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Gao L, Bian F, Pan T, Jiang H, Feng B, Jiang C, Sun J, Xiao J, Yan P, Ji L. Efficacy and safety of cofrogliptin once every 2 weeks in Chinese patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Obes Metab 2025; 27:280-290. [PMID: 39434431 PMCID: PMC11618291 DOI: 10.1111/dom.16014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 09/30/2024] [Accepted: 10/01/2024] [Indexed: 10/23/2024]
Abstract
AIM We conducted a multicentre, randomized phase 3 trial in China to evaluate the efficacy and safety of cofrogliptin (HSK7653), a novel long-acting dipeptidyl peptidase-4 inhibitor, in patients with drug-naïve type 2 diabetes (T2D). MATERIALS AND METHODS Patients with inadequately controlled T2D were randomly assigned (1:1:1) to cofrogliptin 10 mg, cofrogliptin 25 mg or placebo, taken orally once every 2 weeks for a 24-week double-blind period. Eligible patients then received cofrogliptin 25 mg in a 28-week open-label extension. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. RESULTS In total, 475 patients (median age: 54.0 years) were randomized and received at least one dose of cofrogliptin 10 mg (n = 158), cofrogliptin 25 mg (n = 158) or placebo (n = 159); 401 patients entered the open-label extension. At week 24, the least-squares (LS) mean difference (95% confidence interval [CI]) in HbA1c versus placebo was -0.63% (-0.81, -0.46) with cofrogliptin 10 mg and -0.59% (-0.77, -0.42) with cofrogliptin 25 mg (both p < 0.0001). The LS mean (standard error) change in HbA1c from baseline was maintained at the end of the study in patients given open-label cofrogliptin 25 mg for an additional 28 weeks: cofrogliptin 10 mg: -0.86% (0.07); cofrogliptin 25 mg: -0.74% (0.07); placebo: -0.89% (0.07). Over the entire study, common adverse events were hyperuricaemia, hyperlipidaemia, hypertriglyceridaemia, increased lipase, upper respiratory tract infection and urinary tract infection. Hypoglycaemic events did not significantly differ between groups. CONCLUSIONS Cofrogliptin provided glycaemic control over 52 weeks and was generally well tolerated in patients with T2D. CLINICAL TRIAL REGISTRATION Registered on Clinicaltrials.gov with the registration number NCT04556851 (https://clinicaltrials.gov/study/NCT04556851).
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Affiliation(s)
- Leili Gao
- Department of Endocrinology and MetabolismPeking University People's HospitalBeijingChina
| | - Fang Bian
- Department of EndocrinologyCangzhou People's HospitalCangzhouChina
| | - Tianrong Pan
- Department of EndocrinologyThe Second Affiliated Hospital of Anhui Medical University HefeiHefeiChina
| | - Hongwei Jiang
- Department of EndocrinologyThe First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and TechnologyLuoyangChina
| | - Bo Feng
- Department of EndocrinologyShanghai East Hospital, Tongji University School of MedicineShanghaiChina
| | - Chengxia Jiang
- Department of EndocrinologyThe Second People's Hospital of YibinYibinChina
| | - Jia Sun
- Department of Endocrinology and MetabolismZhujiang Hospital, Southern Medical UniversityGuangzhouChina
| | - Jianzhong Xiao
- Department of EndocrinologyBeijing Tsinghua Changgung HospitalBeijingChina
| | - Pangke Yan
- Haisco Pharmaceutical Group Co. Ltd.ChengduChina
| | - Linong Ji
- Department of Endocrinology and MetabolismPeking University People's HospitalBeijingChina
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He L, Wang J, Ping F, Yang N, Huang J, Li W, Xu L, Zhang H, Li Y. Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials. BMJ 2022; 377:e068882. [PMID: 35764326 PMCID: PMC9237836 DOI: 10.1136/bmj-2021-068882] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To examine the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases. DESIGN Systematic review and pairwise and network meta-analysis. DATA SOURCES PubMed, EMBASE, Web of Science, and CENTRAL from inception until 31 July 2021. ELIGIBILITY CRITERIA Randomised controlled trials of adult patients with type 2 diabetes who received dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors compared with placebo or other antidiabetes drugs. MAIN OUTCOME MEASURES Composite of gallbladder or biliary diseases, cholecystitis, cholelithiasis, and biliary diseases. DATA EXTRACTION AND DATA SYNTHESIS Two reviewers independently extracted the data and assessed the quality of the studies. The quality of the evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development and Evaluations framework (GRADE) approach. The meta-analysis used pooled odds ratios and 95% confidence intervals. RESULTS A total of 82 randomised controlled trials with 104 833 participants were included in the pairwise meta-analysis. Compared with placebo or non-incretin drugs, dipeptidyl peptidase-4 inhibitors were significantly associated with an increased risk of the composite of gallbladder or biliary diseases (odds ratio 1.22 (95%confidence interval 1.04 to 1.43); risk difference 11 (2 to 21) more events per 10 000 person years) and cholecystitis (odds ratio 1.43 (1.14 to 1.79); risk difference 15 (5 to 27) more events per 10 000 person years) but not with the risk of cholelithiasis and biliary diseases. The associations tended to be observed in patients with a longer duration of dipeptidyl peptidase-4 inhibitor treatment. In the network meta-analysis of 184 trials, dipeptidyl peptidase-4 inhibitors increased the risk of the composite of gallbladder or biliary diseases and cholecystitis compared with sodium-glucose cotransporter-2 inhibitors but not compared with glucagon-like peptide-1 receptor agonists. CONCLUSIONS Dipeptidyl peptidase-4 inhibitors increased the risk of cholecystitis in randomised controlled trials, especially with a longer treatment duration, which requires more attention from physicians in clinical practice. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42021271647.
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Affiliation(s)
- Liyun He
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jialu Wang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Na Yang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingyue Huang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Li
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lingling Xu
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huabing Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuxiu Li
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Gnesin F, Thuesen ACB, Kähler LKA, Madsbad S, Hemmingsen B. Metformin monotherapy for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev 2020; 6:CD012906. [PMID: 32501595 PMCID: PMC7386876 DOI: 10.1002/14651858.cd012906.pub2] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified. OBJECTIVES To assess the effects of metformin monotherapy in adults with T2DM. SEARCH METHODS We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017). SELECTION CRITERIA We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM. DATA COLLECTION AND ANALYSIS Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument. MAIN RESULTS We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD). Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions. Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD. Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trials no NFMI occurred and in one trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 25/1456 participants (1.7%) in the thiazolidinedione group. One trial reported no NFS occurred. No trial reported on HRQoL or ESRD. Three trials compared metformin with dipeptidyl peptidase-4 inhibitors (one trial each with saxagliptin, sitagliptin, vildagliptin with altogether 1977 participants). There was no substantial difference between the interventions for all-cause mortality, SAE, CVM, NFMI and NFS (very low-certainty evidence for all outcomes). One trial compared metformin with a glucagon-like peptide-1 analogue (very low-certainty evidence for all reported outcomes). There was no substantial difference between the interventions for all-cause mortality, CVM, NFMI and NFS. One or more SAEs were reported in 16/268 (6.0%) of the participants allocated to metformin compared with 35/539 (6.5%) of the participants allocated to a glucagon-like peptide-1 analogue. HRQoL or ESRD were not reported. One trial compared metformin with meglitinide and two trials compared metformin with no intervention. No deaths or SAEs occurred (very low-certainty evidence) no other patient-important outcomes were reported. No trial compared metformin with placebo or a behaviour changing interventions. Four ongoing trials with 5824 participants are likely to report one or more of our outcomes of interest and are estimated to be completed between 2018 and 2024. Furthermore, 24 trials with 2369 participants are awaiting assessment. AUTHORS' CONCLUSIONS There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes.
