Dipeptidyl peptidase-4 DPP-4 inhibitors, characterized by low propensity of hypoglycemia and weight neutrality, have gradually become an important class in the armamentarium of oral glucose-lowering agents 5 , 6. Since sitagliptin, the first DPP-4 inhibitor, launched in , 12 drugs have been available in the market of DPP-4 inhibitors, and by the year , three DPP-4 inhibitors were available in China. So, we initiated the head-to-head study of the three DPP-4 inhibitors sitagliptin, saxagliptin and vildagliptin.
Over a decade, much data have been accumulated from clinical trials and post-marketing studies of the DPP-4 inhibitors. Most current clinical trials focused on evaluating the combination of DPP-4 inhibitors with metformin and other hypoglycemic therapy, or monotherapy with DPP-4 inhibitors with placebo, rather than comparing within the class of DPP-4 inhibitors as the initial single therapy. In addition, Cardiovascular CV Outcomes Trials showed that long-term safety studies on sitagliptin were neutral, whereas CV outcome trials on saxagliptin were associated with a significant increase in the rate of hospitalization for heart failure SAVOR-TIMI 53 , which was saxagliptin treatment only 8 , 9.
No long-term CV outcome trials safety data are available on vildagliptin. There is still scarcity of comparison between various DPP-4 inhibitors in the short-term side effects. Cost and availability aside, sitagliptin and saxagliptin might be likely to be easily prescribed with one available dose, a once-daily dosing regimen, compared with vildagliptin.
There is a paucity of direct head-to-head studies of DPP-4 inhibitors and most comparisons are indirect and the potential for glycemic improvement might not be uniform within the class. In addition, ethnic difference may exist when comparing the effectiveness of DPP-4 inhibitors among patients in various regions.
Previous study indicated that DPP-4 inhibitors exhibit a better glucose-lowering efficacy in Asians than in other ethnic groups However, there exists few evidence on the effectiveness of DPP-4 inhibitors in Asia.
Therefore, we explored the therapeutic equivalence of saxagliptin, sitagliptin and vildagliptin as monotherapy among patients who were either treatment-naive or off prior anti-hyperglycemic agent therapy for at least 3 months, highlighting the differences and similarities between members of the DPP-4 inhibitors. This is a week, multicenter, randomized, double-blind comparative study in patients with newly diagnosed diabetes or off prior anti-hyperglycemic agent therapy for at least 3 months who had inadequate glycemic control undertaken in 16 hospitals in Shandong Province, China from October to January All three gliptins in this study were used at their expected maximal effective and recommended doses in accordance with product labeling for patients with newly diagnosed diabetes.
The purpose of this study is to explore the differences in efficacy and short-term side effects of sitagliptin, vildagliptin and saxagliptin and to find which one is better in treating type 2 diabetes mellitus.
The study was undertaken in accordance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. The Institutional Review Board of Shandong University approved the study protocol, and written informed consent was obtained from all participants.
In order to be strictly double-blinded, we performed randomization within each center. Besides, considering the different appearances of the three gliptins, placebo tablets Qilu Pharmaceutical Co.
We used three kinds of placebos to represent sitagliptin, vildagliptin and saxagliptin, accordingly. All patients in different drug groups received 3 pills in the morning among which one is the true drug, the other two are placebos and 1 pill in the evening among which only participants in the vildagliptin group received the real drug pill, and others received placebo.
Patients were recruited from 16 hospitals in Shandong Province, China. Eligible patients were male or female, 18—78 years of age and had type 2 diabetes with hemoglobin A1c HbA1c values ranging between 6. Women of childbearing potential were required to have a negative urine pregnancy test and agreed to use adequate contraception throughout the study and for up to 4 weeks after completion.
All participants signed the written informed consent. HbA1c was recorded at baseline week 0 , week 6 and week All blood samples were shipped in dry ice to and then tested in the central laboratory in Qianfoshan Hospital, Jinan, Shangdong.
Blood glucose from the fasting and 2-h postloading blood sampling was measured using the glucose oxidase method on an autoanalyzer Cobas ; Roche. SAS version 9. Data are expressed as mean s. Efficacy analysis included all participants randomly assigned to treatment groups who had received at least one dose of study drug and had at least one on-treatment assessment of any primary or secondary efficacy variable.
The adjusted mean changes from baseline to endpoint with last observation carried forward were compared between treatments using an ANCOVA model, and adjusted for age, as age is significantly different at baseline among the three gliptin groups.
Efficacy data were censored at the start of rescue medication. This trial is registered with ClinicalTrials. A total of patients with type 2 diabetes were randomized, and patients comprised the full analysis set.
