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The Cochrane Database of Systematic... Nov 2017Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with increased risk of cardiovascular disease and diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation.
OBJECTIVES
To evaluate the effectiveness and safety of insulin-sensitising drugs in improving reproductive and metabolic outcomes for women with PCOS undergoing ovulation induction.
SEARCH METHODS
We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies.
SELECTION CRITERIA
We included randomised controlled trials of insulin-sensitising drugs compared with placebo, no treatment, or an ovulation-induction agent for women with oligo and anovulatory PCOS.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes, menstrual frequency and metabolic effects. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I statistic and reported quality of the evidence for primary outcomes using GRADE methodology.
MAIN RESULTS
We assessed the interventions metformin, clomiphene citrate, metformin plus clomiphene citrate, D-chiro-inositol, rosiglitazone and pioglitazone. We compared these with each other, placebo or no treatment. We included 48 studies (4451 women), 42 of which investigated metformin (4024 women). Evidence quality ranged from very low to moderate. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatmentThe evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51, 4 studies, 435 women, I = 0%, low-quality evidence). The metformin group experienced more gastrointestinal side effects (OR 4.76, 95% CI 3.06 to 7.41, 7 studies, 670 women, I = 61%, moderate-quality evidence) but had higher rates of clinical pregnancy (OR 1.93, 95% CI 1.42 to 2.64, 9 studies, 1027 women, I = 43%, moderate-quality evidence), ovulation (OR 2.55, 95% CI 1.81 to 3.59, 14 studies, 701 women, I = 58%, moderate-quality evidence) and menstrual frequency (OR 1.72, 95% CI 1.14 to 2.61, 7 studies, 427 women, I = 54%, low-quality evidence). There was no clear evidence of a difference in miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35, 4 studies, 748 women, I = 0%, low-quality evidence). Metformin plus clomiphene citrate versus clomiphene citrate alone There was no conclusive evidence of a difference between the groups in live birth rates (OR 1.21, 95% CI 0.92 to 1.59, 9 studies, 1079 women, I = 20%, low-quality evidence), but gastrointestinal side effects were more common with combined therapy (OR 3.97, 95% CI 2.59 to 6.08, 3 studies, 591 women, I = 47%, moderate-quality evidence). However, the combined therapy group had higher rates of clinical pregnancy (OR 1.59, 95% CI 1.27 to 1.99, 16 studies, 1529 women, I = 33%, moderate-quality evidence) and ovulation (OR 1.57, 95% CI 1.28 to 1.92, 21 studies, 1624 women, I = 64%, moderate-quality evidence). There was a statistically significant difference in miscarriage rate per woman, with higher rates in the combined therapy group (OR 1.59, 95% CI 1.03 to 2.46, 9 studies, 1096 women, I = 0%, low-quality evidence) but this is of uncertain clinical significance due to low-quality evidence, and no clear difference between groups when we analysed miscarriage per pregnancy (OR 1.30, 95% CI 0.80 to 2.12, 8 studies; 400 pregnancies, I = 0%, low-quality evidence). Metformin versus clomiphene citrateWhen all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01, 5 studies, 741 women, I = 86%, very low-quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52, 2 studies, 500 women, I = 0%, very low-quality evidence), while data from the non-obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94, 3 studies, 241 women, I = 78%, very low-quality evidence). Similarly, among obese women taking metformin there were lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55, 2 studies, 500 women, I = 0%, very low-quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43 2 studies, 500 women, I = 0%, low-quality evidence) while among non-obese women, the metformin group had more pregnancies (OR 1.56, 95% CI 1.05 to 2.33, 5 studies, 490 women, I = 41%, very low-quality evidence) and no clear difference in ovulation rates (OR 0.81, 95% CI 0.51 to 1.28, 4 studies, 312 women, low-quality evidence, I=0%). There was no clear evidence of a difference in miscarriage rates (overall: OR 0.92, 95% CI 0.50 to 1.67, 5 studies, 741 women, I = 52%, very low-quality evidence). D-chiro-inositol (2 studies), rosiglitazone (1 study) or pioglitazone (1 study) versus placebo or no treatmentWe were unable to draw conclusions regarding other insulin-sensitising drugs as no studies reported primary outcomes.
