Sitagliptin Combination Therapy Research Articles

Medication adjustment of afatinib and combination therapy with sitagliptin for alleviating afatinib-induced diarrhea in rats

Afatinib, as the first-line treatment for non-small cell lung cancer (NSCLC), causes severe gastrointestinal adverse reactions that greatly affect patients' quality of life and even potentially result in treatment discontinuation. Multiple dose adjustments and concomitant use of anti-diarrheal medications are commonly employed to manage diarrhea, also allowing for a recovery period between each adjustment. However, these approaches are based on empirical guidance and still have limitations. This study aims to explore reliable approaches to alleviate diarrhea by focusing on two strategies: adjusting the dosing regimen of afatinib itself and implementing combination therapy. In this study, we firstly revealed a dose-dependent relationship between afatinib-induced diarrhea and gastrointestinal epithelial damage, resulting in atrophy, reduced expression of tight junction proteins, and increased permeability. We further found that even after discontinuation of the medication, although the severity of diarrhea had improved to baseline, the tight junction proteins and permeability of the intestinal epithelium did not fully recover, and the pharmacokinetics studies showed that drug absorption significantly increased than normal. This indicated the recovery period was longer than expected and may accelerate the occurrence of subsequent episodes of diarrhea. Hence, it would be prudent to consider adjustments to the starting dose or the recovery interval. Furthermore, we initially investigated the relationship between DPP enzyme and afatinib-induced diarrhea and found a significant decrease in plasma DPP enzyme activity following afatinib-induced diarrhea. Subsequently, we conducted continuous treatment with sitagliptin and observed significant improvement in afatinib-induced diarrhea. We observed that sitagliptin can promote the production of anti-inflammatory factors, increase the expression of intestinal epithelial tight junction proteins, and improve intestinal microbiota, further validating the mechanism through the use of GLP-23-33 as GLP-2 receptor inhibitor. In conclusion, sitagliptin exhibits promising potential as a therapeutic option for managing afatinib-induced diarrhea. Taken together, our study provides valuable insights into alleviating afatinib-induced diarrhea through both afatinib medication adjustment and sitagliptin combination therapy.

A novel therapeutic combination of sitagliptin and melatonin regenerates pancreatic β-cells in mouse and human islets

Autoimmune-led challenge resulting in β-cell loss is responsible for the development of type 1 diabetes (T1D). Melatonin, a pineal hormone or sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, has increased β-cell mass in various diabetic models and has immunoregulatory property. Both β-cell regenerative capacity and melatonin secretion decrease with ageing. Thus, we aimed to investigate the therapeutic potential of melatonin combined with sitagliptin on β-cell regeneration under glucotoxic stress, in the streptozotocin-induced young and old diabetic mouse models, and euglycemic humanized islet transplant mouse model. Our results suggest that combination therapy of sitagliptin and melatonin show an additive effect in inducing mouse β-cell regeneration under glucotoxic stress, and in the human islet transplant mouse model. Further, in the young diabetic mouse model, the monotherapies induce β-cell transdifferentiation and reduce β-cell apoptosis whereas, in the old diabetic mouse model, melatonin and sitagliptin induce β-cell proliferation and β-cell transdifferentiation, and it also reduces β-cell apoptosis. Further, in both the models, combination therapy reduces fasting blood glucose levels, increases plasma insulin levels and glucose tolerance and promotes β-cell proliferation, β-cell transdifferentiation, and reduces β-cell apoptosis. It can be concluded that combination therapy is superior to monotherapies in ameliorating diabetic manifestations, and it can be used as a future therapy for β-cell regeneration in diabetes patients.

