-
The Cochrane Database of Systematic... Oct 2019Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists are insulin-sensitising drugs used for the treatment of insulin resistance. In addition to lowering... (Review)
Review
BACKGROUND
Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists are insulin-sensitising drugs used for the treatment of insulin resistance. In addition to lowering glucose in diabetes, these drugs may also protect against hyperlipidaemia and arteriosclerosis, which are risk factors for stroke. This is an update of a review first published in January 2014 and subsequently updated in December 2017.
OBJECTIVES
To assess the efficacy and safety of PPAR-γ agonists in the secondary prevention of stroke and related vascular events for people with stroke or transient ischaemic attack (TIA).
SEARCH METHODS
We searched the Cochrane Stroke Group Trials Register (30 July 2019), the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 7), MEDLINE (1949 to 30 July 2019), Embase (1980 to 30 July 2019), CINAHL (1982 to 30 July 2019), AMED (1985 to 30 July 2019), and 11 Chinese databases (30 July 2019). In an effort to identify further published, unpublished, and ongoing trials, we searched ongoing trials registers, reference lists, and relevant conference proceedings, and contacted authors and pharmaceutical companies. We did not impose any language restrictions.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) evaluating PPAR-γ agonists versus placebo for the secondary prevention of stroke and related vascular events in people with stroke or TIA, with the outcomes of recurrent stroke, vascular events, and adverse events.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy, and assessed methodological quality and risk of bias. We evaluated the quality of evidence for each outcome using the GRADE approach.
MAIN RESULTS
We identified five RCTs with 5039 participants; two studies had a low risk of bias for all domains. Four studies evaluated the drug pioglitazone, and one study evaluated rosiglitazone. The participants in different studies were heterogeneous.Recurrent strokeThree studies evaluated the number of participants with recurrent stroke (4979 participants, a single study contributing 3876 of these). Peroxisome proliferator-activated receptor gamma agonists probably reduce the recurrence of stroke compared with placebo (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.44 to 0.99; moderate-quality evidence).Adverse eventsEvidence that adverse events occurred more frequently in participants treated with PPAR-γ agonists when compared with placebo was uncertain due to wide confidence interval and high levels of statistical heterogeneity: risk difference 10%, 95% CI -8% to 28%; low-quality evidence).Data were available on additional composite outcomes reflecting serious vascular events (all-cause death and other major vascular events; all-cause mortality, non-fatal myocardial infarction or non-fatal stroke) from one study in 984 people. This study provided low-quality evidence that PPAR-γ agonists led to fewer events (data not meta-analysed).Vascular eventsPeroxisome proliferator-activated receptor gamma agonists given over a mean duration of 34.5 months in a single trial of 984 participants may reduce serious vascular events expressed as a composite outcome of total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (RR 0.73, 95% CI 0.54 to 0.99; low-quality evidence).Other outcomesOne study in 20 people measured insulin sensitivity, and one study in 40 people measured the ubiquitin-proteasome activity in carotid plaques. Our confidence in the improvements observed with PPAR-γ agonists were limited by small sample sizes and risk of bias. None of the studies reported the number of participants with disability due to vascular events or improvement in quality of life.
AUTHORS' CONCLUSIONS
Peroxisome proliferator-activated receptor gamma agonists probably reduce recurrent stroke and total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, and may improve insulin sensitivity and the stabilisation of carotid plaques. Their effects on adverse events are uncertain. Our conclusions should be interpreted with caution considering the small number and the quality of the included studies. Further well-designed, double-blind RCTs with large samples are required to assess the efficacy and safety of PPAR-γ agonists in the secondary prevention of stroke and related vascular events in people with stroke or TIA.
PubMed: 31596946
DOI: 10.1002/14651858.CD010693.pub5 -
The Journal of Clinical Endocrinology... Sep 2019The extent to which some pharmacological interventions reduce or increase the risk of biochemical conversion to type 2 diabetes mellitus (T2DM) in at-risk individuals is...