Seven of subjects withdrew from sitagliptin, 6 of from vildagliptin and 10 of from saxagliptin treatment. The withdrawal rates were not significantly different between the groups Supplementary Fig.
Table 1 summarizes the demographic characteristics of study participants at baseline according to the three DPP-4 inhibitors. There were no significant differences in clinical characteristics among the randomized population, except age. Besides, BMI, lipid profiles, blood glucose levels, liver enzymes and creatinine were similar among three DPP-4 inhibitor groups after adjusting for age. Demographic characteristics of study participants at baseline. The biochemical characteristics among participants after week treatment period are represented in Supplementary Table 1.
After adjusting age and baseline HbA1c level, all biochemical variables including BMI, lipid profile, blood glucose levels, liver enzymes and creatinine showed no statistical difference among patients.
Mean HbA1c was 6. The changes of HbA1c from baseline to week 12 in sitagliptin, vildagliptin and saxagliptin groups were 0. Both the levels and changes of HbA1c among the three DPP-4 inhibitor groups showed no significant differences after week treatment. The mean FPG and PPG showed similar trend among sitagliptin, vildagliptin and saxagliptin groups with no statistical changes after week treatment. Besides, HbA1c levels among sitagliptin, vildagliptin and saxagliptin groups from baseline to week 6 and week 12, also showed insignificant difference Fig.
Hemoglobin A1c HbA1c levels among sitagliptin, vildagliptin and saxagliptin groups from baseline to week Citation: Endocrine Connections 8, 4; Changes of biochemical variables including BMI, lipids, liver enzymes and creatinine were shown in Table 3 after week treatment. Notably, patients in vildagliptin group showed a significant decrease in TC levels, compared with participants in sitagliptin and saxagliptin.
Secondary efficacy measurements from baseline to week P value was calculated for Chi-square test across the three groups. During week study, one patient in sitagliptin group withdrew from the study — who discontinued due to asthma with unknown reasons Table 4.
Data are presented as number. Chi-square test was used for comparison of differences in the three groups. This study is the first to directly compare the efficacy and short-term side effects of three DPP-4 inhibitors, namely sitagliptin, vildagliptin and saxagliptin, in patients with newly diagnosed diabetes or off prior anti-hyperglycemic agent therapy for at least 3 months who had inadequate glycemic control in 16 hospitals in Shandong Province, China.
DPP-4 inhibitors have been shown to provide significant improvements in standard indices of glycemic control and are increasingly positioned earlier in treatment algorithms both as monotherapy and as add-on treatment 12 , 13 , Although within the same class, sitagliptin, vildagliptin and saxagliptin have their own characteristics which could influence its effect and usage.
The latest drug trend report by Express Scripts reports that sitagliptin was among the top 10 drugs and the only oral hypoglycemic in the USA based on a per-member-per-year spending in It has been reported that individuals who initiated saxagliptin demonstrated better adherence and were less likely to discontinue therapy compared to those that initiated linagliptin and sitagliptin However, in full disclosure, each of these studies was supported by the manufacturer of saxagliptin.
Adding treatment with saxagliptin, vildagliptin, and sitagliptin all resulted in significant improvements in glycemic control. There was no significant difference among the three treatment groups of HbA1c changes and P2hBG changes, as well as the proportion of achieving target HbA1c levels.
Nevertheless, it was demonstrated that saxagliptin was superior to sitagliptin, while, inferior to vildagliptin in terms of changes in FBG after week treatment. The incidence of adverse events with three DPP-4 inhibitors was similar, and all of them were well tolerated. This study showed no significant reductions in HbA1c from baseline to week 24 among the three DPP-4 inhibitors-added groups, decreasing by 1.
While, previous placebo-controlled trials showed that the DPP-4 inhibitors could decrease HbA1c by about 0. When added to metformin, sulphonylureas or alpha-glucosidase inhibitors, DPP-4 inhibitors could reduce HbA1c by about 0. The differences between our results and previous studies might be influenced by different racial background of study populations, baseline HbA1c levels, BMI, types and dosages of background drugs and prescribed doses of the study drugs.
Most of Previous reports were performed in western countries, a majority of participants are Caucasian, whose baseline HbA1c levels were 8. Whereas the patients of our study are Orientals, who had HbA1c levels of 7. Such difference might be attributed to the subjects in our study having relatively mild hyperglycemia and lower BMIs, as well as, maybe Orientals are more sensitive to DPP-4 inhibitors.
Several clinical trials also showed similar HbA1c reductions 1. As indicated in our study, vildagliptin showed the greatest reductions of FBG, while, sitagliptin showed the smallest reductions.