AUTHORS' CONCLUSIONS
Our updated review suggests that metformin alone may be beneficial over placebo for live birth, although the evidence quality was low. When metformin was compared with clomiphene citrate, data for live birth were inconclusive, and our findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. An improvement in clinical pregnancy and ovulation suggests that clomiphene citrate remains preferable to metformin for ovulation induction in obese women with PCOS.An improved clinical pregnancy and ovulation rate with metformin and clomiphene citrate versus clomiphene citrate alone suggests that combined therapy may be useful although we do not know whether this translates into increased live births. Women taking metformin alone or with combined therapy should be advised that there is no evidence of increased miscarriages, but gastrointestinal side effects are more likely.
Topics: Abortion, Spontaneous; Anovulation; Clomiphene; Female; Humans; Hypoglycemic Agents; Infertility, Female; Inositol; Insulin Resistance; Live Birth; Metformin; Ovulation Induction; Pioglitazone; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Randomized Controlled Trials as Topic; Rosiglitazone; Thiazolidinediones
PubMed: 29183107
DOI: 10.1002/14651858.CD003053.pub6 -
Cureus Aug 2023Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent worldwide, especially in people with obesity, dyslipidemia, type 2 diabetes mellitus (T2DM),... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent worldwide, especially in people with obesity, dyslipidemia, type 2 diabetes mellitus (T2DM), and metabolic syndrome. Weight loss and dietary modifications are established first-line treatments for NAFLD. Currently, there is no approved drug for NAFLD; however, pioglitazone and vitamin E have shown some beneficial effects. This systematic review covers the comparative efficacies of vitamin E, pioglitazone, and vitamin E plus pioglitazone. As of December 2022, the sources for prior literature review included PubMed, PubMed Central, and Medline. We included studies assessing the efficacy of pioglitazone, vitamin E, and vitamin E plus pioglitazone in improving liver histology, liver markers, and lipid profile when compared to other interventions in patients with NAFLD/non-alcoholic steatohepatitis (NASH). Review materials include randomized control trials (RCTs), traditional reviews, systematic reviews, meta-analyses, and observational studies on human participants published within the last five years in the English language. Studies on animals, pediatric populations, and with insufficient data were excluded from the review. Two authors scanned and filtered articles independently and later performed quality checks. A third reviewer resolved any conflicts. The risk of bias was assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines for systematic reviews, the Cochrane Risk of Bias Tool for RCTs, and the Scale for the Assessment of Narrative Review Articles for Traditional Reviews. A total of 21 articles were shortlisted. The results showed that pioglitazone and vitamin E are effective in reducing steatosis, inflammation, and ballooning, reducing liver markers, but there seem to be conflicting data on fibrosis resolution. Pioglitazone decreases triglycerides and increases high-density lipoproteins. One study has suggested that pioglitazone has superior efficacy to vitamin E in fibrosis reduction and vitamin E plus pioglitazone has superior efficacy than pioglitazone alone for NASH resolution. However, these conclusions require further validation through extensive analysis and additional research. In conclusion, diabetic patients with NAFLD can be given pioglitazone, and non-diabetic patients with NAFLD can be given vitamin E.
PubMed: 37719477
DOI: 10.7759/cureus.43635 -
Stroke Feb 2017Pioglitazone reduced major vascular events after ischemic stroke in a recent randomized controlled trial. The purpose of this study was to conduct a meta-analysis of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND PURPOSE
Pioglitazone reduced major vascular events after ischemic stroke in a recent randomized controlled trial. The purpose of this study was to conduct a meta-analysis of randomized controlled trials to evaluate the effect of pioglitazone therapy in reducing the risk of recurrent stroke in stroke patients.