CONTEXT
The extent to which some pharmacological interventions reduce or increase the risk of biochemical conversion to type 2 diabetes mellitus (T2DM) in at-risk individuals is unclear.
METHODS
We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus through 24 August 2017 for randomized controlled trials evaluating the effect of drugs suspected to modify the risk of biochemical conversion to T2DM.
RESULTS
We included 43 trials with 192,156 subjects (mean age, 60 years; 56% men; mean body mass index, 30.4 kg/m2). α-Glucosidase inhibitors, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, metformin, orlistat, phentermine/topiramate, and pioglitazone significantly reduced the risk of biochemical conversion to T2DM, whereas statins and nateglinide increased the risk. There was insufficient direct evidence regarding the effects of sulfonylureas, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors. Most trials were brief and evaluated this outcome during treatment without a withdrawal or washout period.
CONCLUSIONS
Several drugs modify the risk of biochemical conversation to T2DM, although whether this effect is persistent and clinically relevant is unclear. Future studies need to focus on cardiovascular disease prevention, mortality, and patient-important outcomes instead of biochemical conversion to T2DM.
PubMed: 31365088
DOI: 10.1210/jc.2019-01269 -
Diabetes Therapy : Research, Treatment... Jun 2021Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity of type 2 diabetes mellitus (T2DM), and no approved therapies are currently available. A meta-analysis...
INTRODUCTION
Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity of type 2 diabetes mellitus (T2DM), and no approved therapies are currently available. A meta-analysis was performed to investigate the effects of liraglutide on NAFLD in patients with T2DM.
METHODS
Medline (via PubMed), Embase (via Elsevier), and the Cochrane Central Register of Controlled Trials (CENTRAL) (via Cochrane Library) from inception to April 2020 were searched. After screening the literature and extracting data, we assessed the risk of bias of the eligible studies. The Cochrane Collaboration's RevMan software program was used for the statistical analysis.
RESULTS
Eleven trials involving 535 patients were included for the final analysis. Compared to the placebo or control group, liraglutide decreased liver fat (LF) (insulin: mean difference MD - 2.50, 95% confidence interval [CI] - 4.30 to - 0.70), body mass index (BMI) (placebo: MD - 1.13, 95% CI - 2.03 to - 0.23; pioglitazone: MD - 4.10, 95% CI - 6.27 to - 1.93; metformin: MD - 1.07, 95% CI - 2.06 to - 0.08; insulin: MD - 1.01, 95% CI - 1.60 to - 0.43), lipoproteins, including high-density (insulin: MD - 0.10, 95% CI - 0.15 to - 0.05) and low-density lipoproteins (MD - 0.26, 95% CI - 0.43 to - 0.10), glycated hemoglobin A1c (HbA1c) (placebo: MD - 0.86; 95% CI - 1.22 to - 0.51; insulin: MD - 0.22, 95% CI - 0.41 to - 0.04), total cholesterol (placebo: MD - 0.34, 95% CI - 0.65 to - 0.03; metformin: MD 0.09, 95% CI 0.01-0.18), and triglycerides (placebo: MD - 0.29, 95% CI - 0.57 to - 0.01; insulin: MD - 0.80, 95% CI - 1.03 to - 0.57). Liraglutide may be associated with increased gastrointestinal reactions compared to pioglitazone.
CONCLUSION
These findings revealed that liraglutide decreased LF, BMI, lipids, or HbA1c in T2DM patients complicated with NAFLD, indicating its potential therapeutic efficacy.