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Affiliation(s)
- Filip Gnesin
- Department of Endocrinology, Diabetes and Metabolism, Department 7652, Rigshospitalet, Copenhagen, Denmark
| | - Anne Cathrine Baun Thuesen
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark
| | | | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - Bianca Hemmingsen
- Cochrane Metabolic and Endocrine Disorders Group, Institute of General Practice, Medical Faculty of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
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Zilli RW, Rached CDA, Silva FPD, Baena RC. Long-term efficacy of gliflozins versus gliptins for Type 2 Diabetes after metformin failure: a systematic review and network meta-analysis. REVISTA DA ASSOCIACAO MEDICA BRASILEIRA (1992) 2020; 66:458-465. [PMID: 32578779 DOI: 10.1590/1806-9282.66.4.458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 06/29/2019] [Indexed: 11/21/2022]
Abstract
After metformin failure in treatment for diabetes type 2, there is no trivial option for adjuvant medication. The last two oral class medications, gliflozins and gliptins, have different mechanisms of action but have never been compared in long run studies. The aim of the present meta-analysis is to assess the overall long-term efficacy of these drugs after metformin failure. A systematic review and meta-analysis were performed, including all trials with a duration of over 2 years, comparing gliflozins or gliptins after metformin failure in type 2 diabetes. Data Sources: Pubmed (Medline), Embase, Lilacs, and the Cochrane Library from inception through July 2016 without language restrictions. The longest study period found in the literature was 4 years. We selected 1 article on empagliflozin, 1 on dapagliflozin, and 1 on saxagliptin with missing data. After one year of treatment, over 50% of the patients presented HbA1c > 7%. Efficacy rate after 4 years of empagliflozin (23%) was better than dapagliflozin (5%) and saxagliptin (7%); however, it presented statistically non-significant values for HbA1c (7.4 and 7.3% between gliflozins), and missing data for saxaglifozin. Nonetheless, empagliflozin performed better than glimepiride in the 4-year period (standardized mean difference SMD 0.4, confidence interval CI 95% 0.23 to 0.56). The failure of the secondary treatment using gliflozins occurs in less than one year of treatment (less than 50% of the patients presenting HbA1c > 7 %). Empagliflozin offered better glycemic control compared to sulfonylureas but was similar to dapagliflozin.
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Affiliation(s)
| | - Chennyfer Dobbins Abi Rached
- . Programa de Mestrado em Gestão de Sistemas de Saúde, Universidade Nove de Julho (Uninove), São Paulo, SP, Brasil
| | | | - Renato Corrêa Baena
- . Departamento de Clínica Médica, Universidade de São Paulo, São Paulo, Brasil
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Müller‐Wieland D, Kellerer M, Cypryk K, Skripova D, Rohwedder K, Johnsson E, Garcia‐Sanchez R, Kurlyandskaya R, Sjöström CD, Jacob S, Seufert J, Dronamraju N, Csomós K. Efficacy and safety of dapagliflozin or dapagliflozin plus saxagliptin versus glimepiride as add-on to metformin in patients with type 2 diabetes. Diabetes Obes Metab 2018; 20:2598-2607. [PMID: 29947099 PMCID: PMC6220756 DOI: 10.1111/dom.13437] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 05/30/2018] [Accepted: 06/05/2018] [Indexed: 01/10/2023]
Abstract
OBJECTIVE To compare the efficacy and safety of dapagliflozin and dapagliflozin plus saxagliptin vs glimepiride as add-on to metformin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This 52-week, multicentre, double-blind, active-controlled study (NCT02471404) randomized (1:1:1) patients (n = 939; HbA1c 7.5%-10.5%) on metformin monotherapy (≥1500 mg/day) to add-on dapagliflozin 10 mg, dapagliflozin 10 mg plus saxagliptin 5 mg, or glimepiride 1 to 6 mg (titrated). The primary efficacy end point was change in HbA1c from baseline to Week 52. RESULTS Baseline mean age, diabetes duration and HbA1c were 58.4 years, 7.0 years and 8.3%, respectively. Adjusted mean HbA1c change from baseline was -1.20% with dapagliflozin plus saxagliptin and -0.82% with dapagliflozin, vs -0.99% with glimepiride (mean dose at Week 52, 4.6 mg). Changes in body weight (-3.2 kg and -3.5 kg vs +1.8 kg) and systolic blood pressure (SBP; -6.4 mm Hg and -5.6 mm Hg vs -1.6 mm Hg) were significantly greater with dapagliflozin plus saxagliptin and dapagliflozin than with glimepiride. FPG decreased significantly with dapagliflozin plus saxagliptin compared with glimepiride (-2.1 mmol/L vs -1.5 mmol/L) and was similar with dapagliflozin (-1.6 mmol/L) compared with glimepiride. Confirmed incidence of hypoglycaemia was lower with dapagliflozin regimens than with glimepiride (0 and 1 vs 13 patients) and fewer patients required rescue. Genital infections were more frequent with dapagliflozin; other AE profiles were similar. CONCLUSIONS Dapagliflozin, saxagliptin and metformin improved glycaemic control compared with glimepiride plus metformin; add-on of dapagliflozin alone showed efficacy similar to that of glimepiride. Both dapagliflozin regimens decreased body weight and SBP, with a lower incidence of hypoglycaemia compared with glimepiride.
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Affiliation(s)
- Dirk Müller‐Wieland
- Department of Medicine IUniversity Hospital Rheinisch‐Westfälische Technische Hochschule AachenAachenGermany
| | | | - Katarzyna Cypryk
- Department of Internal Medicine and DiabetologyMedical University of LodzLodzPoland
| | - Dasa Skripova
- Outpatient Clinic of Diabetes and Metabolism, DIAMELTrencinSlovakia
| | | | | | | | | | | | - Stephan Jacob
- Cardio‐Metabolic InstituteVillingen‐SchwenningenGermany
| | - Jochen Seufert
- Division of Endocrinology and Diabetology, Department of Medicine IIMedical Center – University of Freiburg, Faculty of Medicine, University of FreiburgFreiburgGermany
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Thalha AM, Mahadeva S, Boon Tan AT, Mun KS. Kombiglyze (metformin and saxagliptin)-induced hepatotoxicity in a patient with non-alcoholic fatty liver disease. JGH OPEN 2018; 2:242-245. [PMID: 30483596 PMCID: PMC6207028 DOI: 10.1002/jgh3.12083] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 07/04/2018] [Accepted: 07/17/2018] [Indexed: 12/24/2022]
Abstract
A 33‐year‐old man was referred with hyperosmotic symptoms of 4 weeks. Clinical examination showed palpable hepatomegaly and no stigmata of liver disease. Findings were random glucose 16.6 mmol/L, HbA1c 12.4%, triglyceride 6.2 mmol/L, normal LFTs and ultrasound liver: increased echogenicity. Management consisted of dietician referral and commencement of metformin 500 mg bd, diamicron MR 60 mg od, and fenofibrate 145 mg od. He was non‐compliant, complaining of “heaviness of head” after consuming oral diabetic agents, without symptoms of hypoglycemia. Treatment was switched to Kombiglyze XR (saxaglipitin 5 mg + metformin 1000 mg) and empagliflozin 25 mg od. He presented 1 week later with generalised pruritus with ALT 307 IU/L and serum GGT 808 IU/L. Following this, a percutaneous liver biopsy was performed, revealing steatohepatitis and marked intra‐hepatic cholestasis. Kombiglyze XR was withheld, with resolution of LFTs to baseline. Phenotypes of liver injury are categorised according to R value, defined as ratio ALT/ULN:ALP/ULN. R value of ≥5:hepatocellular injury, ≤2:cholestatic injury, 2–5:mixed‐type injury. Here, R value points toward mixed type (R = 3.203). Hepatotoxicity in patients with NASH is difficult to diagnose, based on laboratory parameters. Liver histology was useful in indicating additional changes apart from NASH, causing liver derangement. The Rousal Uclaf Causality Assessment Method is a scoring method to determine the probability of drug induced liver injury. RUCAM score for this case was 6 (probable adverse drug reaction). Hepatotoxicity from saxagliptin not been reported prior. Clinicians need to be more vigilant, particularly in patients with NASH.
