Introduction & Objective: In the SURPASS-6 trial, tirzepatide (TZP) added to basal insulin glargine U100 significantly improved HbA1c and body weight in participants with inadequately controlled type 2 diabetes (T2D). Overall, basal insulin dose decreased over time, and up to 19% of TZP-treated participants discontinued basal insulin by Week 52. We aimed to identify clinical parameters associated with insulin regression (use <10 IU/day) at Week 52.​ Methods: Analyses included participants receiving TZP at Week 52 (≥75% adherence) without rescue medication. The outcome was basal insulin discontinuation or <10 IU/day use at Week 52 (“insulin regressor group”) or ≥10 IU/day use at Week 52 (“insulin non-regressor group”). Association between the outcome and baseline variables was assessed by univariate logistic regression. Variables with p<0.2 entered stepwise multivariate logistic regression. Results: A total of 145 and 496 participants were included in the insulin regressor and insulin non-regressor groups, respectively. Overall, 34.2%, 33.9%, and 32.0% of participants were on TZP 5 mg, 10 mg, and 15 mg, respectively. At baseline, mean age was 58.2 years; 59.3% were female; median insulin daily use was 46 IU; and mean fasting serum glucose (FSG) was 158 mg/dL. In the multivariate analysis, baseline factors associated with insulin regression were (odds ratio [OR] [95% CI]): TZP 10 mg vs. 5 mg: 1.84 (1.08-3.13), p=0.024; TZP 15 mg vs. 5 mg: 3.78 (2.25-6.35) p<0.001; female vs. male: 1.74 (1.14-2.67), p=0.011; daily insulin dose (by 1 SD decrease: 1.76 [1.36-2.27], p<0.001); and FSG (by 1 SD decrease: 1.38 [1.08-1.75], p=0.01). Some of the baseline factors not associated with insulin discontinuation or reduction were duration of diabetes, HbA1c, triglycerides, and eGFR. Conclusion: Several clinical factors were associated with basal insulin regression in SURPASS-6, including higher randomized TZP dose, lower insulin daily dose, and lower FSG at baseline. Disclosure C.H. Wysham: Research Support; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Novo Nordisk. Consultant; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Advisory Panel; Abbott. Research Support; Bayer Inc. Advisory Panel; Biomea Fusion, Inc. Research Support; Corcept Therapeutics, AbbVie Inc. J. Rosenstock: Research Support; Biomea Fusion, Inc. Other Relationship; Lilly Diabetes. Research Support; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Corcept Therapeutics. Other Relationship; Novo Nordisk. Research Support; Pfizer Inc. Other Relationship; Sanofi, Boehringer-Ingelheim. Research Support; Shionogi & Co., Ltd. Other Relationship; Structure Therapeutics, Inc. Advisory Panel; Terns Pharmaceuticals, Zealand Pharma A/S. Other Relationship; Applied Therapeutics, Hanmi Pharm. Co., Ltd., Oramed Pharmaceuticals. Advisory Panel; Scholar Rock. S. Tofe: None. V. Thieu: Employee; Eli Lilly and Company. J.I. Kiljanski: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. H. Wang: None. H. Patel: None.