PubMed: 34002333
DOI: 10.1007/s13300-021-01072-4 -
Obesity Reviews : An Official Journal... Oct 2019Certain glucose-lowering medications have been implicated in the risk of fracture. While there is convincing evidence from randomized controlled trials (RCTs) that... (Meta-Analysis)
Meta-Analysis
Certain glucose-lowering medications have been implicated in the risk of fracture. While there is convincing evidence from randomized controlled trials (RCTs) that thiazolidinedione use is associated with a higher risk of fracture, the effects of metformin, insulin, and sulphonylureas on the risk of fracture remain equivocal because these medications are not generally investigated in RCTs. A meta-analysis of observational studies to provide further insights into the association between the use of metformin, insulin, sulphonylureas, or thiazolidinediones and the risk of fracture was performed. PubMed and Web of Science databases were searched to identify relevant observational studies. A random effects model was used to estimate the summary relative risks (RRs) with 95% confidence intervals (CIs). The use of insulin (RR 1.49, 95% CI 1.29, 1.73; n = 23 studies), sulphonylureas (RR 1.30, 95% CI 1.18, 1.43; n = 10), and thiazolidinediones (RR 1.24, 95% CI 1.13, 1.35; n = 14) was associated with an increased risk of fracture, whereas the use of metformin was associated with a reduced risk of fracture (RR 0.86, 95% CI 0.75, 0.99; n = 12). Regarding types of thiazolidinediones, both pioglitazone (RR 1.38, 95% CI 1.23, 1.54; n = 5) and rosiglitazone (RR 1.34, 95% CI 1.14, 1.58; n = 5) were positively associated with the risk of fracture. In summary, there is compelling evidence to discourage the use of thiazolidinediones in individuals with an increased risk of fracture, whereas metformin appears to have a good safety profile for the risk of fracture. The reduced risk of fracture with metformin could possibly be due to the reduced overall risk of fracture among metformin users, as this medication is typically prescribed in the early stages of type 2 diabetes mellitus. The use of insulin or sulphonylureas may increase fracture risk; this risk is most likely attributed to an increased risk of hypoglycaemia-induced falls. Further confirmation by additional RCTs is required to determine whether the observed association between the use of metformin, insulin, or sulphonylureas and the risk of fracture is due to treatment with these medications or confounding factors.
Topics: Accidental Falls; Fractures, Bone; Humans; Hypoglycemic Agents; Observational Studies as Topic; Sulfonylurea Compounds; Thiazolidinediones
PubMed: 31250977
DOI: 10.1111/obr.12885 -
The Cochrane Database of Systematic... Jan 2023Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists are insulin-sensitising drugs used for the treatment of insulin resistance. In addition to lowering... (Review)
Review
BACKGROUND
Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists are insulin-sensitising drugs used for the treatment of insulin resistance. In addition to lowering glucose in diabetes, these drugs may also protect against hyperlipidaemia and arteriosclerosis, which are risk factors for stroke. This is an update of a review first published in January 2014 and subsequently updated in December 2017 and October 2019.
OBJECTIVES
To assess the efficacy and safety of PPAR-γ agonists in the secondary prevention of stroke and related vascular events for people with stroke or transient ischaemic attack (TIA).
SEARCH METHODS
We searched the Cochrane Stroke Group Trials Register (1 January 2022), the Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 12), MEDLINE (1949 to 1 January 2022), Embase (1980 to 1 January 2022), CINAHL (1982 to 1 January 2022), AMED (1985 to 1 January 2022), and 11 Chinese databases (1 January 2022). In an effort to identify further published, unpublished, and ongoing trials, we searched ongoing trials registers, reference lists, and relevant conference proceedings, and contacted authors and pharmaceutical companies. We did not impose any language restrictions.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) evaluating PPAR-γ agonists versus placebo for the secondary prevention of stroke and related vascular events in people with stroke or TIA, with the outcomes of recurrent stroke, vascular events, and adverse events.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy, and assessed methodological quality and risk of bias. We evaluated the certainty of evidence for each outcome using the GRADE approach.