METHODS
Pubmed, EMBASE, Medline, and Cochrane Central Register of Controlled Trials from 1966 to March 2016 were searched to identify relevant studies. We included randomized controlled trials that included comparison of pioglitazone versus control and trials in which quantitative estimates of the hazard ratio and 95% confidence interval for recurrent stroke associated with pioglitazone therapy among stroke patients were reported. Hazard ratios with 95% confidence intervals were used as a measure of the association between use of pioglitazone and risks of recurrent stroke (ischemic and hemorrhagic) and major vascular events (nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death) after pooling data across trials. Between-study heterogeneity was assessed using the I statistic.
RESULTS
Three randomized controlled trials with 4980 participants were identified. Use of pioglitazone in stroke patients with insulin resistance, prediabetes, and diabetes mellitus was associated with lower risk of recurrent stroke (hazard ratio 0.68; 95% confidence interval, 0.50-0.92; P=0.01) and future major vascular events (hazard ratio 0.75; 95% confidence interval, 0.64-0.87; P=0.0001). There was no heterogeneity across trials. There was no evidence of an effect on all-cause mortality and heart failure.
CONCLUSIONS
Pioglitazone reduces recurrent stroke and major vascular events in ischemic stroke patients with insulin resistance, prediabetes, and diabetes mellitus.
Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Resistance; Pioglitazone; Prediabetic State; Randomized Controlled Trials as Topic; Secondary Prevention; Stroke; Thiazolidinediones
PubMed: 27999139
DOI: 10.1161/STROKEAHA.116.013977 -
Diabetes & Metabolic Syndrome Apr 2023Lobeglitazone (LGZ), a newly researched thiazolidinedione (TZD) thought to have lesser side effects compared with pioglitazone (PGZ), has been recently approved for the... (Review)
Review
BACKGROUND AND AIMS
Lobeglitazone (LGZ), a newly researched thiazolidinedione (TZD) thought to have lesser side effects compared with pioglitazone (PGZ), has been recently approved for the treatment of type 2 diabetes (T2D) in India. We aim to conduct an updated systematic review of LGZ to critically appraise its efficacy and safety in the context of PGZ.
METHODS
A systematic literature search was carried out in the electronic database of PubMed until Jan 15, 2023, using specific keywords and MeSH terms. All studies which evaluated LGZ in people with T2D were retrieved and data were synthesized with regard to its efficacy and safety. A comparative critical appraisal was additionally made in the context of PGZ in T2D.
RESULTS
Four randomized controlled, one prospective observational, and two real-world studies have evaluated the safety and efficacy of LGZ against placebo or active comparators either as monotherapy or in combination therapy. HbA1c reduction with LGZ 0.5 mg was superior to the placebo but similar to PGZ 15 mg and sitagliptin (SITA) 100 mg. Weight gain with LGZ was significantly higher compared to placebo and SITA but similar to PGZ. Edema was more frequently observed with LGZ compared to placebo, PGZ, and SITA.
CONCLUSION
No substantial evidence is yet available that suggests LGZ could be a better alternative to PGZ both in the context of glycemic or extra-glycemic effects. At least in the short-term, adverse events of LGZ are indifferent from PGZ. More data is additionally needed to claim any advantage of LGZ over PGZ.
Topics: Humans; Pioglitazone; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Glycated Hemoglobin; Thiazolidinediones; Sitagliptin Phosphate; Observational Studies as Topic
PubMed: 36966544
DOI: 10.1016/j.dsx.2023.102747 -
Journal of Clinical and Experimental... 2022Due to lack of targeted treatment options and inconsistent utilization of histologic endpoints among clinical trials, identifying efficacious pharmacotherapies for...
BACKGROUND
Due to lack of targeted treatment options and inconsistent utilization of histologic endpoints among clinical trials, identifying efficacious pharmacotherapies for nonalcoholic steatohepatitis [NASH] has proven challenging.
METHODS
A thorough systematic review and frequentist random-effects network meta-analysis was performed across all randomized clinical trials reporting a pharmacotherapeutic intervention on biopsy-proven NASH. Primary outcomes were based on the most current, up-to-date recommended histologic endpoints.