Introduction & Objective: In the SURPASS-6 trial, addition of tirzepatide (TZP) to basal insulin glargine U100 in participants with inadequately controlled long-standing type 2 diabetes (T2D), substantially improved HbA1c and body weight. We evaluated degrees of insulin dose reductions and the efficacy and safety of TZP based on residual insulin use at Week 52. Methods: “Insulin regressor” was defined as basal insulin discontinuation or <10 IU/day, and “insulin non-regressor” as ≥10 IU/day, at 52 weeks. Included only participants receiving TZP at Week 52 (≥75% compliance) without rescue medication. Efficacy analyses used a mixed model for repeated measures. Results: Overall, 145 and 496 TZP-treated participants were included in the insulin regressor vs. insulin non-regressor groups, respectively. At baseline, mean age was 58.4 vs. 58.2 years, and median basal insulin dose was 40.0 vs. 48.0 IU/day. From baseline to Week 52 in the insulin regressor and insulin non-regressor groups, respectively, mean HbA1c of 8.5% and 8.9% was reduced to 5.9% and 6.7%, while weight was substantially reduced by 16 kg and 8 kg. Clinically significant hypoglycemia was also less frequent in the insulin regressor group (Table). Conclusion: In basal insulin-treated T2D, participants who regressed on insulin use also achieved near-normoglycemia and substantial weight loss. Disclosure J. Rosenstock: Research Support; Biomea Fusion, Inc. Other Relationship; Lilly Diabetes. Research Support; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Corcept Therapeutics. Other Relationship; Novo Nordisk. Research Support; Pfizer Inc. Other Relationship; Sanofi, Boehringer-Ingelheim. Research Support; Shionogi & Co., Ltd. Other Relationship; Structure Therapeutics, Inc. Advisory Panel; Terns Pharmaceuticals, Zealand Pharma A/S. Other Relationship; Applied Therapeutics, Hanmi Pharm. Co., Ltd., Oramed Pharmaceuticals. Advisory Panel; Scholar Rock. S. Tofe: None. C.H. Wysham: Research Support; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Novo Nordisk. Consultant; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Advisory Panel; Abbott. Research Support; Bayer Inc. Advisory Panel; Biomea Fusion, Inc. Research Support; Corcept Therapeutics, AbbVie Inc. V. Thieu: Employee; Eli Lilly and Company. J.I. Kiljanski: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. H. Wang: None. H. Patel: None.

Tirzepatide (TZP), a once-weekly GIP/GLP-1 receptor agonist, achieved significantly greater HbA1c and body weight (BW) reductions with all doses (5, 10, 15 mg) vs placebo (SURPASS-1 [S-1]) and semaglutide (SEMA) 1 mg (SURPASS-2 [S-2]) in randomized Phase 3 trials in people with type 2 diabetes controlled by diet and exercise (S-1) or metformin (S-2). Exploratory post hoc analyses examined changes from baseline in HbA1c and BW in these studies at 40 weeks across HOMA2-B (C-peptide) and HOMA2-IR (insulin) quartiles (Q) from low (lower beta-cell function/insulin resistance) (Q1) to high (Q4) as assessed by mixed model repeated measures (MMRM). HbA1c reductions were greater with all TZP doses than placebo or SEMA within each HOMA2-B and HOMA2-IR baseline Q. HbA1c reductions were largest in people within HOMA-2B Q1, yet similar across all HOMA2-IR Qs (Fig). BW reductions were greater across Qs with all TZP doses (ranging from 6%-14%) than placebo (up to 2%) or SEMA (up to 7%). TZP was more efficacious than placebo or SEMA in reducing HbA1c and BW across a spectrum of pancreatic beta-cell function, notably achieving greater glycemic improvement in people with markers of diminished pancreatic beta cell function at baseline. Disclosure J.M.Maldonado: Employee; Eli Lilly and Company. C.De block: Advisory Panel; Abbott Diagnostics, Indigo Diabetes, Insulet Corporation, Eli Lilly and Company, Novo Nordisk, Research Support; Boehringer-Ingelheim, AstraZeneca, Indigo Diabetes, Eli Lilly and Company, Speaker's Bureau; Novo Nordisk. J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. K.Brown: Employee; Eli Lilly and Company. H.Wang: None. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