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Affiliation(s)
- Abdul Malik Thalha
- Gastroenterology Unit, Department of Internal Medicine University Malaya Medical Centre Kuala Lumpur Malaysia
| | - Sanjiv Mahadeva
- Gastroenterology Unit, Department of Internal Medicine University Malaya Medical Centre Kuala Lumpur Malaysia
| | - Alexander Tong Boon Tan
- Endocrinology Unit, Department of Internal Medicine University Malaya Medical Centre Kuala Lumpur Malaysia
| | - Kein Seong Mun
- Department of Pathology University Malaya Kuala Lumpur Malaysia
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Men P, Li XT, Tang HL, Zhai SD. Efficacy and safety of saxagliptin in patients with type 2 diabetes: A systematic review and meta-analysis. PLoS One 2018; 13:e0197321. [PMID: 29787616 PMCID: PMC5963790 DOI: 10.1371/journal.pone.0197321] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 04/29/2018] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVE To evaluate the comparative efficacy and safety of saxagliptin for type 2 diabetes (T2D). METHODS A systematic search of PubMed, Embase, the Cochrane Library, Web of Science, ClinicalTrials.gov and two Chinese databases for randomized controlled trials (RCTs) comparing saxagliptin with placebo or active comparators was performed up to July 2017. A complementary search was done to cover literature until March 2018. For continuous data, estimates were pooled using inverse variance methodology to calculate weighted mean differences (WMDs). Dichotomous data were presented as Mantel-Haenzel risk ratios (RRs). RESULTS Thirty-nine references of 30 RCTs involving 29,938 patients were analyzed. Compared with placebo, saxagliptin significantly reduced glycated hemoglobin (HbA1c, WMD -0.52%, 95% CI -0.60 to -0.44) and fasting plasma glucose (WMD -13.78 mg/dL, 95% CI -15.31 to -12.25), and increased the proportion of patients achieving HbA1c <7% (RR 1.64, 95% CI 1.53 to 1.75). When combined with submaximal-dose metformin, saxagliptin significantly increased the proportion of patients achieving HbA1c <7% compared with acarbose (RR 2.38, 95% CI 1.17 to 4.83) and uptitrated metformin (RR 1.30, 95% CI 1.04 to 1.63). Saxagliptin was similar to other DPP-4 inhibitors but inferior to liraglutide and dapagliflozin on glycemic control. Saxagliptin significantly decreased the incidences of overall adverse events compared with acarbose (RR 0.71, 95% CI 0.57 to 0.89) and liraglutide (RR 0.41, 95% CI 0.24 to 0.71) when added to metformin. Weight gain and hypoglycemia with saxagliptin was slightly but significantly higher than placebo and lower than sulfonylureas. Saxagliptin did not increase the risk of arthralgia, heart failure, pancreatitis and other adverse events. CONCLUSIONS Generally, saxagliptin has similar efficacy compared with most oral antidiabetic drugs and may be more effective than acarbose, while having a better safety profile than both acarbose and sulfonylureas.
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Affiliation(s)
- Peng Men
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
| | - Xiao-tong Li
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
| | - Hui-lin Tang
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
| | - Suo-di Zhai
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
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Abstract
PURPOSE OF REVIEW Guidelines for a standard second diabetes medication for the treatment of type 2 diabetes (T2DM) have yet to be established. The rapid increase in the number of newer therapies available makes the choice more difficult. Thus, we reviewed clinical trial evidence evaluating newer therapies available for treatment intensification beyond monotherapy. RECENT FINDINGS Head-to-head studies comparing newer therapies versus traditional (i.e., sulfonylurea) approaches consistently find lower incidence of hypoglycemia and weight gain with newer therapies. Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors demonstrate high glycemic efficacy, while merits of dipeptidyl peptidase-4 (DPP-4) inhibitors include their tolerability. Secondary effects (weight loss, cardiovascular outcomes, renal function) are of growing interest with newer therapies. Choices for treatment intensification in T2DM diabetes are numerous. Understanding the comparative evidence of newer treatment choices, as provided in this review, may help guide clinical decision making.
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Effect of Long-term Incretin-Based Therapies on Ischemic Heart Diseases in Patients with Type 2 Diabetes Mellitus: A Network Meta-analysis. Sci Rep 2017; 7:15795. [PMID: 29150631 PMCID: PMC5694013 DOI: 10.1038/s41598-017-16101-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 11/08/2017] [Indexed: 02/07/2023] Open
Abstract
Patients with type 2 diabetes mellitus (T2DM) experience many cardiovascular complications. Several studies have demonstrated the cardioprotective effects of incretin-based therapies; however, there are few studies on the effects of long-term incretin-based therapies on cardiovascular events. Therefore, the present study conducted a systematic review and network meta-analysis to evaluate the effects of long-term incretin-based therapies on ischaemic diseases. We searched PubMed, CENTRAL, and Clinicaltrial.gov to retrieve randomised control trials reported until December 2016 and enrolled only RCTs with more than a 1-year follow-up. The network meta-analysis was performed using R Software with a GeMTC package. A total of 40 trials were included. Dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 agonists were associated with a lower risk of myocardial infarction (MI) than were sulfonylureas (odds ratio [95% credible interval] 0.41 [0.24–0.71] and 0.48 [0.27–0.91], respectively). These results suggested that patients with T2DM receiving long-term incretin-based therapies have a lower risk of MI than do those receiving sulfonylurea-based therapy. These findings highlight the risks of cardiovascular events in patients who receive long-term incretin-based therapies, and may provide evidence for the selection of antidiabetic therapy in the future.
