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Drugs Feb 2017The dipeptidyl peptidase-4 inhibitor sitagliptin (Januvia; Glactiv; Tesavel; Xelevia™) is approved in more than 130 countries worldwide as monotherapy and in... (Review)
Review
The dipeptidyl peptidase-4 inhibitor sitagliptin (Januvia; Glactiv; Tesavel; Xelevia™) is approved in more than 130 countries worldwide as monotherapy and in combination with other antihyperglycaemic drugs for the treatment of adult patients with type 2 diabetes (T2D). Extensive clinical experience has firmly established the glycaemic efficacy of oral sitagliptin (±other antihyperglycaemic drugs) in a broad spectrum of patients with T2D, including obese, elderly and renally impaired patients and those with established cardiovascular (CV) disease (CVD). Sitagliptin is generally well tolerated, with most adverse events being of mild to moderate intensity and relatively few patients discontinuing treatment because of these events. Sitagliptin treatment was not associated with an increased risk for the known CVD risk factors of hypoglycaemia and bodyweight gain. Of note, in the TECOS CV safety trial in patients with T2D and established CVD, sitagliptin was noninferior to placebo in terms of the risk of the 4-point major adverse cardiac event (MACE) outcome, with no increased risk in hospitalization for heart failure. Albeit discussion is equivocal regarding the potential increased risk of pancreatitis and pancreatic cancer with incretin-based therapies (including sitagliptin), no causal link between incretin-based drugs and these events has been established to date. With its convenient once-daily oral regimen, low potential for pharmacokinetic drug-drug interactions and good efficacy and safety profiles, including CV safety, sitagliptin remains an important option in the management of patients with T2D.
Topics: Diabetes Mellitus, Type 2; Humans; Sitagliptin Phosphate
PubMed: 28078647
DOI: 10.1007/s40265-016-0686-9 -
JAMA Apr 2019Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy. (Comparative Study)
Comparative Study Randomized Controlled Trial
Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial.
IMPORTANCE
Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy.
OBJECTIVE
To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized.
INTERVENTIONS
Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved.
MAIN OUTCOMES AND MEASURES
The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight.
RESULTS
Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, -0.3% [95% CI, -0.4% to -0.1%] and -0.5% [95% CI, -0.6% to -0.4%], respectively; P < .001 for both) and body weight (differences, -1.6 kg [95% CI, -2.0 to -1.1 kg] and -2.5 kg [95% CI, -3.0 to -2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin.
CONCLUSIONS AND RELEVANCE
Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02607865.
Topics: Administration, Oral; Adult; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Sitagliptin Phosphate; Sulfonylurea Compounds
PubMed: 30903796
DOI: 10.1001/jama.2019.2942 -
Science (New York, N.Y.) Aug 2023A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota-host cross-talk. We developed an enzyme...
A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota-host cross-talk. We developed an enzyme activity-screening platform to investigate how gut microbiota-derived enzymes might influence host physiology. We discovered that dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa of the microbiota. Microbial DPP4 was able to decrease the active glucagon like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky gut. Furthermore, the current drugs targeting human DPP4, including sitagliptin, had little effect on microbial DPP4. Using high-throughput screening, we identified daurisoline-d4 (Dau-d4) as a selective microbial DPP4 inhibitor that improves glucose tolerance in diabetic mice.
Topics: Animals; Humans; Mice; Bacteroides; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Feces; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glucose; Host Microbial Interactions; Isoenzymes; Sitagliptin Phosphate; Hypoglycemic Agents
PubMed: 37535747
DOI: 10.1126/science.add5787 -
PloS One 2022Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is used orally in conjunction with diet and exercise to control sugar levels in type 2 Diabetes Mellitus...
Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is used orally in conjunction with diet and exercise to control sugar levels in type 2 Diabetes Mellitus patients. This study aimed to extemporaneously prepare SiP solution (1% w/v) using pure Sitagliptin phosphate (SiP) powder and assess its stability according to pharmaceutical regulatory guidelines. Four SiP solutions, coded T1, T2, T3, and T4, were extemporaneously prepared using pure SiP powder as a source of API. The most suitable one, in terms of general organoleptic properties, was selected for further investigations, including stability studies. For this last purpose, samples of the T4 solution were kept under two storage conditions, room temperature (25˚C and 60% Relative Humidity) and accelerated stability conditions (40˚C and 75% Relative Humidity). Assay, pH, organoleptic properties, related substances, and microbial contamination were evaluated for 4 consecutive weeks. A High-Performance Liquid Chromatography (HPLC) analytical method was developed and validated to be used for the analysis and quantification of SiP in selected solution formulation. The adopted formula had a pH on the average of 3 to 4. During the stability tests, all pH values remained constant. Furthermore, after 4 weeks of storage under both conditions, the SiP concentration was close to 100%. A stable SiP extemporaneous solution was successfully prepared using pure SiP powder. Patients with swallowing problems who use feeding tubes and are unable to take oral solid dosage forms may benefit from this research. Community pharmacists can prepare the solution using sitagliptin powder as the source of the active ingredient.
Topics: Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Drug Compounding; Drug Stability; Drug Storage; Humans; Powders; Sitagliptin Phosphate
PubMed: 35294449
DOI: 10.1371/journal.pone.0262068 -
The Lancet. Diabetes & Endocrinology May 2017Semaglutide is a novel glucagon-like peptide-1 (GLP-1) analogue, suitable for once-weekly subcutaneous administration, in development for treatment of type 2 diabetes.... (Comparative Study)
Comparative Study Randomized Controlled Trial
Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial.
BACKGROUND
Semaglutide is a novel glucagon-like peptide-1 (GLP-1) analogue, suitable for once-weekly subcutaneous administration, in development for treatment of type 2 diabetes. We assessed the efficacy and safety of semaglutide versus the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled on metformin, thiazolidinediones, or both.
METHODS
We did a 56-week, phase 3a, randomised, double-blind, double-dummy, active-controlled, parallel-group, multinational, multicentre trial (SUSTAIN 2) at 128 sites in 18 countries. Eligible patients were aged at least 18 years (or at least 20 years in Japan) and diagnosed with type 2 diabetes, with insufficient glycaemic control (HbA 7·0-10·5% [53·0-91·0 mmol/mol]) despite stable treatment with metformin, thiazolidinediones, or both. We randomly assigned participants (2:2:1:1) using an interactive voice or web response system to 56 weeks of treatment with subcutaneous semaglutide 0·5 mg once weekly plus oral sitagliptin placebo once daily, subcutaneous semaglutide 1·0 mg once weekly plus oral sitagliptin placebo once daily, oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 0·5 mg once weekly, or oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 1·0 mg once weekly. The two oral sitagliptin 100 mg groups (with semaglutide placebo 0·5 mg and 1·0 mg) were pooled for the analyses. The primary endpoint was change in HbA from baseline to week 56, assessed in the modified intention-to-treat population (all randomly assigned participants who received at least one dose of study drug); change in bodyweight from baseline to week 56 was the confirmatory secondary endpoint. Safety endpoints included adverse events and hypoglycaemic episodes. This trial is registered with ClinicalTrials.gov, number NCT01930188.