Study on Synergistic Effect of Bromocriptine and Sitagliptin in Streptozotocin-induced Diabetic Rats

Introduction: Diabetes mellitus is a potentially morbid condition with high prevalence worldwide. Restoration of euglycemia in type 2 diabetes mellitus is difficult to achieve due to its multifactorial pathogenesis and frequently requires multiple anti-diabetic medications with different mechanism of action. This study is based on the possible synergistic effect of Sitagliptin and Bromocriptine in reducing blood sugar in diabetic animal models. Aim: To evaluate the effect of Sitagliptin and Bromocriptinemonotherapy and their combination in three different doses on blood sugar, Lipid profile, Liver and renal parameters in diabetic albino Wistar rats. Materials and Methods: An experimental animal study was conducted on 48 adult male albino wistar rats for a period of one month (August 2014). Streptozotocin induced (40 mg/kg IP) diabetic rats were divided into six groups of eight animals each weighing 150-200 gms. Group I- Vehicle (distilled water), Group II- Sitagliptin (100 mg/kg), Group III- Bromocriptine (10 mg/kg), Group IV- Sitagliptin (75 mg/kg) + Bromocriptine (7.5 mg/kg), Group V- Sitagliptin (100 mg/kg) + Bromocriptine (10 mg/kg), Group VI- Sitagliptin (125 mg/kg) + Bromocriptine (12.5 mg/kg). All drugs were given once daily (p.o) for four weeks. Body weight, fasting blood sugar, fasting lipid profile, liver parameters and renal parameters were estimated before and after administration of the drugs. Results were analyzed with SPSS software version 16.0 using one-way ANOVA followed by post-hoc Dunnett t test. P<0.05 was considered statistically significant. Results: The low dose combination therapy [Sitagliptin (75 mg/kg) + Bromocriptine (7.5 mg/kg)] showed a significant decrease in body weight (p<0.05), fasting blood sugar (p<0.001) compared with the vehicle group. It also showed a favorable lipid profile, renal and liver parameters compared with the vehicle, monotherapy and other combination regimens. Conclusion: The low dose combination therapy of Sitagliptin and Bromocriptine showed a better control over fasting blood sugar along with a beneficial effect on lipid profile, liver parameters and renal parameters than compared to other groups.

Beneficial Effects of Combination Therapy of Sitagliptin and β-carotene Drugs on Streptozotocin-induced Diabetic Rats

Diabetes mellitus (DM), characterized by chronic hyperglycemia is one of the most common chronic diseases affecting millions of people worldwide. A significant component of the risk associated with DM is thought to be because of its abnormal lipid ‘triad’ profile. All the associated complications are mainly due to imbalance between generation of free radicals and the antioxidant systems like catalase (CAT) and super oxide dismutase (SOD) enzymes. Moreover, increased level of serum glutamate pyruvate transaminase (SGPT) and serum glutamate oxaloacetate transaminase (SGOT) are considered a consequence of hepatocyte damage. The current study was designed to investigate the antihyperglycemic and antidyslipidemic effects, oxidative stress and liver dysfunction indices of fixed dose combination therapy of sitagliptin [50 mg/70kg body weight (BW)] and β-carotene (5 mg/70kg BW) on streptozotocin (45 mg/kg BW) induced diabetic rats (SIDRs). The study showed that combination therapy induced a significant decrease in blood glucose level (BGL) from 19.09 ± 0.13 to 6.86 ± 0.11 mmol/l in comparison to the control group after daily treatment for three weeks. In case of dyslipidimic effect, combination therapy reduced total cholesterol (TC) (22.96%), triglycerides (TG) (17.54%) and low-density lipoprotein (LDL)-cholesterol (52.25%) levels significantly and increased high-density lipoprotein (HDL)-cholesterol level (55.98%) in comparison with respective diabetic control groups. We also observed that combination therapy lowered SGPT & SGOT level by 46.39% and 37.23%, respectively and increased SOD & CAT enzyme activity by 63.79% and 48.32%, respectively in comparison with diabetic control groups. These changes were significantly better than those of sitagliptin and β-carotene monotherapy. The suggestions of our findings of this research are that combination therapy is more potent than their individual monotherapy and may be beneficial for the treatment of diabetic patients with associated complications. Bangladesh Pharmaceutical Journal 23(2): 87-95, 2020

Impact of sitagliptin combination therapy and hypoglycemia in Japanese patients with type 2 diabetes: a multi-center retrospective observational cohort study