MAIN RESULTS
We identified five RCTs with 5039 participants; two studies had a low risk of bias for all domains. Four studies evaluated the drug pioglitazone, and one study evaluated rosiglitazone. The participants in different studies were heterogeneous. Recurrent stroke Three studies evaluated the number of participants with recurrent stroke (4979 participants, a single study contributing 3876 of these). Peroxisome proliferator-activated receptor gamma agonists probably reduce the recurrence of stroke compared with placebo (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.44 to 0.99; moderate-certainty evidence). Adverse events Evidence that adverse events occurred more frequently in participants treated with PPAR-γ agonists when compared with placebo was uncertain due to wide confidence intervals and high levels of statistical heterogeneity: risk difference 10%, 95% CI -8% to 28%; low-certainty evidence). Data were available on additional composite outcomes reflecting serious vascular events (all-cause death and other major vascular events; all-cause mortality, non-fatal myocardial infarction or non-fatal stroke) from one study in 984 people. This study provided low-certainty evidence that PPAR-γ agonists led to fewer events (data not meta-analysed). Vascular events Peroxisome proliferator-activated receptor gamma agonists given over a mean duration of 34.5 months in a single trial of 984 participants may reduce serious vascular events expressed as a composite outcome of total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (RR 0.73, 95% CI 0.54 to 0.99; low-certainty evidence). Other outcomes One study in 20 people measured insulin sensitivity, and one study in 40 people measured the ubiquitin-proteasome activity in carotid plaques. Our confidence in the improvements observed with PPAR-γ agonists were limited by small sample sizes and risk of bias. None of the studies reported the number of participants with disability due to vascular events or improvement in quality of life.
AUTHORS' CONCLUSIONS
Peroxisome proliferator-activated receptor gamma agonists probably reduce recurrent stroke and total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, and may improve insulin sensitivity and the stabilisation of carotid plaques. Their effects on adverse events are uncertain. Our conclusions should be interpreted with caution considering the small number and the quality of the included studies. Further well-designed, double-blind RCTs with large samples are required to assess the efficacy and safety of PPAR-γ agonists in the secondary prevention of stroke and related vascular events in people with stroke or TIA.
Topics: Humans; Ischemic Attack, Transient; PPAR gamma; Insulin Resistance; Stroke; Myocardial Infarction; Randomized Controlled Trials as Topic
PubMed: 36625492
DOI: 10.1002/14651858.CD010693.pub6 -
Diabetes, Obesity & Metabolism Dec 2022To clarify the importance of HbA1c reduction and antidiabetic drug use in preventing major adverse cardiovascular events (MACE) for patients with type 2 diabetes (T2D).
AIM
To clarify the importance of HbA1c reduction and antidiabetic drug use in preventing major adverse cardiovascular events (MACE) for patients with type 2 diabetes (T2D).
MATERIALS AND METHODS
We conducted an updated systematic review of contemporary large randomized controlled trials assessing the relative efficacy and safety of antidiabetic drugs with less hypoglycaemia risk in adult T2D patients. Mixed-effects meta-regression was performed to examine the associations of HbA1c reduction with subsequent risk of macrovascular and microvascular events. We evaluated the potential mediating role of HbA1c reduction in the relationship between antidiabetic drugs and MACE.
RESULTS
Eighteen placebo-controlled trials comprising 155 610 participants were included. The effects of treatment differed among antidiabetic drug classes for most adverse outcomes with high heterogeneity (I : 63.7%-95.8%). Mean HbA1c reduction was lowest with dipeptidyl peptidase-4 inhibitors (0.30%), followed by sodium-glucose co-transporter-2 inhibitors (0.46%), and was highest with glucagon-like peptide-1 receptor agonists (0.58%) and thiazolidinediones (0.60%). Lower relative risks of MACE were significantly associated with larger reductions in achieved HbA1c (β -0.3182; 95% CI: -0.5366 to -0.0998; P = .0043), even after adjusting for drug classes. When considering HbA1c lowering as a mediator to be controlled, beneficial effects owing to specific antidiabetic treatment for MACE were not observed (χ = 1.4494; P = .6940). The proportion mediated by HbA1c reduction was 50.0%-63.5% for these antidiabetic agents.
CONCLUSIONS
The main benefits of antidiabetic agents might result from the reduction in blood sugar levels and are generally independent of drugs used. Risk reduction in MACE was proportional to the magnitude of HbA1c decrease conferred by antidiabetic agents with less hypoglycaemic hazard.