This might be explained by the structure of the three DPP-4 inhibitors. Saxagliptin and vildagliptin are cyanopyrrolidines that form a covalent bond with the active site serine [ 40 ], which may result in more robust inhibition to DPP-4 and greater potency of lowering blood glucose level than sitagliptin with nonvalent bond with DPP And it is might be relational that the usage of vildagliptin was twice daily, while, saxagliptin and sitagliptin was once daily.
A previous study showed that vildagliptin induced better circadian glycaemic control than sitagliptin with a significant decrease on overall hyperglycemia, mainly driven by reduction on basal hyperglycaemia [ 41 ].
Several Asian clinical trials demonstrated that vildagliptin 50 mg twice daily was associated with significantly greater HbA1c reduction than sitagliptin mg once daily in patients of mean HbA1c ranged from 7.
The reported numbers of hypoglycaemic events in studies with vildagliptin and sitagliptin are very low. A pooled analysis for sitagliptin in monotherapy showed that the incidence of hypoglycaemia was 1.
Also as add-on therapy to metformin, DPP-4 inhibitiors showed a low degree of hypoglycaemia. When combined with sulphonylurea, DPP-4 inhibitions showed increased risk of hypoglycaemia. Furthermore, when vildagliptin was added to glimepiride, a slight increase in the incidence of hypoglycaemia was reported 1. Overall, these studies show a low risk of hypoglycaemia during treatment with DPP-4 inhibition. In many previous studies, the overall prevalence of adverse events was similar to that seen in placebo groups both in monotherapy and in combination therapy with metformin, sulphonylurea or alpha-glucosidase inhibitors.
Nevertheless, in some studies, adverse events such as upper respiratory tract infection, nasopharyngitis and headache were reported, although the association of these adverse events with the compounds has not been established. So far, vildagliptin and sitagliptin have now been examined in a large number of subjects and shown to be tolerable and safe, both in short-term studies and in studies up to 1 year of duration [ 27 , 37 — 39 , 46 ].
Similarly, saxagliptin is also tolerable and safe [ 29 , 47 ], although experience with this compound is more limited. The main adverse event with metformin was diarrhea, with glimepiride was hypoglycemia and weight gain, with pioglitazone was edema due to fluid retention and weight gain. However, the symptoms were transient in the majority of the study participants and the causal relationship between the study drugs and symptoms is uncertain.
There were still several limitations in our study. Secondly, patients were enrolled based on specific criteria and were followed according to the study schedule, which may not reflect the real clinical use.
Thirdly, as the patients were evaluated at outpatient, no specific compliance data were collected. Moreover, our study is small and had an open-label design, which are both limiting factors for the generalization of the data, the limitation should be considered. The current study demonstrated that the efficacy and tolerability of saxagliptin, vildagliptin, and sitagliptin are similar, with no significant differences, when used to treat type 2 diabetic patients with inadequate blood glucose control by dual combination of metformin and another traditional oral hypoglycemic agent glimepiride, acarbose, or pioglitazone.
But vildagliptin showed grater FBG reduction than sitagliptin. This trial is the first randomized controlled trial to evaluate the efficacy of commonly-used antidiabetic agents in Chinese type 2 diabetic patients. Specific characteristics of the study drugs should be considered when choosing an appropriate agent. To use these results as valuable information for selecting an oral hypoglycemic agent, more detailed subgroup analyses and further investigation would be recommended.
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Chin J Diabetes Mellitus. Google Scholar. American Diabetes Association: Standards of medical care in diabetes— Curr Cardiol Rep. International Diabetes Federation: Clinical guidelines task force, global guideline for type 2 diabetes. DeFronzo RA: From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.
Endocr Pract. Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R: Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with up titration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial.
Int J Clin Pract. Cardiovasc Diabetol. Diabetes Obes Metab. Am J Physiol Endocrinol Metab. J Clin Endocrinol Metab. Curr Med Res Opin. Please refer to this study by its ClinicalTrials. More Information. Publications automatically indexed to this study by ClinicalTrials.
Efficacy and short-term side effects of sitagliptin, vildagliptin and saxagliptin in Chinese diabetes: a randomized clinical trial. Endocr Connect. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Type 2 Diabetes Mellitus. Not Applicable. Study Type :. Interventional Clinical Trial. Estimated Enrollment :.
Triple Participant, Investigator, Outcomes Assessor. Study Start Date :. Estimated Primary Completion Date :. Experimental: Sitagliptin Drug: sitagliptin sitagliptin mg tablet by mouth , once daily for 12 weeks.
Experimental: Vildagliptin Drug: vildagliptin saxagliptin 50mg tablet by mouth , twice daily for 12 weeks.
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