RESULTS
A total of 40 RCTs were identified including 6593 total patients. The most effective and statistically significant treatment interventions for minimum two-point improvement in NAFLD Activity Score were aldafermin 1 mg [RR 7.69, 95% CI 2.00; 29.57], vitamin E 800 IU in combination with pioglitazone 45 mg [RR 3.38, 95% CI 1.88; 6.07], pioglitazone 45 mg [RR 3.29, 95% CI 1.74; 6.22], vitamin E 800 IU [RR 2.06, 95% CI 1.33; 3.18], resmetirom 80 mg [RR 1.74, 95% CI 1.03; 2.94], obeticholic acid 25 mg [RR 1.63, 95% CI 1.32; 2.01], and obeticholic acid 10 mg [RR 1.31, 95% CI 1.02; 1.67]). The most robust pharmacotherapies for NASH resolution without worsening fibrosis were found to be aldafermin 1 mg [RR 5.77, 95% CI 1.48; 22.51], pioglitazone 45 mg [RR 2.65, 95% CI 1.43; 4.91], vitamin E 800 IU in combination with pioglitazone 45 mg [RR 2.64, 95% CI 1.36; 5.12], pioglitazone 30 mg [RR 2.46, 95% CI 1.56; 3.88], vitamin E 800 IU [RR 1.90, 95% CI 1.20; 3.00], and obeticholic acid 25 mg [RR 1.52, 95% CI 1.03; 2.23]). Obeticholic acid had a significant improvement on fibrosis. Multiple interventions were found to improve individual histologic scores across secondary outcome analyses and are detailed below.
CONCLUSION
This novel systematic review and network meta-analysis represents the most comprehensive investigation to date regarding the pharmacotherapeutic options for biopsy-proven NASH using current recommended histologic endpoints.
PubMed: 35814516
DOI: 10.1016/j.jceh.2022.01.011 -
Endocrine, Metabolic & Immune Disorders... 2018Thiazolidinediones are a group of synthetic medications used in type 2 diabetes treatment. Among available thiazolidinediones, pioglitazone is gaining increased... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Thiazolidinediones are a group of synthetic medications used in type 2 diabetes treatment. Among available thiazolidinediones, pioglitazone is gaining increased attention due to its lower cardiovascular risk in type 2 diabetes mellitus sufferers and seems a promising future therapy. Accumulating evidence suggests that diabetic patients may exert bone fractures due to such treatments. Simultaneously, the female population is thought to be at greater risk. Still, the safety outcomes of pioglitazone treatment especially in terms of fractures are questionable and need to be clarified.
METHODS
We searched MEDLINE, Scopus, PsyInfo, eLIBRARY.ru electronic databases and clinical trial registries for studies reporting an association between pioglitazone and bone fractures in type 2 diabetes mellitus patients published before Feb 15, 2016. Among 1536 sources that were initially identified, six studies including 3172 patients proved relevant for further analysis.
RESULT
Pooled analysis of the included studies demonstrated that after treatment with pioglitazone patients with type 2 diabetes mellitus had no significant increase in fracture risk [odds ratio (OR): 1.18, 95% confidence interval (CI): 0.82 to 1.71, p=0.38] compared to other antidiabetic drugs or placebo. Additionally, no association was found between the risk of fractures and pioglitazone therapy duration. The gender of the patients involved was not relevant to the risk of fractures, too.
CONCLUSION
Pioglitazone treatment in diabetic patients does not increase the incidence of bone fractures. Moreover, there is no significant association between patients' fractures, their gender and the period of exposure to pioglitazone. Additional longitudinal studies need to be undertaken to obtain more detailed information on bone fragility and pioglitazone therapy.