Abstract Tirzepatide, a dual GIP/GLP-1 receptor agonist, demonstrated clinically meaningful reductions in HbA1c and body weight that were significantly greater compared with semaglutide in patients with type 2 diabetes on background metformin. In a pre-specified subgroup analysis, we evaluated the efficacy and safety of tirzepatide in the Hispanic or Latino population of SURPASS-2. In this open-label, 40-week, Phase 3 study (N=1878; mean baseline HbA1c 8.28%; BMI 34.2 kg/m2; Hispanic or Latino ethnicity 70%) participants were randomized 1: 1: 1: 1 to tirzepatide (5, 10, 15 mg; doses were double-blinded) or semaglutide (1 mg). Efficacy analyses included all randomised patients who received ≥1 treatment dose (modified intention-to-treat [mITT] population) while patients were on treatment without rescue therapy and excluding patients who discontinued study drug due to inadvertent enrollment (efficacy estimand). Safety analyses were performed in the mITT population, including all data from the start of treatment to the end of the safety follow-up. The least square mean (LSM) change from baseline was calculated within each subgroup using a mixed model for repeated measurements (MMRM) with country, baseline value, treatment group, visit, and treatment-by-visit interaction as the fixed effect, and patient as the random effect. MMRM for weight change also included baseline HbA1c group (≤8.5%, >8.5%) as a covariate. In patients of Hispanic or Latino ethnicity, the LSM change from baseline in HbA1c at 40 weeks was -2.11%, -2.46%, and -2.47% with tirzepatide 5, 10, and 15 mg, respectively, and -1.93% with semaglutide (all p<0.001). The respective changes in patients not of Hispanic or Latino ethnicity were -2.03%, -2.14%, -2.43%, and -1.69% (all p<0.001). Reductions in HbA1c were significantly greater for all tirzepatide doses compared with semaglutide in patients of both Hispanic or Latino and non-Hispanic or Latino ethnicity (all p≤0.027). In Hispanic or Latino patients, body weight change was -6.9 kg with tirzepatide 5 mg, -9.7 kg with 10 mg, -10.5 kg with 15 mg, and -5.6 kg with semaglutide (all p<0.001). In non-Hispanic or Latino patients, the changes from baseline in body weight were -9.9 kg, -11.6 kg, -17.1 kg, and -7.5 kg, for the tirzepatide doses and semaglutide, respectively, (all p<0.001). In both subgroups, reductions in body weight were significantly greater than semaglutide with all tirzepatide doses (all p≤0.013). The most common adverse events were gastrointestinal in the tirzepatide and semaglutide arms, including nausea (Hispanic or Latino 11-17% and 13%; non-Hispanic or Latino 32-36% and 29%), diarrhoea (10-13% and 10%; 15-24% and 17%) and vomiting (4-7% and 7%; 10-16% and 12%). Consistent with the primary SURPASS-2 results, in a Hispanic or Latino population with type 2 diabetes, tirzepatide demonstrated greater reductions from baseline in HbA1c and body weight than the selective GLP-1 receptor agonist semaglutide, with a comparable safety profile. Presentation: Tuesday, June 14, 2022 10:30 a.m. - 10:45 a.m.

Tirzepatide (TZP) is a novel once-weekly dual GIP and GLP-1 receptor agonist evaluated in patients with type 2 diabetes (T2D) . Five Phase 3 SURPASS (S) trials have demonstrated safety and shown robust efficacy of TZP in improvement of glycaemic control and body weight (BW) in adults with T2D. To understand whether the weight-lowering effects of TZP are dependent on baseline BMI, we conducted subgroup analyses of S-1 through -5. BW change in the BMI subgroups (Subgroup 1 [<27 or ≥27 kg/m2] and Subgroup 2 [<30; ≥30 to <35; ≥35 kg/m2]) at primary endpoint was assessed in patients while on treatment without rescue medication (efficacy estimand) in the modified intention-to-treat (mITT) population, defined as all randomized patients who received at least one dose of study drug. All TZP doses (5, 10, 15 mg) lowered BW in patients with T2D irrespective of baseline BMI in both subgroups (p<0.001) . The weight reductions were generally dose-dependent and absolute weight change was generally greater in higher BMI categories. TZP-treated patients with T2D experienced weight loss across a spectrum of mean baseline BMI values in S-1 through -5 studies. The most frequent adverse events were GI-related events that were mild to moderate in severity and occurred during the dose-escalation period. Disclosure A.Kwan: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.M.Maldonado: Employee; Eli Lilly and Company. H.Wang: None. N.Rasouli: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Allergan, Eli Lilly and Company, Novo Nordisk. J.Wilding: Advisory Panel; Alnylam Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Mundipharma, Novo Nordisk A/S, Rhythm Pharmaceuticals, Inc., Sanofi, Research Support; AstraZeneca, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Takeda Pharmaceutical Company Limited. Funding Eli Lilly and Company