FINDINGS
Between Dec 2, 2013, and Aug 5, 2015, we randomly assigned 1231 participants; of the 1225 included in the modified intention-to-treat analysis, 409 received semaglutide 0·5 mg, 409 received semaglutide 1·0 mg, and 407 received sitagliptin 100 mg. Mean baseline HbA was 8·1% (SD 0·93); at week 56, HbA was reduced by 1·3% in the semaglutide 0·5 mg group, 1·6% in the semaglutide 1·0 mg group, and 0·5% with sitagliptin (estimated treatment difference vs sitagliptin -0·77% [95% CI -0·92 to -0·62] with semaglutide 0·5 mg and -1·06% [-1·21 to -0·91] with semaglutide 1·0 mg; p<0·0001 for non-inferiority and for superiority, for both semaglutide doses vs sitagliptin). Mean baseline bodyweight was 89·5 kg (SD 20·3); at week 56, bodyweight reduced by 4·3 kg with semaglutide 0·5 mg, 6·1 kg with semaglutide 1·0 mg, and 1·9 kg with sitagliptin (estimated treatment difference vs sitagliptin -2·35 kg [95% CI -3·06 to -1·63] with semaglutide 0·5 mg and -4·20 kg [-4·91 to -3·49] with semaglutide 1·0 mg; p<0·0001 for superiority, for both semaglutide doses vs sitagliptin). The proportion of patients who discontinued treatment because of adverse events was 33 (8%) for semaglutide 0·5 mg, 39 (10%) for semaglutide 1·0 mg, and 12 (3%) for sitagliptin. The most frequently reported adverse events in both semaglutide groups were gastrointestinal in nature: nausea was reported in 73 (18%) who received semaglutide 0·5 mg, 72 (18%) who received semaglutide 1·0 mg, and 30 (7%) who received placebo, and diarrhoea was reported in 54 (13%) who received semaglutide 0·5 mg, 53 (13%) who received semaglutide 1·0 mg, and 29 (7%) who received placebo. Seven (2%) patients in the semaglutide 0·5 mg group, two (<1%) in the semaglutide 1·0 mg group, and five (1%) in the sitagliptin group had blood-glucose confirmed hypoglycaemia. There were six fatal events (two in the semaglutide 0·5 mg group, one in the semaglutide 1·0 mg group, and three in the sitagliptin group); none were considered likely to be related to the trial drugs.
INTERPRETATION
Once-weekly semaglutide was superior to sitagliptin at improving glycaemic control and reducing bodyweight in participants with type 2 diabetes on metformin, thiazolidinediones, or both, and had a similar safety profile to that of other GLP-1 receptor agonists. Semaglutide seems to be an effective add-on treatment option for this patient population.
FUNDING
Novo Nordisk A/S.
Topics: Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Sitagliptin Phosphate; Thiazolidinediones
PubMed: 28385659
DOI: 10.1016/S2213-8587(17)30092-X -
Advances in Therapy Jul 2023This study compared efficacy and safety of triple drug fixed-dose combination (FDC) of dapagliflozin (DAPA) + sitagliptin (SITA) + metformin (MET) extended... (Randomized Controlled Trial)
Randomized Controlled Trial
Fixed-Dose Combination of Dapagliflozin + Sitagliptin + Metformin in Patients with Type 2 Diabetes Poorly Controlled with Metformin: Phase 3, Randomized Comparison with Dual Combinations.
INTRODUCTION
This study compared efficacy and safety of triple drug fixed-dose combination (FDC) of dapagliflozin (DAPA) + sitagliptin (SITA) + metformin (MET) extended release (ER) with SITA + MET sustained release (SR) and DAPA + MET ER in patients with type 2 diabetes poorly controlled with metformin.
METHODS
This phase 3, randomized, open-label, active-controlled study included adult patients with glycated hemoglobin (HbA1c) ≥ 8% (64 mmol/mol) and ≤ 11% (97 mmol/mol), randomized in 1:1:1 ratio to receive either FDC of DAPA + SITA + MET ER (10 mg + 100 mg + 1000 mg) tablets once daily (n = 137) or co-administration of SITA + MET SR (100 mg + 1000 mg) tablets once daily (n = 139) or FDC of DAPA + MET ER (10 mg + 1000 mg) tablets once daily (n = 139). Primary endpoint was mean change in HbA1c from baseline to week 16.