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Du J, Liang L, Fang H, Xu F, Li W, Shen L, Wang X, Xu C, Bian F, Mu Y. Efficacy and safety of saxagliptin compared with acarbose in Chinese patients with type 2 diabetes mellitus uncontrolled on metformin monotherapy: Results of a Phase IV open-label randomized controlled study (the SMART study). Diabetes Obes Metab 2017; 19:1513-1520. [PMID: 28296055 DOI: 10.1111/dom.12942] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Revised: 02/28/2017] [Accepted: 03/08/2017] [Indexed: 01/19/2023]
Abstract
AIM To investigate the efficacy, safety and tolerability of saxagliptin compared with acarbose in Chinese patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy. METHODS SMART was a 24-week, multicentre, randomized, parallel-group, open-label Phase IV study conducted at 35 sites in China (September 24, 2014 to September 29, 2015). The primary outcome was absolute change from baseline in HbA1c at Week 24. Secondary outcomes assessed at Week 24 included the proportion of patients achieving HbA1c < 7.0%, the proportion of patients with gastrointestinal adverse events (GI AEs), and the proportion of patients achieving HbA1c < 7.0% without GI AEs. Safety and tolerability were also assessed in all patients who received ≥1 dose of study medication. RESULTS Four-hundred and eighty-eight patients were randomized (1:1) to saxagliptin or acarbose via a central randomization system (interactive voice/web response system); 241 and 244 patients received saxagliptin and acarbose, respectively, and 238 and 243 of these had ≥1 pre- and ≥1 post-baseline efficacy values recorded. Saxagliptin was non-inferior to acarbose for glycaemic control [Week 24 HbA1c change: -0.82% and -0.78%, respectively; difference (95% confidence interval): -0.04 (-0.22, 0.13)%], with similar proportions of patients in both treatment groups achieving HbA1c < 7.0%. However, fewer GI AEs were reported with saxagliptin compared with acarbose, and a greater number of patients who received saxagliptin achieved HbA1c < 7.0% without GI AEs compared with those receiving acarbose. CONCLUSION Both therapies had similar efficacy profiles. However, saxagliptin was associated with fewer GI AEs, suggesting it might be preferential for clinical practice. CLINICAL TRIAL REGISTRATION NUMBER NCT02243176, clinicaltrials.gov.
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Affiliation(s)
- Jin Du
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China
| | - Li Liang
- Department of Endocrinology, the People's Hospital of Liaoning Province, Shenyang, People's Republic of China
| | - Hui Fang
- Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, People's Republic of China
| | - Fengmei Xu
- Department of Endocrinology, Hebi Coal (Group) Co., Ltd General Hospital, Hebi, People's Republic of China
| | - Wei Li
- Department of Endocrinology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Liya Shen
- Department of Geriatrics, Wuhan 6th Hospital, Wuhan, People's Republic of China
| | - Xueying Wang
- Department of Endocrinology, Jinzhou Central Hospital, Jinzhou, People's Republic of China
| | - Chun Xu
- Department of Endocrinology, Chinese People's Armed Police Force General Hospital, Beijing, People's Republic of China
| | - Fang Bian
- Department of Endocrinology, Cangzhou People's Hospital, Cangzhou, People's Republic of China
| | - Yiming Mu
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China
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Sjöstrand M, Wei C, Cook W, Johnsson K, Pollack PS, Stahre C, Hirshberg B. Assessment of Saxagliptin Efficacy: Meta-Analysis of 14 Phase 2 and 3 Clinical Trials. Diabetes Ther 2017; 8:587-599. [PMID: 28432619 PMCID: PMC5446386 DOI: 10.1007/s13300-017-0261-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION This meta-analysis of data from 14 phase 2 and 3, double-blind, randomized, controlled 12- and 24-week studies (N = 4632) summarizes saxagliptin efficacy in patients with type 2 diabetes (T2D) across treatment regimens. METHODS Patients received saxagliptin 5 mg/d or control as either monotherapy (n = 1196 vs placebo), add-on therapy (n = 2139 vs placebo and n = 514 vs uptitrated sulfonylurea), or initial combination therapy (n = 619 vs control monotherapy). Patients with renal impairment received saxagliptin 2.5 mg/d or placebo (n = 164). RESULTS Mean baseline glycated hemoglobin (A1C) ranged from 8.07% to 9.43% for the saxagliptin and control groups across treatment regimens. A1C reduction from baseline was greater with saxagliptin versus control for all studies combined (mean treatment difference [95% CI]: -0.55% [-0.63%, -0.47%]) and when used as monotherapy (-0.52% [-0.63, -0.40%]), add-on (-0.55% [-0.69%, -0.40%] vs placebo; -0.72% [-0.88%, -0.56%] vs uptitrated sulfonylurea), initial combination therapy (-0.54% [-0.73%, -0.35%] vs control monotherapy), and in patients with renal impairment (-0.42% [-0.75%, -0.09%]). Similar reductions in A1C versus control were noted for patients <65 years (-0.55% [-0.67%, -0.43%]) and ≥65 years (-0.54% [-0.69%, -0.38%]) and for men (-0.54% [-0.69%, -0.40%]) and women (-0.55% [-0.64%, -0.47%]) across treatment regimens. More patients achieved A1C <7% (39% vs 23%) and A1C ≤6.5% (24% vs 14%) with saxagliptin than with placebo or active-control treatment. Saxagliptin versus control was associated with a reduction in glucagon area under the curve (AUC) from baseline and increases in insulin AUC, C-peptide AUC, and the homeostasis model assessment of β-cell function. CONCLUSION Results of this meta-analysis demonstrate the consistency of saxagliptin efficacy in different subgroups of patients with T2D across treatment regimens. FUNDING AstraZeneca.
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Elgendy IY, Mahmoud AN, Barakat AF, Elgendy AY, Saad M, Abuzaid A, Wayangankar SA, Bavry AA. Cardiovascular Safety of Dipeptidyl-Peptidase IV Inhibitors: A Meta-Analysis of Placebo-Controlled Randomized Trials. Am J Cardiovasc Drugs 2017; 17:143-155. [PMID: 27873238 DOI: 10.1007/s40256-016-0208-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Large randomized trials have shown conflicting evidence regarding the cardiovascular safety of dipeptidyl-peptidase 4 (DPP-4) inhibitors. Systematic reviews have been limited by incomplete data and inclusion of observational studies. This study aimed to systematically evaluate the cardiovascular safety of DPP-4 inhibitors in patients with type 2 diabetes. METHODS Electronic databases were searched for randomized trials that compared DPP-4 inhibitors versus placebo and reported cardiovascular outcomes. The main outcome assessed in this analysis was heart failure. Other outcomes included all-cause mortality, cardiovascular mortality, myocardial infarction, and ischemic stroke. Summary odds ratios (ORs) were primarily constructed using Peto's model. RESULTS A total of 90 trials with 66,730 patients were included. Compared with placebo, DPP-4 inhibitors were associated with a non-significant increased risk of heart failure [OR 1.11, 95% confidence interval (CI) 0.99-1.25, P = 0.07] at a mean of 108 weeks. The risk of all-cause mortality (OR 1.03, 95% CI 0.94-1.12, P = 0.53), cardiovascular mortality (OR 1.02, 95% CI 0.92-1.14, P = 0.72), myocardial infarction (OR 0.98, 95% CI 0.88-1.09, P = 0.69), and ischemic stroke (OR 0.99, 95% CI 0.85-1.15, P = 0.92) was similar between both groups. CONCLUSION In patients with type 2 diabetes, the safety profile of DPP-4 inhibitors is similar to placebo. As a class, there is only weak evidence for an increased risk of heart failure.