Introduction Investigate the effects of switching from two times per day exenatide to once-weekly exenatide administered by autoinjector (exenatide once-weekly suspension by autoinjector (QWS-AI)) or treatment with exenatide QWS-AI for 1 year.Research design and methods In this phase III open-label study, adults with type 2 diabetes were randomized to receive exenatide QWS-AI (2 mg) or exenatide two times per day (5 mcg for 4 weeks, followed by 10 mcg) for 28 weeks. During a subsequent non-randomized 24-week extension, patients who received exenatide two times per day were switched to exenatide QWS-AI and those randomized to exenatide QWS-AI continued this treatment. Efficacy measures included changes from baseline in glycated hemoglobin (A1C), fasting plasma glucose (FPG), and body weight.Results In total, 315 patients (mean baseline A1C of 8.5%) completed the initial 28 weeks of randomized treatment with exenatide QWS-AI (n=197) or exenatide two times per day (n=118) and were included in the 24-week extension (mean A1C of 7.0% and 7.3%, respectively, at week 28). From weeks 28–52, patients who switched from exenatide two times per day to exenatide QWS-AI had additional A1C reductions of approximately 0.5% (mean A1C change from baseline of –1.4% at week 52) and further reductions from baseline in FPG. Patients who continued exenatide QWS-AI treatment for 52 weeks showed clinically relevant A1C reductions (mean A1C change from baseline of –1.3% at week 52). Body-weight reductions achieved through week 28 were sustained at week 52 in both groups. There were no unexpected safety concerns or changes in the safety profile among patients who switched from exenatide two times per day to exenatide QWS-AI or those who continued exenatide QWS-AI treatment for 52 weeks.Conclusions Switching from exenatide two times per day to exenatide QWS-AI resulted in further A1C reductions and maintenance of earlier decreases in body weight, while continued therapy with exenatide QWS-AI for 52 weeks maintained A1C and body-weight reductions, without additional safety or tolerability concerns.Trial registration number NCT01652716.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for treatment of type 2 diabetes mellitus; however, there have been concerns that GLP-1RA treatment may be associated with an increased incidence of pancreatitis. This study aimed to evaluate the incidence of pancreatitis in a pooled population of type 2 diabetes trials from the clinical development program of the GLP-1RA exenatide as well as to describe patient-level data for all reported cases. The primary analysis examined pooled data among patients with type 2 diabetes from the controlled arms of 35 trials (ranging from 4 to 234 weeks’ duration) in the integrated clinical databases for exenatide twice daily, once weekly, and once-weekly suspension, excluding comparator arms with other incretin-based therapies. The exposure-adjusted incidence rate (EAIR) of pancreatitis was calculated for exenatide and non-exenatide (non-incretin-based therapy or placebo) treatment groups. Patient-level data were described for all pancreatitis incidences. The primary analysis included 5596 patients who received exenatide and 4462 in the non-exenatide group. The mean duration of study medication exposure for the exenatide and non-exenatide treatment groups was 57.0 and 47.9 weeks, respectively. Pancreatitis was diagnosed in 14 patients (exenatide, n = 8; non-exenatide, n = 6), of whom 13 recovered with or without sequelae. The pancreatitis EAIR was 0.1195 events per 100 patient-years [95% confidence interval (CI), 0.0516–0.2154] in the exenatide group versus 0.1276 events per 100 patient-years (95% CI 0.0468–0.2482) in the non-exenatide treatment group. The EAIR ratio for the exenatide versus non-exenatide treatment group was 0.761 (95% CI 0.231–2.510). In this pooled analysis of 10,058 patients among studies comparing exenatide with other glucose-lowering medications or placebo, pancreatitis was rare. The EAIRs of pancreatitis were low and similar between exenatide and non-exenatide treatment groups. No evidence of an association between exenatide and pancreatitis was observed. Bristol-Myers Squibb and AstraZeneca. Plain language summary available for this article.

