003eCalcified Tissue Int.\u003c/em\u003e 2018; 102: 1\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang H, Ba Y and Xing Q, et al. Diabetes mellitus and the risk of fractures at specific sites: a meta-analysis. \u003cem\u003eBmj Open\u003c/em\u003e 2019; 9: e24067.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKang M, Jung U and Cho K, et al. Retrospective radiographic observational study of 1692 Straumann tissue-level dental implants over 10 years. II. Marginal bone stability. \u003cem\u003eClin Implant Dent R.\u003c/em\u003e 2018; 20: 875\u0026ndash;881.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"type 2 diabetic mellitus, dental implant, marginal bone loss, hypoglycemic agents, guided bone regeneration","lastPublishedDoi":"10.21203/rs.3.rs-134530/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-134530/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThe clinical and radiographic variables around dental implants in type 2 diabetes mellitus patients with different hypoglycemic agents still remained unclear.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This retrospective cohort study collected the dental records and digital periapical radiographs of type 2 diabetes mellitus patients and implants. These patients were grouped according to their medication: insulin, metformin, and glucagon-like peptide-1 drugs. The radiographic marginal bone loss around implants and clinical parameters, including peri-implant bleeding on probing and probing depth, were compared among groups using the Kruskal-Wallis test.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A total of 150 patients with 308 implants (101 in insulin group, 121 in metformin group and 86 in glucagon-like peptide-1 drugs group) were assessed. The peri-implants marginal bone loss in insulin group (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05) and metformin group (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.01) were significantly higher than glucagon-like peptide-1 drug group. The radiographic bone loss in metformin was higher than insulin group (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). While there was no statistical difference of clinical peri-implant parameters among groups(\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e The radiographic variables were not exactly the same among type 2 diabetes mellitus patients with different hypoglycemic agents. glucagon-like peptide-1 drugs might be more beneficial to bone tissue around implants. More studies are needed to verify the direct effect of these drugs on peri-implant bone.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eClinical trial registration number: \u003c/strong\u003eChiCTR2000034211 (retrospectively registered)\u003c/p\u003e","manuscriptTitle":"Clinical and Radiographic Variables Around Implant With Simultaneous Graft Among Type 2 Diabetic Patients Treated With Different Hypoglycemic Medications: A Retrospective Study.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-12-31 15:58:16","doi":"10.21203/rs.3.rs-134530/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-01-25T14:13:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-01-04T18:35:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"f6068bce-f6c1-4f3d-bfba-87d3e923c302","date":"2020-12-30T15:55:47+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-12-30T15:09:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-12-30T15:08:20+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-12-24T07:45:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-12-24T07:35:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Oral Health","date":"2020-12-23T03:13:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"46c8be9e-50c4-46c9-a92b-4f0a4133bc8a","owner":[],"postedDate":"December 31st, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":1680653,"name":"Dentistry"},{"id":1680654,"name":"Head \u0026 Neck Surgery"}],"tags":[],"updatedAt":"2021-04-16T05:44:05+00:00","versionOfRecord":[],"versionCreatedAt":"2020-12-31 15:58:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-134530","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-134530","identity":"rs-134530","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}