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Affiliation(s)
- Islam Y Elgendy
- Division of Cardiovascular Medicine, Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA.
| | - Ahmed N Mahmoud
- Division of Cardiovascular Medicine, Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA
| | - Amr F Barakat
- Department of Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Akram Y Elgendy
- Division of Cardiovascular Medicine, Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA
| | - Marwan Saad
- Department of Medicine, University of Arkansas, Little Rock, AR, USA
| | - Ahmed Abuzaid
- Division of Cardiovascular Medicine, Jefferson University Hospital/Christiana Care Health System, Newark, DE, USA
| | - Siddarth A Wayangankar
- Division of Cardiovascular Medicine, Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA
| | - Anthony A Bavry
- Division of Cardiovascular Medicine, Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA
- North Florida/South Georgia Veterans Health System, Gainesville, FL, USA
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13
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Xu S, Zhang X, Tang L, Zhang F, Tong N. Cardiovascular effects of dipeptidyl peptidase-4 inhibitor in diabetic patients with and without established cardiovascular disease: a meta-analysis and systematic review. Postgrad Med 2017; 129:205-215. [PMID: 27813442 DOI: 10.1080/00325481.2017.1255537] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 10/28/2016] [Indexed: 02/05/2023]
Abstract
OBJECTIVES We aim to conduct a meta-analysis, by stratifying diabetic patients with or without clinical cardiovascular diseases (CVD), to explore whether there are different cardiovascular effects of dipeptidyl peptidase-4 inhibitors (DPP-4is) on these two different classes of diabetic patients. METHODS We searchedMedline,Embase, theCochrane Libraryand ClinicalTrials.gov for relevant randomized controlled trials (RCTs). The included trials are divided into CVD (+) trials (subjects with established CVD), and CVD (-) trials (subjects with no CVD). We use all-cause mortality and cardiovascular outcomes as primary endpoints. RESULTS (1) Three CVD (+) trials were included and 36,895 subjects were enrolled with a mean follow-up duration of 127.1 weeks. The pooled results showed that DPP-4is treatment, compared with the placebo, did not significantly affect all-cause mortality (RR, 1.03; 95% CI, 0.95 to 1.11), cardiovascular death (1.01, 0.91 to 1.12), myocardial infarction (0.98, 0.88 to 1.08) or stroke (1.02, 0.88 to 1.18) in diabetic patients with coexisting CVD history; however, it significantly increased the risk of heart failure (1.14, 1.01 to 1.27) in this population. 2) Thirty-five CVD (-) trials were included, and 29,600 patients were enrolled with a mean follow-up duration of 77.8 weeks. The analysis comparing DPP-4is with the placebo control showed that DPP-4is treatment did not significantly affect the risk of all-cause mortality or cardiovascular outcomes in diabetic patients free of CVD history. However, when compared with the active control, the pooling data showed that DPP-4is had a significant reduction on the risk of stroke (0.58, 0.34 to 0.99) but did not significantly affect the risk of all-cause mortality and other cardiovascular outcomes. CONCLUSION DPP-4is may have no cardiovascular protective effects in diabetic patients with coexisting CVD, while there is a lack of definitive evidence supporting the cardiovascular benefits of DPP-4is treatment among diabetic patients free of CVD history.
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Affiliation(s)
- Shishi Xu
- a Department of Endocrinology and Metabolism , West China Hospital of Sichuan University , Chengdu , China
| | - Xinyue Zhang
- a Department of Endocrinology and Metabolism , West China Hospital of Sichuan University , Chengdu , China
| | - Lizhi Tang
- a Department of Endocrinology and Metabolism , West China Hospital of Sichuan University , Chengdu , China
| | - Fang Zhang
- a Department of Endocrinology and Metabolism , West China Hospital of Sichuan University , Chengdu , China
| | - Nanwei Tong
- a Department of Endocrinology and Metabolism , West China Hospital of Sichuan University , Chengdu , China
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14
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Verma S, Goldenberg RM, Bhatt DL, Farkouh ME, Quan A, Teoh H, Connelly KA, Leiter LA, Friedrich JO. Dipeptidyl peptidase-4 inhibitors and the risk of heart failure: a systematic review and meta-analysis. CMAJ Open 2017; 5:E152-E177. [PMID: 28459046 PMCID: PMC5403656 DOI: 10.9778/cmajo.20160058] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Given recent discrepant results from randomized controlled trials (RCTs), we examined the totality of RCT evidence assessing the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and heart failure. METHODS MEDLINE, Embase and ClinicalTrials.gov were searched without language restrictions to August 2016 for RCTs comparing DPP-4 inhibitors to placebo or no therapy for a period of 24 weeks or more. We included all heart failure outcomes when listed either as a serious adverse event or adverse event. Pooled analyses used random-effects. RESULTS We identified 100 RCTs (n = 79 867) - 3 large cardiovascular-safety RCTs (SAVOR-TIMI 53[saxagliptin]/n = 16 492, EXAMINE[alogliptin]/n = 5380, and TECOS[sitagliptin]/n = 14 735), and 97 smaller RCTs with a primary outcome that was usually change in glycated hemoglobin. Virtually all RCTs were high-quality, multicentre, placebo-controlled trials. A total of 96% (1192/1244) of heart failure events were prespecified, blindly adjudicated and required hospital admission. Pooled results suggested a 13% increase in heart failure (relative risk [RR] 1.13, 95% confidence interval [CI] 1.01-1.26, I2 = 0%; 32 RCTs, n = 54 640, 1244 events). When including only the 3 large RCTs, the increase was similar, but not significant (RR 1.14, 95% CI 0.97-1.32; 3 RCTs, n = 36 543, 1169 adjudicated events; number needed to harm 246) owing to heterogeneity (I2 = 42%), which lead to wider CIs, because SAVOR-TIMI 53 showed increased heart failure (RR 1.26, 95% CI 1.06-1.49) and TECOS showed no effect (RR 1.00, 95% CI 0.83-1.19). INTERPRETATION Despite pooled data from 79 867 patients, whether DPP-4 inhibitors increase heart failure overall or exhibit within-class differences remains unresolved. Our results highlight the importance of ongoing trials that are comparing DPP-4 inhibitors to placebo, although no large cardiovascular-safety RCTs are comparing different DPP-4 inhibitors to each other; consequently, these will address the overall but not class-difference question.