BackgroundPatients with diabetes are at higher risk of developing polypharmacy because of the high frequency of comorbidities. There have been several reports on the hypoglycemic risk of the combination of hypoglycemic agents and other medications. This study aimed to investigate the hypoglycemic risk of drug-drug interaction between sitagliptin and other oral hypoglycemic agents or antihypertensive agents in Japanese patients with type 2 diabetes.MethodsFrom January 2010 to March 2012, a total of 3247 patients were recruited and evaluated at outpatient clinics at Juntendo University Hospital, other satellite hospitals, and private clinics. This study was a sub-analysis of the Sitagliptin Registration Type 2 Diabetes-Juntendo Collaborating Project. Participants were limited to those treated with oral hypoglycemic agents, excluding insulin users, to investigate the association of the first hypoglycemic events with oral hypoglycemic agents or other medications within 6 months after starting sitagliptin. The factors related to the first hypoglycemic event were analyzed using Cox regression analysis.ResultsIn total, 2956 patients with a mean age of 65.1 ± 11.3 years were included. A total of 46 hypoglycemic events (1.6%) were observed. One patient had severe hypoglycemia followed by emergency transport to the hospital. Sitagliptin was not associated with hypoglycemia, but its combination with sulfonylurea (hazard ratio: 4.42, 95% confidential interval: 1.36–14.42) or β-blocker (hazard ratio, 3.50, 95% confidential interval: 1.54–7.96) was significantly associated with hypoglycemia.ConclusionsThe drug-drug interactions between sitagliptin and sulfonylurea or β-blocker likely increases the hypoglycemic risk in Japanese patients with type 2 diabetes. Pharmacists should consider potential adverse events from drug-drug interaction in type 2 diabetes with polypharmacy, particularly those who are managed by several doctors or clinics.

Metformin and sitagliptin combination therapy ameliorates polycystic ovary syndrome with insulin resistance through upregulation of lncRNA H19

ABSTRACT Insulin resistance (IR) is prevalent in women with polycystic ovary syndrome (PCOS). Improvement in insulin sensitivity remains one of the most effective treatment strategies for women with PCOS. This study aims to investigate the efficacy and potential mechanism of the combination therapy with metformin (DMBG) and sitagliptin (TECOS) in PCOS. To address this, insulin was used to treat rat ovarian granulosa cells to establish the cellular PCOS model. Insulin and human chorionic gonadotropin (HCG) were subcutaneously injected into SD rats to establish a rat model of hyperandrogenism with pathogenesis similar to PCOS. Our results showed that co-treatment with TECOS and DMBG attenuated the induced apoptosis and insulin resistance (IR) in PCOS model cells, and improved reproductive hormone disorders, ovarian polycystic changes, and IR of PCOS rats. Mechanistically, upregulation of H19 by H19-expressing lentiviruses enhanced efficacy of combination therapy. Furthermore, co-treatment with TECOS and DMBG induced H19 expression via suppressing the PI3K/AKT-DNMT1 pathway. Collectively, these findings demonstrate that combination treatment with TECOS and DMBG ameliorates PCOS with IR, at least partially, through upregulation of lncRNA H19.

Efficacy and safety of nateglinide plus sitagliptin combination therapy in type 2 diabetes patients inadequately controlled by sitagliptin monotherapy: a phase 3, multicenter, open-label, long-term study.

Combination therapies of drugs with distinct mechanisms of action are emerging as ways to achieve strict glycemic control, thus preventing the onset and progression of diabetic complications in type 2 diabetes patients. A rapid-acting insulin secretagog, nateglinide, and a potent dipeptidyl peptidase-4 inhibitor, sitagliptin, meet such criteria. A total of 121 patients inadequately controlled with sitagliptin monotherapy received 52-week combination therapy (nateglinide+sitagliptin). The primary endpoint was the safety of the therapy, and its efficacy was also evaluated. A meal tolerance test was performed 4weeks before the start of combination therapy (week -4) and at week 24 and week 52 after the start of combination therapy. HbA1c levels were lower at week 52 than at week 0 [-0.42% (95% confidence interval -0.53, -0.31)]. Fasting plasma glucose levels tended to decrease from baseline (week 0) to week 52 [-4.8mg/dl (-9.4, -0.2)]. In the meal tolerance test, postprandial plasma glucose levels and area under the curve of glucose from before to 2h after the meal load were lower at week 24 and week 52 than at week -4. In addition, the levels of insulin and active glucagon-like peptide-1 were higher at week 52 than at week -4. Furthermore, the incidence of adverse events in combination therapy with sitagliptin was similar to those previously shown in nateglinide monotherapy. Compared with sitagliptin monotherapy, the combination therapy of nateglinide plus sitagliptin was more effective in type 2 diabetes patients at improving glycemic control while showing similar safety.