Topics: Humans; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 35848464
DOI: 10.1111/dom.14819 -
The Cochrane Database of Systematic... Jul 2020Kidney transplantation is the preferred management for patients with end-stage kidney disease (ESKD). However, it is often complicated by worsening or new-onset... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Kidney transplantation is the preferred management for patients with end-stage kidney disease (ESKD). However, it is often complicated by worsening or new-onset diabetes. The safety and efficacy of glucose-lowering agents after kidney transplantation is largely unknown. This is an update of a review first published in 2017.
OBJECTIVES
To evaluate the efficacy and safety of glucose-lowering agents for treating pre-existing and new onset diabetes in people who have undergone kidney transplantation.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 16 January 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
All randomised controlled trials (RCTs), quasi-RCTs and cross-over studies examining head-to-head comparisons of active regimens of glucose-lowering therapy or active regimen compared with placebo/standard care in patients who have received a kidney transplant and have diabetes were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Four authors independently assessed study eligibility and quality and performed data extraction. Continuous outcomes were expressed as post-treatment mean differences (MD) or standardised mean difference (SMD). Adverse events were expressed as post-treatment absolute risk differences (RD). Dichotomous clinical outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI).
MAIN RESULTS
Ten studies (21 records, 603 randomised participants) were included - three additional studies (five records) since our last review. Four studies compared more intensive versus less intensive insulin therapy; two studies compared dipeptidyl peptidase-4 (DPP-4) inhibitors to placebo; one study compared DPP-4 inhibitors to insulin glargine; one study compared sodium glucose co-transporter 2 (SGLT2) inhibitors to placebo; and two studies compared glitazones and insulin to insulin therapy alone. The majority of studies had an unclear to a high risk of bias. There were no studies examining the effects of biguanides, glinides, GLP-1 agonists, or sulphonylureas. Compared to less intensive insulin therapy, it is unclear if more intensive insulin therapy has an effect on transplant or graft survival (4 studies, 301 participants: RR 1.12, 95% CI 0.32 to 3.94; I = 49%; very low certainty evidence), delayed graft function (2 studies, 153 participants: RR 0.63, 0.42 to 0.93; I = 0%; very low certainty evidence), HbA1c (1 study, 16 participants; very low certainty evidence), fasting blood glucose (1 study, 24 participants; very low certainty evidence), kidney function markers (1 study, 26 participants; very low certainty evidence), death (any cause) (3 studies, 208 participants" RR 0.68, 0.29 to 1.58; I = 0%; very low certainty evidence), hypoglycaemia (4 studies, 301 participants; very low certainty evidence) and medication discontinuation due to adverse effects (1 study, 60 participants; very low certainty evidence). Compared to placebo, it is unclear whether DPP-4 inhibitors have an effect on hypoglycaemia and medication discontinuation (2 studies, 51 participants; very low certainty evidence). However, DPP-4 inhibitors may reduce HbA1c and fasting blood glucose but not kidney function markers (1 study, 32 participants; low certainty evidence). Compared to insulin glargine, it is unclear if DPP-4 inhibitors have an effect on HbA1c, fasting blood glucose, hypoglycaemia or discontinuation due to adverse events (1 study, 45 participants; very low certainty evidence). Compared to placebo, SGLT2 inhibitors probably do not affect kidney graft survival (1 study, 44 participants; moderate certainty evidence), but may reduce HbA1c without affecting fasting blood glucose and eGFR long-term (1 study, 44 participants, low certainty evidence). SGLT2 inhibitors probably do not increase hypoglycaemia, and probably have little or no effect on medication discontinuation due to adverse events. However, all participants discontinuing SGLT2 inhibitors had urinary tract infections (1 study, 44 participants, moderate certainty evidence). Compared to insulin therapy alone, it is unclear if glitazones added to insulin have an effect on HbA1c or kidney function markers (1 study, 62 participants; very low certainty evidence). However, glitazones may make little or no difference to fasting blood glucose (2 studies, 120 participants; low certainty evidence), and medication discontinuation due to adverse events (1 study, 62 participants; low certainty evidence). No studies of DPP-4 inhibitors, or glitazones reported effects on transplant or graft survival, delayed graft function or death (any cause).