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Affiliation(s)
- Subodh Verma
- Divisions of Cardiac Surgery (Verma, Quan, Teoh), Endocrinology and Metabolism (Teoh, Leiter) and Cardiology (Connelly), and Departments of Surgery (Verma), Medicine (Connelly, Leiter, Friedrich) and Critical Care (Friedrich), Li Ka Shing Knowledge Institute of St. Michael's Hospital; Departments of Surgery (Verma), Medicine (Farkouh, Connelly, Leiter, Friedrich), Nutritional Sciences (Leiter) and Interdepartmental Division of Critical Care (Friedrich), University of Toronto, Toronto, Ont.; LMC Diabetes & Endocrinology (Goldenberg), Thornhill, Ont.; Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School (Bhatt), Boston, Mass.; Peter Munk Cardiac Centre (Farkouh), University Health Network, Toronto, Ont
| | - Ronald M Goldenberg
- Divisions of Cardiac Surgery (Verma, Quan, Teoh), Endocrinology and Metabolism (Teoh, Leiter) and Cardiology (Connelly), and Departments of Surgery (Verma), Medicine (Connelly, Leiter, Friedrich) and Critical Care (Friedrich), Li Ka Shing Knowledge Institute of St. Michael's Hospital; Departments of Surgery (Verma), Medicine (Farkouh, Connelly, Leiter, Friedrich), Nutritional Sciences (Leiter) and Interdepartmental Division of Critical Care (Friedrich), University of Toronto, Toronto, Ont.; LMC Diabetes & Endocrinology (Goldenberg), Thornhill, Ont.; Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School (Bhatt), Boston, Mass.; Peter Munk Cardiac Centre (Farkouh), University Health Network, Toronto, Ont
| | - Deepak L Bhatt
- Divisions of Cardiac Surgery (Verma, Quan, Teoh), Endocrinology and Metabolism (Teoh, Leiter) and Cardiology (Connelly), and Departments of Surgery (Verma), Medicine (Connelly, Leiter, Friedrich) and Critical Care (Friedrich), Li Ka Shing Knowledge Institute of St. Michael's Hospital; Departments of Surgery (Verma), Medicine (Farkouh, Connelly, Leiter, Friedrich), Nutritional Sciences (Leiter) and Interdepartmental Division of Critical Care (Friedrich), University of Toronto, Toronto, Ont.; LMC Diabetes & Endocrinology (Goldenberg), Thornhill, Ont.; Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School (Bhatt), Boston, Mass.; Peter Munk Cardiac Centre (Farkouh), University Health Network, Toronto, Ont
| | - Michael E Farkouh
- Divisions of Cardiac Surgery (Verma, Quan, Teoh), Endocrinology and Metabolism (Teoh, Leiter) and Cardiology (Connelly), and Departments of Surgery (Verma), Medicine (Connelly, Leiter, Friedrich) and Critical Care (Friedrich), Li Ka Shing Knowledge Institute of St. Michael's Hospital; Departments of Surgery (Verma), Medicine (Farkouh, Connelly, Leiter, Friedrich), Nutritional Sciences (Leiter) and Interdepartmental Division of Critical Care (Friedrich), University of Toronto, Toronto, Ont.; LMC Diabetes & Endocrinology (Goldenberg), Thornhill, Ont.; Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School (Bhatt), Boston, Mass.; Peter Munk Cardiac Centre (Farkouh), University Health Network, Toronto, Ont
| | - Adrian Quan
- Divisions of Cardiac Surgery (Verma, Quan, Teoh), Endocrinology and Metabolism (Teoh, Leiter) and Cardiology (Connelly), and Departments of Surgery (Verma), Medicine (Connelly, Leiter, Friedrich) and Critical Care (Friedrich), Li Ka Shing Knowledge Institute of St. Michael's Hospital; Departments of Surgery (Verma), Medicine (Farkouh, Connelly, Leiter, Friedrich), Nutritional Sciences (Leiter) and Interdepartmental Division of Critical Care (Friedrich), University of Toronto, Toronto, Ont.; LMC Diabetes & Endocrinology (Goldenberg), Thornhill, Ont.; Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School (Bhatt), Boston, Mass.; Peter Munk Cardiac Centre (Farkouh), University Health Network, Toronto, Ont
| | - Hwee Teoh
- Divisions of Cardiac Surgery (Verma, Quan, Teoh), Endocrinology and Metabolism (Teoh, Leiter) and Cardiology (Connelly), and Departments of Surgery (Verma), Medicine (Connelly, Leiter, Friedrich) and Critical Care (Friedrich), Li Ka Shing Knowledge Institute of St. Michael's Hospital; Departments of Surgery (Verma), Medicine (Farkouh, Connelly, Leiter, Friedrich), Nutritional Sciences (Leiter) and Interdepartmental Division of Critical Care (Friedrich), University of Toronto, Toronto, Ont.; LMC Diabetes & Endocrinology (Goldenberg), Thornhill, Ont.; Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School (Bhatt), Boston, Mass.; Peter Munk Cardiac Centre (Farkouh), University Health Network, Toronto, Ont
| | - Kim A Connelly
- Divisions of Cardiac Surgery (Verma, Quan, Teoh), Endocrinology and Metabolism (Teoh, Leiter) and Cardiology (Connelly), and Departments of Surgery (Verma), Medicine (Connelly, Leiter, Friedrich) and Critical Care (Friedrich), Li Ka Shing Knowledge Institute of St. Michael's Hospital; Departments of Surgery (Verma), Medicine (Farkouh, Connelly, Leiter, Friedrich), Nutritional Sciences (Leiter) and Interdepartmental Division of Critical Care (Friedrich), University of Toronto, Toronto, Ont.; LMC Diabetes & Endocrinology (Goldenberg), Thornhill, Ont.; Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School (Bhatt), Boston, Mass.; Peter Munk Cardiac Centre (Farkouh), University Health Network, Toronto, Ont
| | - Lawrence A Leiter
- Divisions of Cardiac Surgery (Verma, Quan, Teoh), Endocrinology and Metabolism (Teoh, Leiter) and Cardiology (Connelly), and Departments of Surgery (Verma), Medicine (Connelly, Leiter, Friedrich) and Critical Care (Friedrich), Li Ka Shing Knowledge Institute of St. Michael's Hospital; Departments of Surgery (Verma), Medicine (Farkouh, Connelly, Leiter, Friedrich), Nutritional Sciences (Leiter) and Interdepartmental Division of Critical Care (Friedrich), University of Toronto, Toronto, Ont.; LMC Diabetes & Endocrinology (Goldenberg), Thornhill, Ont.; Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School (Bhatt), Boston, Mass.; Peter Munk Cardiac Centre (Farkouh), University Health Network, Toronto, Ont
| | - Jan O Friedrich
- Divisions of Cardiac Surgery (Verma, Quan, Teoh), Endocrinology and Metabolism (Teoh, Leiter) and Cardiology (Connelly), and Departments of Surgery (Verma), Medicine (Connelly, Leiter, Friedrich) and Critical Care (Friedrich), Li Ka Shing Knowledge Institute of St. Michael's Hospital; Departments of Surgery (Verma), Medicine (Farkouh, Connelly, Leiter, Friedrich), Nutritional Sciences (Leiter) and Interdepartmental Division of Critical Care (Friedrich), University of Toronto, Toronto, Ont.; LMC Diabetes & Endocrinology (Goldenberg), Thornhill, Ont.; Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School (Bhatt), Boston, Mass.; Peter Munk Cardiac Centre (Farkouh), University Health Network, Toronto, Ont
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Abstract
There is a relative lack of long-term data for individual glucose-lowering therapies for the treatment of type 2 diabetes mellitus. A systematic search of published literature reporting data of approximately ≥3 years of follow-up from randomized controlled trials and their extensions was conducted. Trials to evaluate the efficacy and/or safety of glucose-lowering drugs currently approved for the treatment of adults with type 2 diabetes were included. Search results included long-term published data for traditional oral glucose-lowering drugs, insulin, α-glucosidase inhibitors, and incretin-based therapies. In general, results indicated that the short-term risk/benefit profile of these therapies is in line with longer-term evaluations. Individual results from these trials are reviewed in this report. These findings support the use of approved drug classes for longer-term treatment of type 2 diabetes.