This analysis assessed whether responses with exenatide once weekly plus dapagliflozin (n = 231), exenatide once weekly alone (n = 230), or dapagliflozin alone (n = 233) differed in key patient subpopulations of the DURATION-8 trial. Potential treatment-by-subgroup interactions for changes in glycated haemoglobin (HbA1c) and body weight after 28 weeks were evaluated among subgroups determined by baseline HbA1c, age, sex, body mass index, type 2 diabetes duration, race, ethnicity and estimated glomerular filtration rate (eGFR). Exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all subgroups: least-squares mean reductions ranged from -8.4 to -26.1 mmol/mol (-0.77% to -2.39%) for HbA1c and from -2.07 to -4.55 kg for body weight. Potential treatment-by-subgroup interactions (P < .10) were found for HbA1c change by age (P = .016) and eGFR (P = .097). Age subgroup analysis findings were not consistent with expected mechanistic effects, with the small number of patients aged ≥65 years (n = 74 vs n = 499 for patients aged <65 years) limiting the interpretability of the interaction term. In the exenatide once weekly plus dapagliflozin and dapagliflozin groups, but not the exenatide once weekly group, HbA1c reductions were greater among patients with eGFR ≥90 vs ≥60 to <90 mL/min/1.73 m2 (least-squares mean reductions of -23.6 vs -19.0 mmol/mol [-2.16% vs -1.74%], -17.3 vs -12.0 mmol/mol [-1.58% vs -1.10%], and -17.7 vs -16.9 mmol/mol [-1.62% vs -1.55%] for the respective treatments); this was consistent with the mechanism of action of dapagliflozin. A potential treatment-by-subgroup interaction was observed for change in body weight by sex (P = .099), with greater weight loss for women vs men across all treatments (range -2.56 to -3.98 kg vs -0.56 to -2.99 kg). In conclusion, treatment with exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all patient subgroups and was more effective than exenatide once weekly or dapagliflozin alone in all adequately sized subgroups.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycemia in patients with type 2 diabetes, but heart rate increases have been observed.

OBJECTIVE Among patients with type 2 diabetes uncontrolled with metformin, exenatide once weekly (QW) plus dapagliflozin combination produced greater reductions in glycemia, weight, and systolic blood pressure (SBP) at 28 weeks than exenatide QW or dapagliflozin alone (DURATION-8). Here, we investigated the safety and maintenance of efficacy at 52 weeks, after a 24-week extension. RESEARCH DESIGN AND METHODS This phase 3, multicenter, double-blind study randomized adults with type 2 diabetes (with glycated hemoglobin [HbA1c] 8.0–12.0% [64–108 mmol/mol] and on metformin ≥1,500 mg/day) to exenatide QW (2-mg subcutaneous injection) plus once-daily dapagliflozin (10-mg oral tablet), exenatide QW plus oral placebo, or dapagliflozin plus injected placebo. Extension-period P values were nominal. RESULTS Of 1,375 patients screened, 695 were randomized (mean baseline HbA1c 9.3% [78 mmol/mol]); 81.2% completed the study, and 75.3% completed treatment. At 52 weeks, HbA1c reductions were greater with exenatide QW plus dapagliflozin (least squares mean change −1.75% [−19.1 mmol/mol]) versus exenatide QW (−1.38% [−15.1 mmol/mol]; P = 0.006) or dapagliflozin (−1.23% [−13.4 mmol/mol]; P < 0.001); mean HbA1c values were 6.9% (52 mmol/mol), 7.2% (55 mmol/mol), and 7.4% (57 mmol/mol), respectively. Weight and SBP reductions were greater with exenatide QW plus dapagliflozin (−3.31 kg and −4.5 mmHg) versus exenatide QW (−1.51 kg and −0.7 mmHg; both P < 0.001) but similar to those with dapagliflozin (−2.28 kg and −2.7 mmHg; P = 0.057 and P = 0.100, respectively). The exenatide QW plus dapagliflozin regimen was well tolerated with no unexpected safety findings; more patients treated with exenatide QW experienced gastrointestinal and injection site–related adverse events. No major hypoglycemia occurred. CONCLUSIONS Among patients with type 2 diabetes uncontrolled with metformin, exenatide QW plus dapagliflozin provided sustained improvements in glycemia, weight, and SBP over 52 weeks, with no unexpected safety findings.