Chitosan oligosaccharide improves the therapeutic efficacy of sitagliptin for the therapy of Chinese elderly patients with type 2 diabetes mellitus.

Sitagliptin improves glycemic control in type 2 diabetes mellitus (T2DM) patients but its side effects are undesirable. Chitosan oligosaccharide (COS) is expected to improve the therapeutic result as a natural product. A total of 200 elderly T2DM patients were evenly assigned into four groups: sitagliptin group (SG), receiving sitagliptin 100 mg/day; COS group (CG), receiving COS 100 mg/day; combination therapy of sitagliptin and COS group (SCG), receiving both sitagliptin and COS 100 mg/day; and placebo group (PG), receiving placebo 100 mg/day. After 42-week therapy, biochemical indices and clinical parameters for the alterations from start points were analyzed. The related molecular mechanism was tested by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot at cell level. Lower risk of hypoglycemia was found in the SCG group when compared with SG and other groups (P<0.05). More patients from the SCG group than other groups attained hemoglobin A1c (HbA1c) reduction >2.5% (P<0.05). Weight reduction of 1.2±0.9, 2.6±0.8, 4.7±1.3, and 0.9±0.6 kg was observed in the patients from SG, CG, SCG, and PG groups, respectively (P<0.05). The combined treatment of COS and sitagliptin presented better therapeutic results by improving insulin sensitivity, lipid profile, adiponectin levels, and glucagon-like peptide 1 and reducing side effects, insulin resistance, HbA1c, body mass index, resistin, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) (P<0.05). qRT-PCR and Western blot analysis also showed that COS treatment reduced the levels of resistin, TNF-α, and CRP, and increased the level of adiponectin. The combination of COS and sitagliptin provided better glycemic control with fewer side effects and with more weight reduction in the elderly participants with T2DM.

Lansoprazole enhances the antidiabetic effect of sitagliptin in mice with diet-induced obesity and healthy human subjects†

Proton pump inhibitors as adjunctive therapy would improve diabetes control and could enhance the hypoglycaemic activity of DPP-4 inhibitors. The aim of the study was to investigate the short-term effects of lansoprazole (LPZ), sitagliptin (SITA) and their combination therapy on glucose regulation and gut peptide secretion. Glucose and gut peptide were determined and compared after short-term administration of LPZ or SITA, or in combination to mice with diet-induced obesity (DIO) and to healthy human subjects (n = 16) in a 75 g oral glucose tolerance test (OGTT) by a crossover design. In DIO mice, LPZ significantly improve glucose metabolism, increase plasma C-peptide and insulin compared with vehicle treatment. Furthermore, the combination of LPZ and SITA improved glucose tolerance additively, with higher plasma insulin and C-peptide levels compared with SITA-treated mice. Similarly, in human in the OGTT, the combination showed significant improvement in glucose-lowering and insulin increase vs SITA-treated group. However, no significant differences in area under curve (AUC) of insulin, glucose and C-peptide between the LPZ-treated group and baseline, except that mean AUCgastrin was significantly increased by LPZ. LPZ and SITA combination therapy appears to have complementary mechanisms of action and additive antidiabetic effect.