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Abstract
INTRODUCTION Type 2 diabetes mellitus (T2DM) is a complex disease in which multiple organs and hormones contribute to the pathogenesis of disease. The intestinal hormone, glucagon-like peptide-1 (GLP-1), secreted in response to nutrient ingestion, increases insulin secretion from pancreatic β-cells and reduces glucagon secretion from pancreatic α-cells. GLP-1 is inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme. Saxagliptin is a DPP-4 inhibitor that prevents the degradation of endogenous GLP-1 and prolongs its actions on insulin and glucagon secretion. This article reviews the efficacy and safety of saxagliptin in patients with T2DM. METHODS A PubMed literature search was conducted to identify relevant, peer-reviewed saxagliptin clinical trial articles published between January 2008 and June 2015. Search terms included "saxagliptin" and "DPP-4 inhibitors". RESULTS In clinical trials, saxagliptin significantly improved glycemic control when used as monotherapy or as add-on therapy to other antidiabetes agents and was associated with a low risk of hypoglycemia. In a large cardiovascular (CV) outcomes trial (SAVOR) in patients with T2DM and with established CV disease or multiple CV risk factors, saxagliptin neither increased nor decreased CV risk compared with placebo as assessed by the composite end point of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. Unexpectedly, more patients in the saxagliptin (3.5%) than in the placebo group (2.8%) were hospitalized for heart failure. CONCLUSION Saxagliptin demonstrated statistically significant and clinically meaningful improvements in glycemic control and a low risk of hypoglycemia in patients with T2DM. However, this positive profile needs to be tempered by the observation of an increased risk of hospitalization for heart failure in the SAVOR trial. Results from ongoing CV outcome trials with other DPP-4 inhibitors may provide additional data on how best to manage patients with T2DM who are at risk for heart failure. FUNDING AstraZeneca LP.
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Affiliation(s)
- Rajeev Jain
- Aurora Advanced Healthcare, Milwaukee, WI, USA.
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18
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Abstract
INTRODUCTION Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) occupy a growing place in the armamentarium of drugs used for the management of hyperglycemia in type 2 diabetes, although some safety concerns have been raised in recent years. AREAS COVERED An updated review providing an analysis of available safety data (meta-analyses, randomized controlled trials, observational cohort and case-control studies and pharmacovigilance reports) with five commercialized DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin). A special focus is given to overall safety profile; pancreatic adverse events (AEs) (acute pancreatitis, pancreatic cancer); overall cardiovascular safety (myocardial infarction and stroke); congestive heart failure concern and finally, safety in special populations (elderly, renal impairment). EXPERT OPINION The good tolerance/safety profile of DPP-4 inhibitors has been largely confirmed, including in more fragile populations (elderly, renal impairment) with almost no increased risk of infection or gastrointestinal AEs, no weight gain and a minimal risk of hypoglycemia. Although an increased risk of acute pancreatitis and pancreatic cancer was suspected, the complete set of available data appears reassuring so far. Cardiovascular safety of DPP-4 inhibitors has been proven but an unexpected increased risk of heart failure has been reported which should be confirmed in ongoing trials and better understood. Further postmarketing surveillance is recommended.
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Affiliation(s)
- André J Scheen
- University of Liège, CHU Sart Tilman, Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine , (B35), B-4000 Liege 1 , Belgium +32 4 3667238 ; +32 4 3667068 ; andre.scheen @ chu.ulg.ac.be
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Bryzinski B, Allen E, Cook W, Hirshberg B. Saxagliptin efficacy and safety in patients with type 2 diabetes receiving concomitant statin therapy. J Diabetes Complications 2014; 28:887-93. [PMID: 25168266 DOI: 10.1016/j.jdiacomp.2014.07.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 06/27/2014] [Accepted: 07/10/2014] [Indexed: 01/29/2023]
Abstract
AIMS To examine whether concomitant statin therapy affects glycemic control with saxagliptin 2.5 and 5mg/d in patients with type 2 diabetes mellitus (T2DM). METHODS Efficacy and safety were analyzed post hoc for pooled data from 9 saxagliptin randomized, placebo-controlled trials with a primary 24-week treatment period (4 monotherapy, 2 add-on to metformin, 1 each add-on to a sulfonylurea, thiazolidinedione, or insulin±metformin). Safety was also assessed in an 11-study, 24-week pool and an extended 20-study pool, which included 9 additional 4- to 52-week randomized studies. Comparisons were performed for patient groups defined by baseline statin use. RESULTS Saxagliptin produced greater mean reductions in glycated hemoglobin than placebo, with no interaction between treatment and baseline statin use (P=0.47). In patients receiving saxagliptin 2.5 and 5mg and placebo, the proportion of patients with ≥1 adverse event (AE) was 78.1%, 64.0%, and 63.2%, respectively, in patients with any statin use and 70.6%, 57.9%, and 55.0% in patients with no statin use. Serious AEs, deaths, and symptomatic confirmed hypoglycemia (fingerstick glucose ≤50mg/dL) were few and similar, irrespective of baseline statin use. CONCLUSIONS Saxagliptin improves glycemic control and is generally well tolerated in patients with T2DM, irrespective of concomitant statin therapy.
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Tomkin GH. Treatment of type 2 diabetes, lifestyle, GLP1 agonists and DPP4 inhibitors. World J Diabetes 2014; 5:636-650. [PMID: 25317241 PMCID: PMC4138587 DOI: 10.4239/wjd.v5.i5.636] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2014] [Revised: 07/23/2014] [Accepted: 07/29/2014] [Indexed: 02/05/2023] Open
Abstract
In recent years the treatment focus for type 2 diabetes has shifted to prevention by lifestyle change and to more aggressive reduction of blood sugars during the early stage of treatment. Weight reduction is an important goal for many people with type 2 diabetes. Bariatric surgery is no longer considered a last resort treatment. Glucagon-like peptide-1 agonists given by injection are emerging as a useful treatment since they not only lower blood sugar but are associated with a modest weight reduction. The role of the oral dipeptidyl peptidase 4 inhibitors is emerging as second line treatment ahead of sulphonylureas due to a possible beneficial effect on the beta cell and weight neutrality. Drugs which inhibit glucose re-absorption in the kidney, sodium/glucose co-transport 2 inhibitors, may have a role in the treatment of diabetes. Insulin treatment still remains the cornerstone of treatment in many patients with type 2 diabetes.
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Abstract
Combination therapy for type 2 diabetes using agents with complementary mechanisms of action may improve glycemic control to a greater extent than monotherapy and allow the use of lower doses of antihyperglycemic medications. Dipeptidyl peptidase-4 inhibitors, including saxagliptin, are recommended as add-on therapy to metformin and as part of two- or three-drug combinations in patients not meeting individualized glycemic goals with metformin alone or as part of a dual-therapy regimen. This article reviews the efficacy and safety of saxagliptin as an add-on therapy to metformin, glyburide, a thiazolidinedione, or insulin (with or without metformin) and as a component of triple therapy with metformin and a sulfonylurea.