AimsTo compare the efficacy and safety of adding the glucagon‐like peptide‐1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes who were inadequately controlled despite titrated insulin glargine (IG) ± metformin.MethodsThis multicentre, double‐blind study (ClinicalTrials.gov identifier: NCT02229383) randomized (1:1) patients with persistent hyperglycaemia after an 8‐week titration phase (glycated haemoglobin [HbA1c] 7.0%‐10.5% [53‐91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2‐hour postprandial glucose, and mean daily IG dose.ResultsOf 464 randomized patients (mean: age, 58 years; HbA1c, 8.5% [69 mmol/mol]; diabetes duration, 11.3 years), 91% completed 28 weeks. Exenatide QW + IG vs placebo + IG significantly reduced HbA1c (least‐squares mean difference, −0.73% [−8.0 mmol/mol]; 95% confidence interval, −0.93%, −0.53% [−10.2, −5.8 mmol/mol]; P < .001; final HbA1c, 7.55% [59 mmol/mol] and 8.24% [67 mmol/mol], respectively); body weight (−1.50 kg; −2.17, −0.84; P < .001); and 2‐hour postprandial glucose (−1.52 mmol/L [−27.5 mg/dL]; −2.15, −0.90 [−38.7, −16.2]; P < .001). Significantly more exenatide QW + IG‐treated patients vs placebo + IG‐treated patients reached HbA1c <7.0% (<53 mmol/mol) (32.5% vs 7.4%; P < .001); daily IG dose increased by 2 and 4 units, respectively. Gastrointestinal and injection‐site adverse events were more frequent with exenatide QW + IG (15.1% and 7.8%, respectively) than with placebo + IG (10.8% and 3.0%, respectively); hypoglycaemia incidence was similar between the exenatide QW + IG (29.7%) and placebo + IG (29.0%) groups, with no major hypoglycaemic events.ConclusionsAmong patients with inadequate glycaemic control, exenatide QW significantly improved glucose control and decreased body weight, without increased hypoglycaemia or unexpected safety findings.

The efficacy and safety of seven regimens based on metformin (placebo plus metformin, dapagliflozin plus metformin, vildagliptin plus metformin, saxagliptin plus metformin, empagliflozin plus metformin, exenatide plus metformin and sitagliptin plus metformin) on type 2 diabetes (T2D) were compared based on network meta-analysis. PubMed, Embase and Cochrane Library were applied in the computer-based retrieval process. Randomized controlled trials (RCTs) which were related with the above seven regimens based on metformin in the treatment of T2D were included in this study. Network meta-analysis merged the direct and indirect comparison evidence for the estimation of the weighted mean difference (WMD), odd ratios (ORs) and surface under the cumulative sequencing ranking curve (SUCRA) values. Eight eligible RCTs were applied in this network meta-analysis. The results demonstrated that: in terms of efficacy, the glycated hemoglobin (HbA1c) levels of T2D patients receiving vildagliptin plus metformin were relatively lower when compared with placebo plus metformin (WMD=-1.95, 95%CI=-3.70--0.23); in comparison with exenatide plus metformin, the triglyceride level in T2D patients taking vildagliptin plus metformin remained relatively lower (WMD=-1.36, 95%CI=-2.64--0.01). In terms of safety, the rate of adverse events in patients with T2D who received empagliflozin plus metformin was relatively lower when compared with saxagliptin plus metformin (OR=0.37, 95%CI=0.14-0.98). Furthermore, the SUCRA value of vildagliptin plus metformin was comparatively higher in efficacy, and that the SUCRA value of saxagliptin plus metformin was relatively lower in safety. The efficacy of vildagliptin plus metformin in patients with T2D is relatively better, while the safety of saxagliptin plus metformin in patients with T2D is relatively poorer.