RESULTS
Mean baseline HbA1c was approximately 9% (75 mmol/mol) in each treatment group. At week 16, adjusted mean reduction in HbA1c from baseline was significantly greater with DAPA + SITA + MET ER (- 1.73% [- 19.0 mmol/mol]) compared to SITA + MET SR (- 1.28% [- 14.1 mmol/mol]; difference of - 0.46% [- 5.1 mmol/mol], p < 0.001) and DAPA + MET ER (- 1.33% [- 14.6 mmol/mol]; difference - 0.4% [4.4 mmol/mol], p < 0.001). Similarly, at week 12, reduction in HbA1c from baseline was significantly greater with DAPA + SITA + MET ER compared to SITA + MET SR (p = 0.0006) and DAPA + MET ER (p = 0.0276). At week 16, DAPA + SITA + MET ER showed significant reduction in postprandial blood glucose compared to DAPA + MET ER (p = 0.0394) and significant reduction in fasting blood glucose with DAPA + SITA + MET ER compared to SITA + MET SR (p = 0.0226). The proportion of patients achieving HbA1c < 7.0% (53 mmol/mol) at week 16 was significantly higher with DAPA + SITA + MET ER (38.5%) versus SITA + MET SR (12.8%) (p < 0.001) and DAPA + MET ER (21.3%) (p = 0.0023). All study medications were well tolerated.
CONCLUSION
Triple FDC of DAPA + SITA + MET ER tablets once daily was significantly better in achieving glycemic control versus dual combination once daily in patients with type 2 diabetes poorly controlled with metformin without any significant safety concerns.
TRIAL REGISTRATION
CTRI/2021/11/038176, registered on 22 November 2021.
Topics: Adult; Humans; Diabetes Mellitus, Type 2; Metformin; Sitagliptin Phosphate; Hypoglycemic Agents; Blood Glucose; Glycated Hemoglobin; Treatment Outcome; Drug Therapy, Combination; Double-Blind Method
PubMed: 37258803
DOI: 10.1007/s12325-023-02523-z -
Scientific Reports Jan 2023Sitagliptin has been suggested as a treatment option for older adults with type 2 diabetes (T2D). However, no randomized controlled trial has been performed to evaluate... (Randomized Controlled Trial)
Randomized Controlled Trial
Sitagliptin has been suggested as a treatment option for older adults with type 2 diabetes (T2D). However, no randomized controlled trial has been performed to evaluate the efficacy and safety of sitagliptin treatment in older Japanese patients with T2D. The STREAM study was a multicenter, open-label, randomized controlled trial. T2D outpatients aged 65-80 years with moderately controlled glycemic levels (HbA1c 7.4-10.4%) under lifestyle interventions without or with oral anti-diabetic drugs excluding DPP4 inhibitors or GLP-1 receptor agonists were recruited (n = 176). The participants were randomized into sitagliptin group (n = 88) who received sitagliptin as an initial or an additive anti-diabetic drug and control group (n = 88) who did not. The treatment goal was HbA1c level < 7.4%. Efficacy and safety during 12-month treatment period were investigated. The mean (± SD) ages were 70.6 ± 3.9 and 71.9 ± 4.4 years old in sitagliptin and control groups, respectively. According to a mixed-effects model analysis, average changes from baseline over the treatment period in fasting plasma glucose (FPG), HbA1c, and glycated albumin (GA) were - 27.2 mg/dL, - 0.61%, and - 2.39%, respectively, in sitagliptin group, and 0.50 mg/dL, - 0.29%, and - 0.93%, respectively, in control group. The reductions in FPG, HbA1c, and GA were significantly greater in sitagliptin group (P < 0.0001, P < 0.01, and P < 0.0001, respectively). There were no differences in the incidence of adverse effects, except for cystatin C elevation and platelet count reduction in sitagliptin group. Sitagliptin treatment effectively improved the glycemic profile without any serious adverse effects in older T2D patients.Trial registration number: UMIN000010376.
Topics: Aged; Humans; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Glycated Hemoglobin; Hypoglycemic Agents; Sitagliptin Phosphate; Treatment Outcome
PubMed: 36599895
DOI: 10.1038/s41598-022-27301-9 -
The New England Journal of Medicine Jan 2021
Topics: Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Sitagliptin Phosphate
PubMed: 33406333
DOI: 10.1056/NEJMe2032581 -
Pharmaceutical Development and... Jul 2022Direct compression (DC) is the simplest and most economical way to produce pharmaceutical tablets. Ideally, it consists of only two steps: dry blending of a drug...