Topics: Diabetes Mellitus, Type 2; Female; Fractures, Bone; Humans; Hypoglycemic Agents; Incidence; Male; Pioglitazone; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 29683100
DOI: 10.2174/1871530318666180423121833 -
Cancer Medicine Apr 2018Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the... (Meta-Analysis)
Meta-Analysis
Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the use of pioglitazone and identify modifiers that affect the results. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to 25 August 2016 for randomized controlled trials (RCTs) and observational studies that evaluated the association between pioglitazone and bladder cancer risk. Conventional and cumulative meta-analyses were used to calculate the odds ratio (OR) with 95% confidence interval (CI). A restricted spline regression analysis was used to examine the dose-response relationship with a generalized least-squares trend test. We included two RCTs involving 9114 patients and 20 observational studies (n = 4,846,088 individuals). An increased risk of bladder cancer in patients treated with pioglitazone versus placebo was noted from RCTs (OR, 1.84; 95%CI, 0.99 to 3.42). In observational studies, the increased risk of bladder cancer was slight but significant among ever-users of pioglitazone versus never-users (OR, 1.13; 95%CI, 1.03 to 1.25), which appeared to be both time- (P = 0.003) and dose-dependent (P = 0.05). In addition, we observed the association differed by region of studies (Europe, United States, or Asia) or source of funding (sponsored by industry or not). Current evidence suggests that pioglitazone may increase the risk of bladder cancer, possibly in a dose- and time-dependent manner. Patients with long-term and high-dose exposure to pioglitazone should be monitored regularly for signs of bladder cancer.
Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Odds Ratio; Pioglitazone; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Urinary Bladder Neoplasms
PubMed: 29476615
DOI: 10.1002/cam4.1354 -
Cancer Management and Research 2018Pioglitazone has been reported to increase the risk of bladder cancer but the conclusions of published clinical studies are confusing. We conducted a systematic review... (Review)
Review
Pioglitazone has been reported to increase the risk of bladder cancer but the conclusions of published clinical studies are confusing. We conducted a systematic review and meta-analysis of all eligible randomized controlled trial (RCT) studies and observational studies, in order to identify a more precise relationship between pioglitazone and risk of bladder cancer. We searched for publications up to January 24, 2018, in PubMed, EMBASE, Scopus, Web of Science, Cochrane register, and Chinese National Knowledge Infrastructure databases, and the references of the retrieved articles and relevant reviews were also checked. Relative risk and 95% confidence interval (CI) were used to assess this correlation. A dose-related meta-analysis was performed as well. Data on RCT studies showed a null association between pioglitazone and bladder cancer. The pooled RR estimates of the 12 included studies illustrated that pioglitazone is associated with a 14% increased risk of bladder cancer (95% CI 1.03-1.26). No evidence of publication bias was detected. In the dose effect analysis, patients who used a higher dose of pioglitazone had an increased risk of bladder cancer. In conclusion, this meta-analysis indicated that pioglitazone is associated with an increased risk of bladder cancer. Further research should be conducted to confirm our findings and reveal the potential biological mechanisms.
PubMed: 29970962
DOI: 10.2147/CMAR.S164840 -
Cardiovascular Diabetology Oct 2017Pioglitazone targets multiple pathogenic pathways involved in the development of cardiovascular diseases (CVD). The aim of this systematic review and meta-analysis is to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
Pioglitazone targets multiple pathogenic pathways involved in the development of cardiovascular diseases (CVD). The aim of this systematic review and meta-analysis is to assess the effects of pioglitazone treatment on the secondary prevention of CVD.
METHODS
Randomized-controlled trials of pioglitazone in patients with CVD were identified through PubMed, Embase, Cochrane and CINAHL, in a search up to May 2016. Studies were included if pioglitazone was compared with any control (usual care, placebo or active comparator) and if patients were previously diagnosed with CVD. The outcomes of interest included major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, all-cause mortality and heart failure (HF). All outcomes were compared by pooled risk ratios (RR) with a 95% confidence interval (CI). Pooled estimates were calculated using a random-effects model.
RESULTS
Ten studies reported the effects of pioglitazone on any of the outcomes of interest. Pioglitazone reduced recurrent MACE (RR 0.74, 95% 0.60-0.92; I = 35), MI (RR 0.77, 95% CI 0.64-0.93; I = 0%), or stroke (RR 0.81, 95% CI 0.68-0.96; I = 0%). Pioglitazone did not reduce all-cause mortality (RR 0.94, 95% CI 0.81-1.08; I = 0%), whereas pioglitazone treatment was associated with an increased risk of HF (RR 1.33, 95% CI 1.14-1.54).
CONCLUSIONS
Pioglitazone lowers the risk of recurrent MACE, stroke, or MI in patients with clinical manifest vascular disease. Pioglitazone does not lower the risk for all-cause mortality, and increases the risk for the development of HF.