Efficacy and safety of initial combination treatment with sitagliptin and pioglitazone—a factorial study

To evaluate the efficacy and safety of initial combination therapy of sitagliptin 100 mg/day coadministered with all marketed doses of pioglitazone in patients with type 2 diabetes. Patients with A1c ≥7.5 and ≤11.0% were randomized among seven arms that received, once daily, 100 mg sitagliptin alone; 15, 30 or 45 mg pioglitazone alone, or 100 mg sitagliptin plus 15, 30 or 45 mg pioglitazone for 54 weeks. The primary endpoint was change from baseline in A1c at week 24. Protocol-specified analyses compared combination therapies with monotherapies at respective dose-strengths and combination of sitagliptin plus pioglitazone 30 mg with pioglitazone 45 mg monotherapy. Post-hoc analyses compared sitagliptin plus pioglitazone 15 mg with pioglitazone monotherapy at the two higher doses. Initial combination therapy with sitagliptin and pioglitazone provided significantly greater reductions in A1c (0.4-0.7% differences) and other glycaemic endpoints than either monotherapy at the same doses. Combining sitagliptin with low-dose pioglitazone generally produced greater glycaemic improvements than higher doses of pioglitazone monotherapy (0.3-0.4% differences in A1c). Combination therapy was generally well tolerated; adverse events (AEs) of hypoglycaemia were reported with similar incidence (7.8-11.1%) in all treatment groups over the 54 weeks of study; oedema was reported in 0.5% of patients in the sitagliptin monotherapy group and 2.7-5.3% among pioglitazone-treated groups. Significant weight gain was observed in all combination-treated groups compared with the sitagliptin monotherapy group. Initial combination therapy with sitagliptin and pioglitazone provided better glycaemic control than either monotherapy and was generally well tolerated.

Risk Factors for Adverse Symptoms During Dipeptidyl Peptidase-IV Inhibitor Therapy: A Questionnaire-Based Study Carried Out by the Japan Pharmaceutical Association Drug Event Monitoring Project in Kumamoto Prefecture

Meta-analyses of randomized clinical trials have reported that dipeptidyl peptidase IV (DPP-4) inhibitors are well tolerated and that the incidence of hypoglycemia with the use of DPP-4 inhibitors is similar to that observed with placebos. However, in general, provider-oriented methods using medical record reviews offer lower rates of non-serious, symptomatic adverse drug reactions (ADRs) than patient-oriented methods. Moreover, severe hypoglycemia occurred in three clinical trials using sitagliptin, but in two of these trials this phenomenon has been previously described only in the drug application data in the US. The aim of this study was to assess the profile of patient-reported symptomatic ADRs under DPP-4 inhibitor therapy and to detect risk factors for hypoglycemic and non-hypoglycemic adverse symptoms in daily clinical practice. We analyzed a subpopulation of participants in the Drug Event Monitoring (DEM) project of the Japan Pharmaceutical Association. An anonymous survey was conducted in February 2012 to assess the self-perception of adverse symptoms during a median 28 (4-88)days after the last prescription of DPP-4 inhibitors by means of interviews of pharmacists using structured questionnaires. A total of 864 males and 686 females were included. The prescribed DPP-4 inhibitors included sitagliptin (75.4%), alogliptin (15.5%), vildagliptin (8.8%) and linagliptin (0.3%). Mild hypoglycemic symptoms were reported by 34 individuals (2.2%) receiving monotherapy of sitagliptin (10/402) or alogliptin (3/65), or combination therapy of sitagliptin (15/767) or alogliptin (6/176) with other hypoglycemic agents. In the multiple regression model, hypoglycemic symptoms were found to be significantly associated with liver disease, female sex and alcohol consumption more than three times per week. Non-hypoglycemic symptoms were reported by 57 individuals (3.7%), the most common symptoms of which were gastrointestinal symptoms (2.1%). Combination therapy was only found to be associated with nonhypoglycemic symptoms. The present study suggested that hypoglycemic symptoms under therapy with sitagliptin or alogliptin may be associated with liver disease, female sex and alcohol consumption, all of which are potentially capable of leading to poor gluconeogenesis because they decrease the counter-regulatory hormonal responses to hypoglycemia.