Direct compression (DC) is the simplest and most economical way to produce pharmaceutical tablets. Ideally, it consists of only two steps: dry blending of a drug substance(s) with excipients followed by compressing the powder mixture into tablets. In this study, immediate-release film-coated tablets containing either Sitagliptin phosphate or Sitagliptin hydrochloride were developed using DC technique. After establishing the optimum ratio of ductile and brittle excipients, five formulations were compressed into tablets using a rotary press and finally film coated. Both powders and tablets were examined by standard pharmacopoeial methods. It has been shown that the simultaneous use of excipients with different physical properties, i.e. ductile microcrystalline cellulose and brittle anhydrous dibasic calcium phosphate, produces a synergistic effect, allowing preparation of Sitagliptin DC tablets with good mechanical strength (tensile strength over 2 N/mm), rapid disintegration (shorter than 2 min), and fast release of the drug substance (85% of the drug is dissolved within 15 min). It was found that the type of calcium phosphate excipient used had a large effect on the properties of the sitagliptin tablets. All formulations developed showed good chemical stability, even when stored under stress conditions (50 °C/80% RH).
Topics: Calcium Phosphates; Drug Compounding; Excipients; Plastics; Powders; Sitagliptin Phosphate; Tablets; Tensile Strength
PubMed: 35913021
DOI: 10.1080/10837450.2022.2107013 -
Diabetes, Obesity & Metabolism Jun 2023To compare the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 inhibitors on ectopic fat accumulation and tissue-specific... (Randomized Controlled Trial)
Randomized Controlled Trial
Empagliflozin versus sitagliptin for ameliorating intrahepatic lipid content and tissue-specific insulin sensitivity in patients with early-stage type 2 diabetes with non-alcoholic fatty liver disease: A prospective randomized study.
AIM
To compare the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 inhibitors on ectopic fat accumulation and tissue-specific insulin sensitivity.
MATERIALS AND METHODS
This randomized controlled trial enrolled 44 patients with type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). They were randomly assigned to receive either empagliflozin 10 mg/day or sitagliptin 100 mg/day for 12 weeks. The primary endpoint was the change in intrahepatic lipid content (IHL) measured using proton magnetic resonance spectroscopy ( H-MRS). The secondary endpoints included intramuscular and extramuscular lipid content seen in H-MRS, body composition seen through dual-energy X-ray absorptiometry and tissue-specific insulin sensitivity shown through hyperinsulinaemic-euglycaemic clamp using stable isotopic glucose. Liver biopsy samples were pathologically evaluated at baseline.
RESULTS
At baseline, the mean duration of diabetes, HbA1c level and IHL were 3.7 years, 7.2% and 20.9%, respectively. The median NAFLD activity score was 3.0. IHL was significantly more decreased in the empagliflozin group than that in the sitagliptin group (between-group difference was -5.2% ± 1.1% and -1.9% ± 1.2%, respectively, (95% confidence interval); -3.3 (-6.5, -0.1), P = .044). However, there were no significant between-group differences in the change of insulin sensitivity in the liver, muscle or adipose tissues. Interestingly, hepatic insulin sensitivity was significantly increased only in the empagliflozin group and was significantly negatively associated with the change in IHL.
CONCLUSIONS
Empagliflozin significantly improves hepatic steatosis compared with sitagliptin, and this may protect against subsequent hepatic insulin resistance. Early administration of SGLT2 inhibitors is preferable for T2D patients with NAFLD.
Topics: Humans; Diabetes Mellitus, Type 2; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate; Insulin Resistance; Prospective Studies; Sodium-Glucose Transporter 2 Inhibitors; Glucose; Lipids
PubMed: 36749298
DOI: 10.1111/dom.15006