Topics: Cardiovascular Diseases; Humans; Hypoglycemic Agents; Pioglitazone; Randomized Controlled Trials as Topic; Secondary Prevention; Thiazolidinediones
PubMed: 29037211
DOI: 10.1186/s12933-017-0617-4 -
Frontiers in Medicine 2022To evaluate the effects of vitamin E, pioglitazone, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists in patients...
Efficacy of Off-Label Therapy for Non-alcoholic Fatty Liver Disease in Improving Non-invasive and Invasive Biomarkers: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.
OBJECTIVE
To evaluate the effects of vitamin E, pioglitazone, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with non-alcoholic fatty liver disease (NAFLD).
DESIGN
A network meta-analysis.
DATA SOURCES
PubMed, Embase, Cochrane Library, and Web of Science databases from their inception until September 1, 2021.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Randomized controlled trials (RCTs) comparing the effects of four different drugs in patients with NAFLD were included. All superiority, non-inferiority, phase II and III, non-blinded, single-blinded, and double-blinded trials were included. Interventions of interest included vitamin E (α-tocopherol and δ-tocotrienol), pioglitazone, three kinds of GLP-1 receptor agonists (liraglutide, semaglutide, and dulaglutide), four SGLT2 inhibitors (dapagliflozin, empagliflozin, ipragliflozin, and tofogliflozin), and comparisons of these different drugs, and placebos.
MAIN OUTCOME MEASURES
The outcome measures included changes in non-invasive tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), controlled attenuation parameter (CAP), enhanced liver fibrosis (ELF) score, liver fat content (LFC), and keratin-18 (K-18)] and invasive tests [fibrosis score and resolution of non-alcoholic steatohepatitis (NASH)].
RESULTS
Twenty-seven trials including 3,416 patients were eligible for inclusion in the study. Results refer to vitamin E, pioglitazone, GLP-1 receptor agonists, and SGLT2 inhibitors. First, placebos were used as a reference. δ-Tocotrienol was superior to placebo in decreasing the GGT level. Semaglutide, ipragliflozin, and pioglitazone induced a significantly higher decrease in the ALT level than a placebo. Semaglutide, pioglitazone, and dapagliflozin were superior to placebo in decreasing the AST level. Tofogliflozin and pioglitazone induced a significantly higher decrease in the K-18 level than a placebo. Liraglutide was superior to placebo in decreasing CAP. Liraglutide, pioglitazone, and vitamin E induced a significantly higher increase in resolution of NASH than a placebo. As for pairwise comparisons, semaglutide and pioglitazone were superior to liraglutide in decreasing the ALT level. Semaglutide induced a significantly higher decrease in the ALT level than dulaglutide. Semaglutide was obviously superior to empagliflozin, liraglutide, dulaglutide, and tofogliflozin in decreasing the AST level. Pioglitazone induced a significantly higher decrease in the GGT level than ipragliflozin. δ-Tocotrienol was superior to liraglutide in decreasing the GGT level. Tofogliflozin and pioglitazone induced a significantly higher decrease in the K-18 level than dulaglutide. Pioglitazone was superior to vitamin E in increasing the resolution of NASH. Furthermore, liraglutide treatment had the highest SUCRA ranking in decreasing CAP and ELF scores and increasing the resolution of NASH. Pioglitazone treatment had the highest SUCRA ranking in decreasing LFC and fibrosis scores. Tofogliflozin treatment had the highest SUCRA ranking in decreasing K-18, while dapagliflozin treatment had the highest SUCRA ranking in decreasing the GGT level. Semaglutide treatment had the highest SUCRA ranking in decreasing the levels of ALT and AST.
CONCLUSION
The network meta-analysis provided evidence for the efficacy of vitamin E, pioglitazone, SGLT2 inhibitors, and GLP-1 receptor agonists in treating patients with NAFLD. To find the best guide-level drugs, it is necessary to include more RCTs with these off-label drugs, so that patients and clinicians can make optimal decisions together.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero, identifier: CRD42021283129.
PubMed: 35280867
DOI: 10.3389/fmed.2022.793203