AUTHORS' CONCLUSIONS
The efficacy and safety of glucose-lowering agents in the treatment of pre-existing and new-onset diabetes in kidney transplant recipients is questionable. Evidence from existing studies examining the effect of intensive insulin therapy, DPP-4 inhibitors, SGLT inhibitors and glitazones is mostly of low to very low certainty. Appropriately blinded, larger, and higher quality RCTs are needed to evaluate and compare the safety and efficacy of contemporary glucose-lowering agents in the kidney transplant population.
Topics: Adamantane; Bias; Cause of Death; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Fasting; Glycated Hemoglobin; Graft Survival; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Kidney Transplantation; Nitriles; Pioglitazone; Postoperative Complications; Pyrrolidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidinediones; Transplant Recipients; Vildagliptin
PubMed: 32803882
DOI: 10.1002/14651858.CD009966.pub3 -
The Cochrane Database of Systematic... Nov 2020The term prediabetes is used to describe a population with an elevated risk of developing type 2 diabetes mellitus (T2DM). With projections of an increase in the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The term prediabetes is used to describe a population with an elevated risk of developing type 2 diabetes mellitus (T2DM). With projections of an increase in the incidence of T2DM, prevention or delay of the disease and its complications is paramount. It is currently unknown whether pioglitazone is beneficial in the treatment of people with increased risk of developing T2DM.
OBJECTIVES
To assess the effects of pioglitazone for prevention or delay of T2DM and its associated complications in people at risk of developing T2DM.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Chinese databases, ICTRP Search Portal and ClinicalTrials.gov. We did not apply any language restrictions. Further, we investigated the reference lists of all included studies and reviews. We tried to contact all study authors. The date of the last search of databases was November 2019 (March 2020 for Chinese databases).
SELECTION CRITERIA
We included randomised controlled trials (RCTs) with a minimum duration of 24 weeks, and participants diagnosed with intermediate hyperglycaemia with no concomitant diseases, comparing pioglitazone as monotherapy or part of dual therapy with other glucose-lowering drugs, behaviour-changing interventions, placebo or no intervention.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened abstracts, read full-text articles and records, assessed risk of bias and extracted data. We performed meta-analyses with a random-effects model and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, with 95% confidence intervals (CIs) for effect estimates. We evaluated the certainty of the evidence with the GRADE.
MAIN RESULTS
We included 27 studies with a total of 4186 randomised participants. The size of individual studies ranged between 43 and 605 participants and the duration varied between 6 and 36 months. We judged none of the included studies as having low risk of bias across all 'Risk of bias' domains. Most studies identified people at increased risk of T2DM by impaired fasting glucose or impaired glucose tolerance (IGT), or both. Our main outcome measures were all-cause mortality, incidence of T2DM, serious adverse events (SAEs), cardiovascular mortality, nonfatal myocardial infarction or stroke (NMI/S), health-related quality of life (QoL) and socioeconomic effects. The following comparisons mostly reported only a fraction of our main outcome set. Three studies compared pioglitazone with metformin. They did not report all-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects. Incidence of T2DM was 9/168 participants in the pioglitazone groups versus 9/163 participants in the metformin groups (RR 0.98, 95% CI 0.40 to 2.38; P = 0.96; 3 studies, 331 participants; low-certainty evidence). No SAEs were reported in two studies (201 participants; low-certainty evidence). One study compared pioglitazone with acarbose. Incidence of T2DM was 1/50 participants in the pioglitazone group versus 2/46 participants in the acarbose group (very low-certainty evidence). No participant experienced a SAE (very low-certainty evidence).One study compared pioglitazone with repaglinide. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 1/48 participants in the repaglinide group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). One study compared pioglitazone with a personalised diet and exercise consultation. All-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects were not reported. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 5/48 participants in the diet and exercise consultation group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). Six studies compared pioglitazone with placebo. No study reported on QoL or socioeconomic effects. All-cause mortality was 5/577 participants the in the pioglitazone groups versus 2/579 participants in the placebo groups (Peto odds ratio 2.38, 95% CI 0.54 to 10.50; P = 0.25; 4 studies, 1156 participants; very low-certainty evidence). Incidence of T2DM was 80/700 participants in the pioglitazone groups versus 131/695 participants in the placebo groups (RR 0.40, 95% CI 0.17 to 0.95; P = 0.04; 6 studies, 1395 participants; low-certainty evidence). There were 3/93 participants with SAEs in the pioglitazone groups versus 1/94 participants in the placebo groups (RR 3.00, 95% CI 0.32 to 28.22; P = 0.34; 2 studies, 187 participants; very low-certainty evidence). However, the largest study for this comparison did not distinguish between serious and non-serious adverse events. This study reported that 121/303 (39.9%) participants in the pioglitazone group versus 151/299 (50.5%) participants in the placebo group experienced an adverse event (P = 0.03). One study observed cardiovascular mortality in 2/181 participants in the pioglitazone group versus 0/186 participants in the placebo group (RR 5.14, 95% CI 0.25 to 106.28; P = 0.29; very low-certainty evidence). One study observed NMI in 2/303 participants in the pioglitazone group versus 1/299 participants in the placebo group (RR 1.97: 95% CI 0.18 to 21.65; P = 0.58; very low-certainty evidence). Twenty-one studies compared pioglitazone with no intervention. No study reported on cardiovascular mortality, NMI/S, QoL or socioeconomic effects. All-cause mortality was 11/441 participants in the pioglitazone groups versus 12/425 participants in the no-intervention groups (RR 0.85, 95% CI 0.38 to 1.91; P = 0.70; 3 studies, 866 participants; very low-certainty evidence). Incidence of T2DM was 60/1034 participants in the pioglitazone groups versus 197/1019 participants in the no-intervention groups (RR 0.31, 95% CI 0.23 to 0.40; P < 0.001; 16 studies, 2053 participants; moderate-certainty evidence). Studies reported SAEs in 16/610 participants in the pioglitazone groups versus 21/601 participants in the no-intervention groups (RR 0.71, 95% CI 0.38 to 1.32; P = 0.28; 7 studies, 1211 participants; low-certainty evidence). We identified two ongoing studies, comparing pioglitazone with placebo and with other glucose-lowering drugs. These studies, with 2694 participants. may contribute evidence to future updates of this review.
AUTHORS' CONCLUSIONS
Pioglitazone reduced or delayed the development of T2DM in people at increased risk of T2DM compared with placebo (low-certainty evidence) and compared with no intervention (moderate-certainty evidence). It is unclear whether the effect of pioglitazone is sustained once discontinued. Pioglitazone compared with metformin neither showed advantage nor disadvantage regarding the development of T2DM in people at increased risk (low-certainty evidence). The data and reporting of all-cause mortality, SAEs, micro- and macrovascular complications were generally sparse. None of the included studies reported on QoL or socioeconomic effects.
Topics: Acarbose; Bias; Carbamates; Cardiovascular Diseases; Confidence Intervals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Pioglitazone; Piperidines; Placebos; Randomized Controlled Trials as Topic; Risk
PubMed: 33210751
DOI: 10.1002/14651858.CD013516.pub2 -
PloS One 2024Stroke stands as a significant macrovascular complication among individuals with Type 2 diabetes mellitus (T2DM), often resulting in the primary cause of mortality and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Stroke stands as a significant macrovascular complication among individuals with Type 2 diabetes mellitus (T2DM), often resulting in the primary cause of mortality and disability within this patient demographic. Presently, numerous studies have been conducted to investigate the underlying causes of stroke in individuals with T2DM, yet the findings exhibit inconsistencies.