Factors predicting therapeutic efficacy of combination treatment with sitagliptin and metformin in type 2 diabetic patients: the COSMETIC study

We assessed the predictive parameters for therapeutic efficacy of initial combination therapy with sitagliptin and metformin in drug-naïve type 2 diabetic patients. DeSIGN, PATIENTS, AND MEASUREMENTS: In this 52-week treatment study, 150 patients (mean age, 54·9 ± 12·5 years) with type 2 diabetes and HbA1c of 7·0-10% were treated with sitagliptin 100 mg once and metformin 500 mg twice daily. To assess the predictive parameters for therapeutic efficacy, a multivariate regression analysis was performed with baseline fasting glucose, insulin, C-peptide, and glucagon levels, homoeostasis model assessment-insulin resistance (HOMA-IR) and β-cell function (HOMA-B), insulinogenic index (IGI, defined as 30-0 min insulin/30-0 min glucose), and area under the curve for glucose, insulin, and C-peptide obtained after 75-g oral glucose tolerance test. After 52 weeks, mean HbA1c levels and fasting and postload 2-h glucose were significantly decreased from 8·7 ± 1·4% to 7·2 ± 1·3%, 9·2 ± 3·0 to 7·2 ± 1·8 mm, and 17·5 ± 5·1 to 10·9 ± 3·6 mm, respectively (P < 0·01). HOMA-B and IGI increased significantly from 50·3 ± 33·5 to 75·1 ± 32·8 and from 11·3 ± 1·3 to 35·0 ± 6·3 at 52 weeks, respectively (P < 0·01). Multivariate regression analysis indicated that the reduction in HbA1c was significantly associated with high baseline HbA1c, low IGI, and short duration of diabetes after adjusting for age, sex, body mass index, blood pressure, triglycerides, creatinine, high-sensitivity CRP, glucagon, C-peptide, HOMA-B, and HOMA-IR. No severe adverse events were observed. These results suggest that drug-naïve type 2 diabetic patients with low β-cell function would benefit the most from early initial combination therapy of sitagliptin and metformin.

Efficacy of Sitagliptin When Added to Ongoing Therapy in Korean Subjects with Type 2 Diabetes Mellitus

BackgroundTo evaluate the clinical efficacy of sitagliptin for reducing plasma glucose levels in Korean subjects with type 2 diabetes mellitus during a 14-week treatment period.MethodsOur study design involved the addition of 100 mg sitagliptin once-daily to three ongoing combination therapy regimens and changing from glimepiride and metformin to sitagliptin and metformin.ResultsThe addition of sitagliptin 100 mg/day produced a statistically significant reduction in mean HbA1c level (mean HbA1c reduction of 0.99±0.85%, P<0.01). In the group taking a combination of sitagliptin and metformin (n=143, initial mean HbA1c level=7.48%), the reductions in HbA1c, 2-hour postprandial glucose, and fasting glucose levels were 0.72±0.76% (P<0.01), 47±65 mg/dL (P<0.01), and 15±44 mg/dL (P<0.01), respectively. In the group taking a combination of sitagliptin, glimepiride, and metformin (n=125, initial mean HbA1c level=8.42%), the reductions in HbA1c, 2-hour postprandial glucose, and fasting glucose levels were 1.09±0.86% (P<0.01), 62±64 mg/dL (P<0.01), and 31±45 mg/dL (P<0.01), respectively. In the group taking a combination of sitagliptin, glimepiride, metformin, and α-glucosidase inhibitor (n=63, initial mean HbA1c level=9.19%), the reductions in HbA1c, 2-hour postprandial glucose, and fasting glucose levels were 1.27±0.70% (P<0.01), 72±65 mg/dL (P<0.01), and 35±51 mg/dL (P<0.01), respectively. In the group that had previous hypoglycemic events and that changed from glimepiride to sitagliptin, HbA1c level did not change but fasting glucose increased significantly (14±29 mg/dL, P<0.01).ConclusionSitagliptin combination therapy for 14 weeks significantly improved glycemic control and was well-tolerated in Korean subjects with type 2 diabetes mellitus.