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Iqbal N, Allen E, Öhman P. Long-term safety and tolerability of saxagliptin add-on therapy in older patients (aged ≥ 65 years) with type 2 diabetes. Clin Interv Aging 2014; 9:1479-87. [PMID: 25214775 PMCID: PMC4158996 DOI: 10.2147/cia.s68193] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Background Treatment decisions for older patients with type 2 diabetes mellitus must balance glycemic control and adverse event risk. The objective of this study was to evaluate the long-term safety and tolerability of saxagliptin 5 mg as add-on therapy to common antihyperglycemic drugs in patients aged ≥65 years and <65 years. Methods Pooled adverse event data from three placebo-controlled trials of 76–206 weeks’ duration in older (≥65 years) and younger (<65 years) patients receiving saxagliptin 5 mg or matching placebo added to metformin, glyburide, or a thiazolidinedione were analyzed. Measurements were calculated from day of first dose to specified event or last dose and included time at risk for adverse events, treatment-related adverse events, serious adverse events, adverse events leading to discontinuation, and events of special interest. Weighted incidence rates (number of events/total time) and incidence rate ratios (saxagliptin/placebo) with 95% confidence intervals were calculated (Mantel-Haenszel test). Results A total of 205 older (mean age 69 years; saxagliptin, n=99; placebo, n=106) and 1,055 younger (mean age 52 years; saxagliptin, n=531; placebo, n=524) patients were assessed. Regardless of age category, the adverse event incidence rates were generally similar between treatments, with confidence intervals for incidence rate ratios bridging 1. Treatment-related adverse events occurred in 36 older patients receiving saxagliptin versus 32 receiving placebo (incidence rate 34.1 versus 27.1 per 100 person-years) and in 150 younger patients in both treatment groups (incidence rate 24.0 versus 27.8 per 100 person-years). With saxagliptin versus placebo, serious adverse events occurred in eight versus 14 older (incidence rate 5.7 versus 9.9 per 100 person-years) and 49 versus 44 younger patients (incidence rate 6.5 versus 6.6 per 100 person-years). There were two deaths (one patient ≥65 years) with saxagliptin and six (none aged ≥65 years) with placebo. Older patients rarely experienced symptomatic confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL; saxagliptin, n=1; placebo, n=2). Conclusion Saxagliptin add-on therapy was generally well tolerated in older patients aged ≥65 years with type 2 diabetes mellitus, with a long-term safety profile similar to that of placebo.
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Saxagliptin: a guide to its use in type 2 diabetes mellitus. DRUGS & THERAPY PERSPECTIVES 2014. [DOI: 10.1007/s40267-013-0101-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Iqbal N, Parker A, Frederich R, Donovan M, Hirshberg B. Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials. Cardiovasc Diabetol 2014; 13:33. [PMID: 24490835 PMCID: PMC3918110 DOI: 10.1186/1475-2840-13-33] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 01/26/2014] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND It is important to establish the cardiovascular (CV) safety profile of novel antidiabetic drugs. METHODS Pooled analyses were performed of 20 randomized controlled studies (N = 9156) of saxagliptin as monotherapy or add-on therapy in patients with type 2 diabetes mellitus (T2DM) as well as a subset of 11 saxagliptin + metformin studies. Adjudicated major adverse CV events (MACE; CV death, myocardial infarction [MI], and stroke) and investigator-reported heart failure were assessed, and incidence rates (IRs; events/100 patient-years) and IR ratios (IRRs; saxagliptin/control) were calculated (Mantel-Haenszel method). RESULTS In pooled datasets, the IR point estimates for MACE and individual components of CV death, MI, and stroke favored saxagliptin, but the 95% CI included 1. IRR (95% CI) for MACE in the 20-study pool was 0.74 (0.45, 1.25). The Cox proportional hazard ratio (95% CI) was 0.75 (0.46, 1.21), suggesting no increased risk of MACE in the 20-study pool. In the 11-study saxagliptin + metformin pool, the IRR for MACE was 0.93 (0.44, 1.99). In the 20-study pool, the IRR for heart failure was 0.55 (0.27, 1.12). CONCLUSIONS Analysis of pooled data from 20 clinical trials in patients with T2DM suggests that saxagliptin is not associated with an increased CV risk.
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Affiliation(s)
- Nayyar Iqbal
- Bristol-Myers Squibb, Route 206 & Providence Line Rd, Princeton, NJ 08543, USA
| | - Artist Parker
- AstraZeneca, 1800 Concord Pike, Wilmington, DE 19850, USA
| | - Robert Frederich
- Bristol-Myers Squibb, Route 206 & Providence Line Rd, Princeton, NJ 08543, USA
| | - Mark Donovan
- Bristol-Myers Squibb, Route 206 & Providence Line Rd, Princeton, NJ 08543, USA
| | - Boaz Hirshberg
- AstraZeneca, 1800 Concord Pike, Wilmington, DE 19850, USA
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Alanazi AS. Systematic review and meta-analysis of efficacy and safety of combinational therapy with metformin and dipeptidyl peptidase-4 inhibitors. Saudi Pharm J 2014; 23:603-13. [PMID: 26702254 PMCID: PMC4669429 DOI: 10.1016/j.jsps.2013.12.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 12/14/2013] [Indexed: 01/28/2023] Open
Abstract
Combinational therapies are often required in the management of type 2 diabetes mellitus (T2DM). Among the important candidates, dipeptidyl peptidase-4 inhibitors (DPPIs) and metformin combination (DPPI-MET) have shown promising endeavors. In order to examine the efficacy and safety of such a combination therapy in T2DM patients finding inadequate control with metformin, this systematic review and meta-analysis has been conducted. Literature search was made in multiple electronic databases. Inclusion criteria included; RCTs examining the efficacy and safety of DPPI-MET against placebo-MET or MET-only groups of T2DM patients by observing changes in disease endpoints including HbA1c and FPG, and the length of trial be at least 12 weeks. Mean differences based meta-analyses were performed and heterogeneity assessment was carried out. Nineteen studies were selected and included in the meta-analyses. DPPI-MET significantly improved all disease endpoints and the difference could be noticed up to 2 years in the majority of outcome measures. In comparison with PBO-MET, the DPPI-MET combinational therapy resulted in the percent HbA1c changes from baseline with a mean difference [95% CI] of −0.77 [−0.86, −0.69] in 3-month (P < 0.00001), −0.67 [−0.76, −0.59] in 6-month (P < 0.00001), −0.67 [−0.88, −0.47] in 1-year (P < 0.00001) and −0.36 [−0.53, −0.20] in 2-year trials (P < 0.0003). Reduction in body weight and safety profile in the treated and control groups were not different. A combinational therapy with DPPI and metformin significantly improves diabetes clinical indicators and this effect has been observed for up to 2 years herein. Safety and tolerability of DPPI-MET combination have been found well-manageable with a very similar adverse event profile in both treated and control groups.
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Affiliation(s)
- Abdulrahman S Alanazi
- Department of Clinical Pharmacy, Unaizah College of Pharmacy, Qassim University, P.O. Box 1627, Hail 81441, Saudi Arabia
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Rafieian-Kopaie M. Metformin and renal injury protection. J Renal Inj Prev 2013; 2:91-2. [PMID: 25340138 PMCID: PMC4206022 DOI: 10.12861/jrip.2013.29] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 06/20/2013] [Indexed: 01/19/2023] Open
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[Computerized tomography and densitometry using computerized tomography in abdominal injuries]. Zentralbl Chir 1981; 56:11-24. [PMID: 7282159 DOI: 10.1007/s40262-016-0421-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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