OBJECTIVE
This paper aims to consolidate and summarize the available evidence concerning the influential factors contributing to stroke among patients diagnosed with T2DM.
METHODS
We conducted a comprehensive search across multiple databases, including Cochrane Library, PubMed, Web Of Science, Embase, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and Weipu up to August 2023. Google Scholar was also searched to retrieve gray literature. We calculated odds ratios (OR) and 95% confidence intervals (CI) using Stata software.
RESULTS
Our analysis encompassed 43 observational studies, exploring factors across sociodemographic, biochemical, complications, and hypoglycemic agent categories. The findings identified several risk factors for stroke in patients with T2DM: age, gender, T2DM duration, hypertension, body-mass index (BMI), smoking, Glycated hemoglobin (HbA1c), estimated Glomerular Filtration Rate (eGFR), albuminuria, Triglycerides (TG), Low density lipoprotein cholesterol (LDL-C), Coronary heart disease (CHD), Atrial fibrillation (AF), diabetic retinopathy (DR), Peripheral vascular disease (PVD), and carotid plaque. Conversely, exercise, High density lipoprotein cholesterol (HDL-C), metformin (MET), pioglitazone, and metformin combination therapy emerged as protective factors.
CONCLUSION
This study underscores the multitude of influencing factors contributing to stroke in people with T2DM patients, among which the microvascular complications of T2DM play an most important role. Therefore, we emphasize the importance of screening for microvascular complications in patients with T2DM. However, due to limitations arising from the number of articles reviewed, there remain areas where clarity is lacking. Further research efforts are warranted to expand upon and reinforce our current findings.
Topics: Diabetes Mellitus, Type 2; Humans; Stroke; Risk Factors; Hypoglycemic Agents; Glycated Hemoglobin
PubMed: 38913694
DOI: 10.1371/journal.pone.0305954 -
Diabetes & Metabolism Nov 2020There are no approved drugs for the treatment of non-alcoholic fatty liver disease (NAFLD). However, many randomized controlled trials (RCT) have examined the effect of...
Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: An updated systematic review of randomized controlled trials.
AIM
There are no approved drugs for the treatment of non-alcoholic fatty liver disease (NAFLD). However, many randomized controlled trials (RCT) have examined the effect of anti-hyperglycaemic agents on NAFLD in patients with and without type 2 diabetes mellitus (T2DM), since both T2DM and insulin resistance are closely linked to this burdensome liver disease.
METHODS
We systematically searched publication databases using predefined keywords to identify head-to-head or placebo-controlled RCTs (published until September 30, 2019) of NAFLD individuals testing the efficacy of anti-hyperglycaemic drugs to specifically treat NAFLD or non-alcoholic steatohepatitis (NASH). Outcomes of interest included changes in serum liver enzyme levels, liver fat, liver fibrosis, or histologic resolution of NASH.
RESULTS
We included 29 RCTs involving a total of 2,617 individuals (∼45% had T2DM) that have used metformin (n=6 studies), glitazones (n=8 studies), glucagon-like peptide-1 receptor agonists (n=6 studies), dipeptidyl peptidase-4 inhibitors (n=4 studies) or sodium-glucose cotransporter-2 inhibitors (n=7 studies) to treat NAFLD. Although most anti-hyperglycaemic drugs improved serum liver enzyme levels, only glitazones (especially pioglitazone) and liraglutide showed an improvement of histologic features of NAFLD, with a mild beneficial effect also on liver fibrosis for pioglitazone only.
CONCLUSION
RCT evidence supports the efficacy of some anti-hyperglycaemic agents (especially pioglitazone) in patients with NAFLD or NASH, though weight gain with pioglitazone may warrant caution. Further well-designed RCTs are needed to better characterize the efficacy and safety of monotherapy and combination therapy with anti-hyperglycaemic agents in patients with NAFLD.
Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Metformin; Non-alcoholic Fatty Liver Disease; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidinediones; Treatment Outcome
PubMed: 31923578
DOI: 10.1016/j.diabet.2019.12.007