Sitagliptin and Metformin in Fixed Dose Combination:&amp;nbsp; The Emerging Evidence of its Therapeutic Impact in Type 2 Diabetes

Type 2 diabetes is a metabolic disease that is characterized by two important defects: insulin resistance and a defect in the integrated function of pancreatic islets. Metformin is the first-line therapy in type 2 diabetes and improves insulin resistance by reducing hepatic glucose output. Sitagliptin is the first DPP-4 (dipeptidyl-peptidase-4) inhibitor that was introduced into type 2 diabetes therapy in 2006. It raises endogenous plasma concentrations of the incretin hormone GLP-1 (glucagon-like peptide-1) and thereby restores glucose dependent insulin- and glucagon secretions of the pancreatic beta- and alpha-cells, respectively. Metformin and sitagliptin combination therapy therefore offers a beneficial and complementary addition of two agents acting on important defects in type 2 diabetes. Both agents can be given either in a free combination or as a fixed dose combination. This article reviews the published clinical studies on a metformin and sitagliptin combination therapy that improves glycaemic parameters more potently than either agent alone and is well tolerated.

Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study

ABSTRACTObjective: To assess the 54-week efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control (HbA1c 7.5–11%) on diet and exercise.Methods and materials: This was multinational study conducted at 140 clinical sites in 18 countries. Following an initial 24-week, double-blind, placebo-controlled period, patients entered a double-blind continuation period for an additional 30 weeks. Following the week 24 evaluation, patients remained on their previously assigned active, oral treatments: sitagliptin 50 mg b.i.d. + metformin 1000 mg b.i.d. (S100 + M2000), sitagliptin 50 mg b.i.d. + metformin 500 mg b.i.d. (S100 + M1000), metformin 1000 mg b.i.d. (M2000), metformin 500 mg b.i.d. (M1000), and sitagliptin 100 mg q.d. (S100). Patients initially randomized to placebo were switched to M2000 (designated PBO/M2000) at week 24. This report summarizes the overall safety and tolerability data for the 54-week study and presents efficacy results for patients randomized to continuous treatments who entered the 30-week continuation period.Results: Of the 1091 randomized patients, 906 completed the 24-week placebo-controlled phase and 885 patients continued into the 30-week continuation period (S100 + M2000 n = 161, S100+M1000 n = 160, M2000 n = 153, M1000 n = 147, S100 n = 141, PBO/M2000 n = 123). At baseline, patients included in the efficacy analysis had mean age of 54 years, mean BMI of 32 kg/m2, mean HbA1c of 8.7% (8.5–8.8% across groups), and mean duration of type 2 diabetes of 4 years. At week 54, in the all-patients-treated analysis of continuing patients, least-squares (LS) mean changes in HbA1c from baseline were −1.8% (S100 + M2000), −1.4% (S100 + M1000), −1.3% (M2000), −1.0% (M1000), and −0.8% (S100). The proportions of continuing patients with an HbA1c < 7% at week 54 were 67% (S100 + M2000), 48% (S100 + M1000), 44% (M2000), 25% (M1000), and 23% (S100). For the patients completing treatment through week 54, LS mean changes in HbA1c from baseline were −1.9% (S100 + M2000), −1.7% (S100 + M1000), −1.6% (M2000), −1.2% (M1000), and −1.4% (S100). Glycemic response was generally durable over time across treatments. All treatments improved measures of β-cell function (e.g., HOMA-β, proinsulin/insulin ratio). Mean body weight decreased from baseline in the combination and metformin monotherapy groups and was unchanged from baseline in the sitagliptin monotherapy group. The incidence of hypoglycemia was low (1–3%) across treatment groups. The incidence of gastrointestinal adverse experiences with the co-administration of sitagliptin and metformin was similar to that observed with metformin alone.Limitations: The patient population evaluated in the 54-week efficacy analysis was a population of patients who entered the continuation period without receiving glycemic rescue therapy in the 24-week placebo-controlled period. Because the baseline HbA1c inclusion criteria ranged from 7.5 to 11% and the glycemic rescue criterion was an HbA1c > 8% after week 24, there was a greater likelihood of glycemic rescue in the monotherapy groups; this led to more missing data in the continuation all-patients-treated population(CAPT) analysis and fewer patients contributing to the completers analysis in the monotherapy groups.Conclusions: In this study, initial treatment with sitagliptin, metformin, or the combination therapy of sitagliptin and metformin provided substantial and durable glycemic control, improved markers of β-cell function, and was generally well-tolerated over 54 weeks in patients with type 2 diabetes.